Manish Butte

Medicine (Baltimore). 2026 Feb 20;105(8):e47744. doi: 10.1097/MD.0000000000047744.

ABSTRACT

Pregnancy management in women with primary immunodeficiencies (PIDs) is an increasing clinical focus due to improved life expectancy. However, evidence guiding optimal maternal immunoglobulin G (IgG) levels to ensure favorable outcomes is limited, with no consensus on therapeutic targets. This study aimed to evaluate the association between maternal IgG levels, both preconceptionally and during the third trimester, and pregnancy outcomes in women with PIDs. We conducted a retrospective, single-center study reviewing medical records of 25 pregnancies in 18 women with a confirmed PID diagnosis. Key clinical and immunological parameters were analyzed. Associations between maternal serum IgG levels (measured preconceptionally and in the third trimester) and maternal, obstetric, and neonatal outcomes were assessed. A third-trimester IgG threshold of 1000 mg/dL was used for risk stratification analysis. The live birth rate was 80%. Pregnancies resulting in live birth were associated with significantly higher preconceptional IgG levels (median 1090.0 vs 421.0 mg/dL, P = .002) and a longer duration since PID diagnosis (median 62.0 vs 12.0 months, P = .007). The primary finding was that third-trimester IgG levels below 1000 mg/dL were strongly associated with an increased rate of maternal infections (55.6% vs 0.0%; odds ratio 27.5, 95% CI: 1.21-625.41; P = .008). No clear statistical association was found between IgG levels and most neonatal outcomes, including preterm birth or low birth weight. Third-trimester maternal IgG levels are a strong predictor of infection risk during pregnancy in women with PID. Additionally, higher preconceptional IgG levels are associated with successful live births, highlighting the importance of pre-pregnancy immune optimization. Although these findings from a small, retrospective cohort are hypothesis-generating, the 1000 mg/dL IgG threshold appears to be a promising signal for clinical risk stratification. Our results suggest that vigilant monitoring and individualized IgG therapy are crucial for optimizing outcomes in these high-risk pregnancies.

PMID:41731816 | DOI:10.1097/MD.0000000000047744

Front Pediatr. 2026 Feb 5;13:1755761. doi: 10.3389/fped.2025.1755761. eCollection 2025.

NO ABSTRACT

PMID:41727854 | PMC:PMC12916642 | DOI:10.3389/fped.2025.1755761

Front Immunol. 2026 Feb 6;17:1742811. doi: 10.3389/fimmu.2026.1742811. eCollection 2026.

ABSTRACT

INTRODUCTION: Here, we present the results of a nationwide newborn screening (NBS) program in Russia, covering over 2.3 million newborns and employing TREC and KREC quantification to improve the identification of severe forms of T and/or B cell immunodeficiencies and enable early treatment initiation.

METHODS: A two-tier PCR testing strategy was used to define the screen-positive cohort, followed by confirmatory flow cytometry and genetic diagnostics, including fluorescent in situ hybridization (FISH) and whole-exome sequencing (WES).

RESULTS: A total of 191 patients were diagnosed with defined forms of primary immunodeficiencies (PID), encompassing several groups of inborn errors of immunity (IEI): severe combined immunodeficiency (SCID), agammaglobulinemia, combined immunodeficiency less severe than SCID, and syndromic forms of PID. The overall birth prevalence of severe forms of T and/or B cell immunodeficiencies was 1 in 12,298 live births (95%CI: 1:10,672-1:14,247), corresponding to 8.13 cases per 100,000 newborns (95%CI: 7.02-9.37). Although the positive predictive value of KREC-based screening was relatively low, its use enabled the detection of a substantial proportion of patients with syndromic forms of PID, including Nijmegen breakage syndrome and ataxia-telangiectasia, along with various forms of agammaglobulinemia. Interestingly, 16% of diagnosed newborns had a positive family history, often with previously undiagnosed affected siblings or parents. Additionally, a considerable number of newborns detected by NBS presented with syndromic disorders not currently classified as IEI, suggesting potential avenues for future expansion of the IEI list.

DISCUSSION: Importantly, early diagnosis through NBS allowed for the timely initiation of disease-specific treatments, including hematopoietic stem cell transplantation (HSCT), immunoglobulin replacement therapy, and targeted immunosuppressive or supportive care strategies. Early intervention may reduce the risk of severe infections, improve neurodevelopmental outcomes, and prevent irreversible organ damage or malignancies in predisposed syndromes. Overall, our study demonstrates the effectiveness of large-scale implementation of TREC/KREC-based NBS in identifying a broad spectrum of immunodeficiencies and highlights future directions for improving NBS algorithms, follow-up protocols, and individualized medical management for affected infants.

PMID:41727503 | PMC:PMC12920452 | DOI:10.3389/fimmu.2026.1742811

Front Immunol. 2026 Feb 6;17:1751423. doi: 10.3389/fimmu.2026.1751423. eCollection 2026.

ABSTRACT

Severe combined immunodeficiency (SCID) is a life-threatening inborn error of immunity (IEI) that is potentially curable when diagnosed early but is associated with high morbidity and mortality when recognition is delayed. In settings without universal newborn screening (NBS), and where vaccination programs rely heavily on live vaccines, affected infants are at risk of preventable complications. We report an Indonesian girl, the first child of non-consanguineous parents, who at the age of three months, developed a generalized maculopapular rash, followed by febrile encephalopathy with acute flaccid paralysis and hepatomegaly at four months of age. Investigations revealed pan-hypogammaglobulinemia (IgG <1.09 g/L, IgA <0.05 g/L, IgM 0.06 g/L) and marked eosinophilia (7554 cells/uL). On transfer to Singapore, detailed immunophenotyping revealed T cell lymphocytopenia with the vast majority being 99.3% CD45RO+ on CD3+CD4+ cells, and absent B cells. The diagnosis of SCID with Omenn syndrome was made, with genetic analysis revealing compound heterozygosity for pathogenic RAG1 variants. As the child received oral polio vaccine (OPV) at day 8 of life, vaccine-associated paralytic poliomyelitis (VAPP) was suspected, which was confirmed with positive enterovirus PCR in the cerebral spinal fluid; Sabin-like poliovirus serotype 1 was isolated from stool. Hematopoietic stem cell transplantation (HSCT) was discussed but the family opted for supportive palliative care. The child died of a febrile illness at 8 months of age. Although IEI was initially suspected, the use of limited flow cytometric diagnostic evaluation delayed the definitive diagnosis in the child. The lack of NBS for SCID, together with the continued usage of OPV in the routine childhood vaccination program in most lower to middle income countries is the perfect storm for VAPP in children born with IEIs in these settings. This case highlights that 1) there is an urgent need to strengthen diagnostic capabilities in resource-limited settings, 2) the transition from OPV to inactivated polio vaccine (IPV) is a public health priority, and 3) there are significant barriers to the implementation of SCID NBS in Southeast Asia. Addressing these systemic gaps is critical to improve survival outcomes for children with severe but treatable IEIs.

PMID:41727494 | PMC:PMC12920594 | DOI:10.3389/fimmu.2026.1751423

Front Immunol. 2026 Feb 5;17:1728245. doi: 10.3389/fimmu.2026.1728245. eCollection 2026.

ABSTRACT

BACKGROUND: SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis) syndrome is a rare autoinflammatory disease. Paradoxical reactions and immune deviation following biologic therapy are occasionally observed in clinical practice; however, to our knowledge, no previous cases of paradoxical skin rash accompanied by Hyperimmunoglobulinemia E have been reported.

CASE PRESENTATION: A 35-year-old male with SAPHO syndrome experienced significant exacerbation of palmoplantar pustulosis and a sharp increase in immunoglobulin E(IgE) levels following treatment with secukinumab and infliximab. After one month of upadacitinib therapy, the patient showed marked improvement in cutaneous lesions and bone pain, along with significant normalization of inflammatory markers and a pronounced reduction in IgE levels.

CONCLUSION: This case suggests that upadacitinib may be a valuable therapeutic option for patients with refractory SAPHO syndrome, particularly those presenting with paradoxical reactions or hypersensitivity. The unique mechanism of action of Janus kinase (JAK) inhibitors may offer superior efficacy in such cases, though further clinical validation and mechanistic studies are warranted.

PMID:41727442 | PMC:PMC12916696 | DOI:10.3389/fimmu.2026.1728245

Can Liver J. 2025 Nov 26;8(4):597-601. doi: 10.3138/canlivj-2025-0019. eCollection 2025 Nov.

ABSTRACT

BACKGROUND: The majority of patients with Epstein-Barr virus (EBV)-associated hepatitis have a mild clinical course; most infections resolve spontaneously. However, in rare cases, or in patients with underlying immune deficits, outcomes can be fatal.

METHODS: We used a single-centre case series.

RESULTS: In this report, we describe two cases of acute EBV hepatitis. The first patient developed fulminant hepatitis with multi-organ failure and severe immune dysregulation; he died despite maximal intensive-care management. Post-mortem, his bone marrow biopsy results revealed an X-linked lymphoproliferative disease. This primary immunodeficiency impairs the body’s ability to control EBV infection and is a risk factor for developing an EBV-positive T-cell lymphoma in childhood. The second patient presented with hepatitis, cytopenias, and hepatosplenomegaly in the context of persistent EBV viremia and responded well to treatment (dexamethasone, rituximab, and supportive care). Immunodeficiency testing was negative in this case.

CONCLUSIONS: Prompt multidisciplinary management is recommended in cases of severe EBV-associated liver injury.

PMID:41725795 | PMC:PMC12923320 | DOI:10.3138/canlivj-2025-0019

BMJ Case Rep. 2026 Feb 20;19(2):e267490. doi: 10.1136/bcr-2025-267490.

ABSTRACT

Cartilage-hair hypoplasia (CHH) is a rare autosomal recessive skeletal dysplasia. It is often associated with short stature, metaphyseal abnormalities, hair hypoplasia and immune dysfunction. This case describes a pregnant woman in her mid-30s with two previous children diagnosed with CHH with molecular confirmation of two pathogenic variants of the ribonuclease mitochondrial RNA processing gene. The couple is healthy and non-consanguineous. Routine ultrasound examination of the current pregnancy suggested this fetus was also likely to be affected. The couple opted not to perform invasive prenatal diagnosis. Umbilical cord blood was collected at birth for genetic testing, confirming the diagnosis. CHH has a significant impact on the quality of life of those affected. Genetic counselling may help parents understand the disease and its prognosis. Obstetric ultrasound plays an important role in the diagnosis by allowing early detection of suspected cases as well as assessing fetal growth.

PMID:41720498 | DOI:10.1136/bcr-2025-267490

Orphanet J Rare Dis. 2026 Feb 19;21(1):70. doi: 10.1186/s13023-025-04134-z.

ABSTRACT

BACKGROUND: Hereditary angioedema (HAE) is a rare genetic disease manifesting as recurrent painful, burdensome, and potentially life-threatening swelling attacks. This noninterventional, cross-sectional, web-based survey of adult (aged ≥ 18 years) participants with HAE from Argentina, Brazil, Colombia, Croatia, Denmark, Germany, Hungary, Ireland, Norway, Poland, Portugal, Romania, and Sweden sought to deepen the understanding of HAE burden. Individuals were eligible if they had a self-reported physician diagnosis of HAE, ≥ 1 HAE attack or prodromal symptom within the last year, and received HAE medications within the last 2 years. Data were collected on participant demographics, clinical characteristics, and patient-reported outcomes using validated questionnaires; these included disease control (Angioedema Control Test [AECT]), health-related quality of life (HRQoL; Angioedema Quality of Life [AE-QoL]), general health status (12-Item Short Form Survey [SF-12 v2]), anxiety and depression (Hospital Anxiety and Depression Scale [HADS]), and work productivity impairment (Work Productivity and Activity Impairment: General Health [WPAI:GH]).

RESULTS: Overall, 260 participants were included; age (mean ± SD) was 43.3 ± 13.5 years; 72.7% of participants were female, 89.6% had HAE due to C1 inhibitor deficiency, and 78.5% reported family history of HAE. Participants reported 11.5 ± 14.2 (mean ± SD) HAE attacks in the 6 months before the survey, with 68.5% reporting their most recent attack occurring within the last 4 weeks. Of 260 participants, 153 (58.8%) reported currently using any medication for long-term prophylaxis, but only 56/153 (36.6%) reported using a first-line LTP option per international guidelines. Patient-reported disease burden included, on average, moderate to large HRQoL impairment (AE-QoL total score [mean ± SD] 42.9 ± 23.2), poor disease control (AECT score [mean ± SD] 7.4 ± 3.1), and work productivity impairment (WPAI:GH overall work productivity loss score [mean ± SD] 26.9% ± 32.2). Participants with a lower versus higher number of HAE attacks in the past 6 months reported better disease control, less HRQoL impairment, and less work productivity loss.

CONCLUSION: Results of this large multinational survey highlight that patients included in this study, most of whom were not using first-line LTP, reported being burdened by their disease, including frequent HAE attacks, HRQoL impairment, poor disease control, and work productivity impairment.

PMID:41715164 | DOI:10.1186/s13023-025-04134-z

Eur J Pediatr. 2026 Feb 20;185(3):138. doi: 10.1007/s00431-026-06810-z.

ABSTRACT

Inborn errors of immunity (IEI) are inherited disorders with heterogeneous clinical, immunological, and genetic features; genetic testing is now indispensable for accurate diagnosis and treatment planning. This study aimed to evaluate the diagnostic yield, inheritance patterns, and clinical impact of genetic testing on IEIs at a tertiary care center in Turkey over a 10-year period. This retrospective cohort included 1407 patients diagnosed with or followed for IEI between 2010 and 2020 at Ankara University Faculty of Medicine. Clinical, immunologic, and molecular data were analyzed to assess subgroup distribution, genetic testing methods, turnaround times, and the influence of genetic results on diagnosis and treatment. Predominantly antibody deficiencies were the most common IEI subgroup (67.8%), followed by combined T- and B-cell immunodeficiencies (12.2%). Parental consanguinity was present in 32.1% of patients. Genetic testing was performed in 417 patients (29.6%), and pathogenic variants were identified in 325 (77.9% of the tested population), involving 94 different genes. Most variants exhibited autosomal recessive inheritance (71.4%). The diagnostic yield was 66.8% for targeted gene panels and 68.4% for whole-exome sequencing. Turnaround times markedly decreased from 28.1 months in 2010 to 2.3 months in 2020. Genetic findings led to diagnostic or therapeutic modifications in 20.6% of patients, primarily through disease reclassification or personalized treatment adjustments.

CONCLUSION: Comprehensive clinical and immunological evaluations remain fundamental to accurate genotypic characterization of patients with IEI. To ensure timely and precise diagnosis, genetic analyses should be initiated early and conducted through close collaboration between clinical immunologists and genetic specialists.

WHAT IS KNOWN: • Inborn errors of immunity are clinically and genetically heterogeneous disorders that often require molecular confirmation for accurate diagnosis. • Genetic testing supports individualized management when integrated with detailed clinical and immunological evaluation.

WHAT IS NEW: • In this 10-year, large national cohort from Turkey, clinically guided genetic testing achieved a high diagnostic yield and identified pathogenic variants in the majority of tested patients. • Genetic results led to diagnostic or therapeutic modifications in approximately one-fifth of cases, emphasizing the importance of early, coordinated collaboration between clinical immunologists and genetic specialists.

PMID:41714534 | DOI:10.1007/s00431-026-06810-z

J Clin Immunol. 2026 Feb 20. doi: 10.1007/s10875-026-01999-y. Online ahead of print.

NO ABSTRACT

PMID:41714512 | DOI:10.1007/s10875-026-01999-y