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Biomedicines. 2025 Jul 28;13(8):1836. doi: 10.3390/biomedicines13081836.

ABSTRACT

Primary and secondary immunodeficiencies comprise a wide array of illnesses marked by immune system abnormalities, resulting in heightened vulnerability to infections, autoimmunity, and cancers. Notwithstanding progress in diagnostic instruments and an enhanced comprehension of the underlying pathophysiology, delayed diagnosis and underreporting persist as considerable obstacles. The implementation of artificial intelligence into clinical practice has surfaced as a viable method to enhance early detection, risk assessment, and management of immunodeficiencies. Recent advancements illustrate how artificial intelligence-driven models, such as predictive algorithms, electronic phenotyping, and automated flow cytometry analysis, might enable early diagnosis, minimize diagnostic delays, and enhance personalized treatment methods. Furthermore, artificial intelligence-driven immunopeptidomics and phenotypic categorization are enhancing vaccine development and biomarker identification. Successful implementation necessitates overcoming problems associated with data standardization, model validation, and ethical issues. Future advancements will necessitate a multidisciplinary partnership among physicians, data scientists, and governments to effectively use the revolutionary capabilities of artificial intelligence, therefore ushering in an age of precision medicine in immunodeficiencies.

PMID:40868091 | DOI:10.3390/biomedicines13081836

J Exp Med. 2025 Nov 3;222(11):e20250499. doi: 10.1084/jem.20250499. Epub 2025 Aug 27.

ABSTRACT

Human ADA2 deficiency (DADA2) is an inborn error of immunity with a broad clinical phenotype, which encompasses vasculopathy and hemato-immunological features. Diagnosis is based on the combination of decreased serum ADA2 activity and the identification of biallelic deleterious alleles in the ADA2 gene. DADA2 carriers harbor a single pathogenic variant in ADA2 and are mostly considered healthy and asymptomatic. Here, we report ten patients from seven kindreds presenting with a phenotype indicative of DADA2, in whom only a single pathogenic variant was identified. We investigated the effect of these and additional reported ADA2 missense variants on ADA2 protein expression, secretion, and enzymatic activity. Our studies indicate that p.G47A, p.G47R, p.G47V, p.R169Q, p.E328K, p.H424N, and p.Y453C exert a dominant negative effect on ADA2 enzymatic activity, dimerization, and/or secretion. We conclude that humans with heterozygous dominant negative missense variants in ADA2 are at risk of DADA2.

PMID:40864493 | DOI:10.1084/jem.20250499

J Med Virol. 2025 Sep;97(9):e70550. doi: 10.1002/jmv.70550.

ABSTRACT

COVID-19 has worse clinical outcomes in inborn errors of immunity (IEI) patients. We aimed to determine COVID-19-related hospitalization/ICU admission/mortality risk in patients with IEI. We included 62 COVID-19 (29 children and 33 adults) in a referral center. F/M ratio was 0.94 with median age, 19 (8 months-64 years) years. 53.2% had primary antibody deficiency. Hospitalization rate was 11/29 in children, 21/33 in adults and 7/11 in patients with combined immunodeficiency diseases. Myalgia was more common in adults compared to children (p = 0.013). Inpatients have more cough compared to outpatients (p = 0.002). D-dimer and ferritin levels were higher in inpatients (p = 0.033 and p = 0.046, respectively). Cough (OR: 6.05; [95% CI: 1.76-20.74], p = 0.004) and immunoglobulin replacement therapy use in IEI (OR: 5.15; [95% CI: 1.46-18.11], p = 0.010) were related to hospitalization risk. Inpatients with intensive care unit (ICU) admission had higher ferritin levels (p = 0.02). 77.4% had at least one comorbidity like pulmonary (45.2%), autoimmune (38.7%), and gastrointestinal diseases (32.3%). ICU admission was high in agammaglobulinemia (40%) and immune dyseregulation (ID) (16.6%). An LRBA deficiency patient experienced MIS-C (Multisystem Inflammatory Syndrome in Children) and another died. Eight patients, four in the present center, received convalescent plasma (X-linked agammaglobulinemia [XLA] [n = 3], autosomal recessive agammaglobulinemia [n = 1], LRBA deficiency [n = 1], and CTLA4 deficiency [n = 1], CVID [n = 1], and STAT1 deficiency [n = 1]). Overall mortality was 6.5%, high in ID (16.6%), none in children. Higher D-dimer and ferritin levels is associated with a higher hospitalization ratio- twice in adults compared to children. Overall mortality (6.5%) was about six times the general population with no mortality in children. A high ICU ratio in agammaglobulinemia, suggesting the importance of mucosal IgA in COVID-19 defense. Convalescent plasma helps shorten hospitalization period in agammaglobulinemia.

PMID:40862510 | DOI:10.1002/jmv.70550

Front Genet. 2025 Aug 8;16:1584681. doi: 10.3389/fgene.2025.1584681. eCollection 2025.

ABSTRACT

BACKGROUND: The majority of monogenic inborn errors of immunity presenting as actinopathies were reported originally from the Middle East and North Africa (MENA) countries indicating a high prevalence of these entities in the region. However, their prognosis is unclear due to rarity and lack of comprehensive treatment outcomes.

METHODS: We evaluated clinical, immunological, and genetic abnormalities associated with 15 genetic entities of actinopathies. Based on the function of mutant genes in actin-regulatory pathways, patients were classified into CDC42- and RAC2-related subcategories.

RESULTS: A total of 503 individuals (29.5% females) from 17 countries were considered with a median age of 120 months. Although most patients presented initially with allergic phenotypes (37.7%), the most prevalent manifestations throughout the lifespan were infection in respiratory tracts (72.2%). Primary clinical diagnosis was mainly combined immunodeficiencies (48.3%) and the majority of cases were molecularly assigned to the CDC42 pathway (64.8%). The most common genetic defects were reported within the DOCK8 (n = 209) followed by the WAS (n = 94) and the CARMIL2 (n = 15) genes. Hematopoietic stem cell transplantation (HSCT) was conducted on 24.0% of patients, which significantly improved survival in patients with defects in WAS, DOCK8 and DOCK2. Overall mortality was 23.0%, mainly due to sepsis and malignancy.

CONCLUSION: Patients with defects in RAC2-associated regulators of actin usually present with late-onset symptoms due to normal immune profiles, but a higher rate of EBV and HPV infections, autoimmune cytopenia, asthma, and lymphoproliferation compared to defects in the CDC42 pathway. The severity of mutations in patients of the CDC42 group helps to estimate the prognosis of the disease and prioritization of HSCT.

PMID:40860338 | PMC:PMC12370701 | DOI:10.3389/fgene.2025.1584681

J Clin Immunol. 2025 Aug 25;45(1):125. doi: 10.1007/s10875-025-01904-z.

ABSTRACT

PURPOSE: Patients with (X-linked) agammaglobulinemia (XLA) suffer from severe, recurrent infections potentially leading to life-threatening complications such as sepsis, meningoencephalitis and chronic lung disease. Early diagnosis and timely treatment can prevent infections and secondary complications, emphasizing a role for early detection of XLA via newborn screening (NBS). Our international multicenter survey study aimed to evaluate self-reported outcomes and parental perspectives in XLA patients to determine whether an early diagnosis is associated with better quality of life (QoL).

METHODS: QoL-questionnaires included the PedsQL for children and SF-36, CVID_QOL, PADQOL-16 for adults. A new questionnaire was specifically developed for parents about an early diagnosis of XLA.

RESULTS: In total, 88 adult and 65 pediatric XLA patients, and 69 parents from 14 countries completed the survey. Patients with an early diagnosis reported less severe, recurrent infections and less hospitalization (p < 0.05). QoL was significantly lower in multiple health domains for pediatric and adult patients with a late diagnosis compared to the general population. Patients with an early diagnosis reported similar QoL outcomes compared to the general population. Parents showed immense support for NBS for XLA stating that an early diagnosis prevents emotional insecurity, health damage, unnecessary diagnostics and allows early access to medical care and informed family planning.

CONCLUSION: Our study has shown supportive evidence to pursue an early diagnosis of XLA from both a self-reported clinical, health related QoL and parental perspective. The main plea from patients and parents is to achieve an early diagnosis for XLA and severe B-lymphocyte deficiencies with NBS.

PMID:40853601 | DOI:10.1007/s10875-025-01904-z

Front Immunol. 2025 Aug 7;16:1604460. doi: 10.3389/fimmu.2025.1604460. eCollection 2025.

ABSTRACT

Griscelli syndrome type 2 (GS-2) is a rare congenital immune dysfunction characterized by partial albinism and recurrent episodes of hemophagocytic lymphohistiocytosis (HLH). It is caused by a variant in the gene encoding Rab27a leading to a degranulation defect in melanocytes, natural killer (NK)- and T cells. Prognosis of patients with GS-2 is limited by repetitive episodes of life-threatening HLH with onset in early childhood. The only curative treatment is an allogeneic hematopoietic stem cell transplantation (HSCT). Here, we report on an 18 year old female patient with a homozygous missense p.Arg50Glnfs*35 variant in exon 2 of RAB27A who presented with an exceptionally late onset of severe HLH. Her phenotypically inapparent albinism complicated to correctly diagnose GS-2. Immune function assays confirmed a T- and NK cell degranulation deficiency characteristic for patients with primary HLH, while microscopic hair analysis revealed melanin clumps secondary to melanocyte functional impairment. To understand why disease onset occurred unusually late in this patient, we investigated the patient’s T cell and polymorphonuclear neutrophil (PMN) function in more detail. We could show that intracellular granzyme B storage in cytotoxic T cells was increased compared to healthy donors and that the patient’s T cells maintained some degranulation activity. Both, antigen-specific cytotoxic response and proliferation capacity of the patient’s T cells were preserved. We demonstrate for the first time that also PMN degranulation, assessed as stimulation-induced CD66b and CD11b cell membrane expression, is dysfunctional in patients with Rab27a deficiency-associated primary HLH. The patient was treated with steroids and cyclosporine A for immunosuppression to control the HLH. After two severe episodes within only a few months, she eventually received an allogeneic HSCT and has not experienced further HLH episodes for now more than 3 years after the HSCT procedure. This case should raise awareness for the possibility of initial manifestation of primary, genetically-determined HLH even in adult patients.

PMID:40852732 | PMC:PMC12367682 | DOI:10.3389/fimmu.2025.1604460

Neurol Sci. 2025 Aug 23. doi: 10.1007/s10072-025-08417-y. Online ahead of print.

ABSTRACT

BACKGROUND: Ataxia-telangiectasia (A-T) is a rare autosomal recessive disorder caused by mutations in the ATM gene, leading to defective DNA repair, genomic instability, and immune surveillance dysfunction. Therefore, A-T patients are predisposed to cancers, particularly hematological malignancies like lymphoma and leukemia.

METHODS: To identify the characteristics of A-T cases with multiple cancers, we searched the Iranian A-T registry with 324 cases and conducted a systematic literature search in PubMed and Embase using appropriate keywords. Studies reporting A-T patients with two or more distinct cancers were included and compared with cases identified from our national registry.

RESULTS: Multiple cancers were reported in one 19-year-old male with A-T who presented diffuse large B-cell lymphoma (DLBCL) and renal cell carcinoma (RCC) due to a homozygous severe splicing mutation in ATM. In our literature review, we found 14 cases of A-T patients diagnosed with at least two distinct types of cancer. Among the secondary cancers in the 14 patients, hematologic cancer was observed in 3 patients (21.4%), while non-hematologic cancers were seen in 11 patients (78.6%). Similar to our case, two A-T patients were diagnosed with RCC but only as a primary tumor.

CONCLUSION: The combination of hematological and solid tumors underscores the significance of cancer predisposition in A-T patients. Given their heightened cancer risk, A-T patients should benefit from regular cancer screening and tailored therapeutic approaches to minimize treatment-related complications.

PMID:40848100 | DOI:10.1007/s10072-025-08417-y

J Clin Immunol. 2025 Aug 23;45(1):124. doi: 10.1007/s10875-025-01912-z.

ABSTRACT

Hereditary angioedema with normal C1 inhibitor (HAE-nC1-INH) is a rare and genetically heterogeneous disorder with an incomplete molecular understanding. This study aimed to identify novel genetic variants associated with HAE-nC1-INH, characterize their clinical manifestations, and evaluate real-world treatment responses. Whole-exome sequencing of 27 HAE patients, including eight with HAE-nC1-INH, identified four previously unreported MYOF variants and additional pathogenic variants in KNG1 and HS3ST6, expanding the genetic spectrum of the disease. MYOF variants were associated with recurrent edema episodes, often with prolonged duration. The HS3ST6 variant was linked to refractory angioedema with non-resolving lower extremity involvement, highlighting atypical, persistent clinical phenotypes beyond the classical self-limiting presentation of HAE. Lanadelumab effectively reduced attack frequency in most patients; however, the variability in treatment response, particularly in MYOF and HS3ST6 carriers, highlights the need for individualized therapeutic approaches. These findings provide new insights into the genetic and clinical complexity of HAE-nC1-INH and emphasize the importance of genetic testing in refining diagnosis and optimizing treatment strategies, contributing to a more precise understanding of hereditary angioedema.

PMID:40848077 | DOI:10.1007/s10875-025-01912-z

PLoS One. 2025 Aug 21;20(8):e0330495. doi: 10.1371/journal.pone.0330495. eCollection 2025.

ABSTRACT

OBJECTIVES: SARS-CoV-2 RNAemia at diagnosis is associated with mortality. The aims were to identify factors associated with the development of RNAemia.

METHODS: Multicenter COVID-19 cohort study was conducted between January 2020 and May 2023. Demographics, chronic underlying diseases, symptoms and signs, analytical and radiological variables, cytokines, and neutralizing antibodies were evaluated on admission. RNAemia was the primary endpoint.

RESULTS: We included 1011 patients, 392 (38.8%) immunocompromised and 619 (61.2%) immunocompetent. RNAemia occurred in 49.7% and 18.7% (p < 0.001), respectively, being independently associated with 30-day all-cause mortality. In immunocompromised patients, factors independently associated with RNAemia were Alpha and Omicron VOC periods (OR: 1.95 [1.01-3.79]), pneumonia (OR: 1.96 [1.10-3.50]), LDH > 300 UI/L (OR: 1.64 [1.02-2.63]) and neutralizing antibodies absence (OR: 2.51 [1.57-4.00]). In immunocompetent patients, the factors associated with RNAemia were Delta and Omicron VOC periods (OR: 2.27 [1.46-3.52]), lymphocyte count < 1000/µL (OR: 1.81 [1.16-2.80]) and LDH levels > 300 IU/L (OR: 3.99 [2.51-6.36]).

CONCLUSIONS: Immunodeficiency almost tripled SARS-CoV-2 RNAemia. Omicron VOC period, LDH as inflammatory biomarker, and a lower immune response in all patients, neutralizing antibodies absence in immunocompromised and lymphopenia in immunocompetent, and pneumonia in immunocompromised patients were associated with RNAemia.

PMID:40839611 | DOI:10.1371/journal.pone.0330495

Pediatr Infect Dis J. 2025 Aug 21. doi: 10.1097/INF.0000000000004950. Online ahead of print.

ABSTRACT

BACKGROUND: Congenital cytomegalovirus infection (cCMV) is the most common congenital infection worldwide. Identifying early prognostic markers of sequelae is crucial for improving follow-up protocols, especially for asymptomatic patients at birth. We aimed to determine the association of urine cytomegalovirus (CMV) viral load (VL) at birth with symptomatic disease and the development of sequelae in a cohort of Spanish patients with cCMV.

METHODS: Patients for whom a positive quantitative CMV urine VL was available in the neonatal period were included. Exclusion criteria were urine VL performed beyond day 28 of life, having initiated antiviral treatment and concomitant primary or secondary immunodeficiency disorders. Sequelae were assessed in children with at least 6 months of follow-up.

RESULTS: Overall, 357 patients were included and sequelae were assessed in 282 (79.0%). At birth, 30.2% were asymptomatic, 11.8% had mild and 58.0% had moderate-to-severe cCMV disease. Higher urine CMV VL at birth was associated with thrombocytopenia, chorioretinitis and neuroimaging abnormalities, but not with disease severity. At the last available follow-up (median age: 30.1 months), 68 (24.1%) children presented with sequelae, mainly sensorineural hearing loss (n = 60). Sequelae were more common among children with moderate-to-severe cCMV disease at birth. In multivariate analysis, hepatomegaly [adjusted odds ratios (aOR): 7.9, 95% confidence intervals (CI): 1.5-63.3], hypotonia (aOR: 4.4, 95% CI: 1.2-18.3), abnormalities in cranial ultrasound (aOR: 3.3, 95% CI: 1.9-5.7) and urine CMV VL at birth (aOR: 1.3 per 1 log10 increase, 95% CI: 1.1-1.6) were associated with a higher risk of sequelae.

CONCLUSIONS: Urine CMV VL at birth was associated with some symptoms and signs of cCMV and positively correlated with the risk of sequelae.

PMID:40838759 | DOI:10.1097/INF.0000000000004950