Explore the vast range of titles available.

Severe combined immunodeficiency (SCID) and other T cell lymphopenias can be detected during newborn screening (NBS) by measuring T cell receptor excision circles (TRECs) in dried blood spot (DBS) DNA. Second tier next generation sequencing (NGS) with an amplicon based targeted gene panel using the same DBS DNA was introduced as part of our prospective pilot research project in 2015. With parental consent, 21 000 newborns were TREC-tested in the pilot. Three newborns were identified with SCID, and disease-causing variants in , and were confirmed by NGS on the initial DBS DNA. The molecular findings directed follow-up and therapy: the -SCID underwent early hematopoietic stem cell transplantation (HSCT) without any complications; the leaky SCID received prophylactic antibiotics, antifungals, and immunoglobulin infusions, and underwent HSCT at 1 year of age. The child with -SCID had complete Hirschsprung disease and died at 1 month of age. Since January 2018, all newborns in Norway have been offered NBS for SCID using 1st tier TRECs and 2nd tier gene panel NGS on DBS DNA. During the first 20 months of nationwide SCID screening an additional 88 000 newborns were TREC tested, and four new SCID cases were identified. Disease-causing variants in , and were molecularly confirmed on day 8, 15, 8 and 6, respectively after birth, using the initial NBS blood spot. Targeted gene panel NGS integrated into the NBS algorithm rapidly delineated the specific molecular diagnoses and provided information useful for management, targeted therapy and follow-up i.e., X rays and CT scans were avoided in the radiosensitive SCID. Second tier targeted NGS on the same DBS DNA as the TREC test provided instant confirmation or exclusion of SCID, and made it possible to use a less stringent TREC cut-off value. This allowed for the detection of leaky SCIDs, and simultaneously reduced the number of control samples, recalls and false positives. Mothers were instructed to stop breastfeeding until maternal (CMV) status was determined. Our limited data suggest that shorter time-interval from birth to intervention, may prevent breast milk transmitted CMV infection in classical SCID.

Severe combined immunodeficiency (SCID) is the most severe form of primary immunodeficiency, which is characterized by the dysfunction and/or absence of T lymphocytes. Early diagnosis of SCID is crucial for overall survival, and if it remains untreated, SCID is often fatal. Next-generation sequencing (NGS) has become a rapid, high-throughput technology, and has already been proven to be beneficial in medical diagnostics. In this study, a targeted NGS panel was developed to identify the genetic variations of SCID by using SmartChip-TE technology, and a novel pathogenic frameshift variant was found in the CD3E gene. Sanger sequencing has confirmed the segregation of the variant among patients. We found a novel deletion in the CD3E gene (NM000733.3:p.L58Hfs*9) in two T-B+ NK+ patients. The variant was not found in the databases of dbSNP, ExAC, and 1000G. One sibling in family I was homozygous and the rest of the family members were heterozygous for this variant. T cell receptor excision circle (TREC) and kappa-deleting recombination excision circle (KREC) analyses were performed for T and B cell maturation. TRECs were not detected in both patients and the KREC copy numbers were similar to the other family members. In addition, heterozygous family members showed decreased TREC levels when compared with the wild-type sibling, indicating that carrying this variant in one allele does not cause immunodeficiency, but does effect T cell proliferation. Here, we report a novel pathogenic frameshift variant in CD3E gene by using targeted NGS panel.

Background Patients with COVID-19 (COVID) may develop acute respiratory distress syndrome with or without sepsis, coagulopathy and visceral damage. While chest CT scans are routinely performed in the initial assessment of patients with severe pulmonary forms, thymus involvement and reactivation have not been investigated so far. Methods In this observational study, we systematically scored the enlargement of the thymus and the lung involvement, using CT scans, in all adult patients admitted to the ICU for COVID or any other cause (control group) at one centre between March and April 2020. Initial biological investigations included nasal detection of SARS-CoV-2 ribonucleic acid by polymerase chain reaction (PCR). In a subgroup of 24 patients with different degrees of pulmonary involvement and thymus hypertrophy, plasma cytokine concentrations were measured and the export of mature T cells from the thymus was estimated simultaneously by PCR quantification of T cell receptor excision circles (TRECs). Results Eighty-seven patients were studied: 50 COVID patients and 37 controls. Non-atrophic or enlarged thymus was more commonly observed in COVID patients than in controls (66% vs. 24%, p  < 0.0001). Thymus enlargement in COVID patients was associated with more extensive lung injury score on CT scans (4 [3–5] vs. 2 [1.5–4], p  = 0.01), but a lower mortality rate (8.6% vs. 41.2%, p  < 0.001). Other factors associated with mortality were age, lymphopaenia, high CRP and co-morbidities. COVID patients had higher concentrations of IL-7 (6.00 [3.72–9.25] vs. 2.17 [1.76–4.4] pg/mL; p  = 0.04) and higher thymic production of new lymphocytes (sj/βTREC ratio = 2.88 [1.98–4.51] vs. 0.23 [0.15–0.60]; p  = 0.004). Thymic production was also correlated with the CT scan thymic score ( r  = 0.38, p  = 0.03) and inversely correlated with the number of lymphocytes ( r  = 0.56, p  = 0.007). Conclusion In COVID patients, thymus enlargement was frequent and associated with increased T lymphocyte production, which appears to be a beneficial adaptation to virus-induced lymphopaenia. The lack of thymic activity/reactivation in older SARS-CoV-2 infected patients could contribute to a worse prognosis.

Background Newborn screening (NBS) by quantification of T-cell receptor excision circles (TREC) identifies a considerable number of infants with T-cell lymphopenia (TCL) other than severe combined immunodeficiency (SCID). While some of these children have well-defined inborn errors of immunity (IEI), many lack a clear genetic diagnosis, complicating their management and causing prognostic uncertainty. Objective To characterize the natural history of non-SCID TCL detected through NBS in Swiss infants between 2019 and 2023. Methods Clinical, genetic and laboratory data from all non-SCID TCL cases were extracted from the national NBS registry and analyzed. Results Out of 435 985 screened infants, 42 patients were identified with non-SCID, non-congenital athymia TCL, without an obvious secondary cause. A clear genetic diagnosis of IEI was established in 20 (48%) patients. Infants with confirmed IEI had significantly lower total T-cell, CD4 + T-cell and recent thymic emigrant (RTE) counts on initial lymphocyte phenotyping. In contrast, those with an unclear genetic diagnosis despite full investigations demonstrated faster normalization of total T-cell counts (hazard ratio 5.2, 95% CI 1.9 to 14.5, p  = 0.001). All infants with initial CD4 + T-cell < 0.3 × 10 9 /L showed minimal recovery of T-cell counts and remained on long-term prophylactic measures. All infants with an unclear genetic diagnosis despite investigations were able to discontinue prophylaxis at median age 6 months without experiencing opportunistic or severe infections. Conclusion Infants with non-SCID TCL identified by NBS represent a heterogenous group, ranging from severe, persistent TCL to mild, transient lymphopenia. Management should be tailored based on individual immunological and genetic profiles. Highlights Initial T-cell counts and genetic diagnosis are key prognostic factors in newborn screening-identified non-SCID T-cell lymphopenia. Patients with milder lymphopenia and no genetic diagnosis are more likely to experience T-cell recovery.

Enhancing radar data assimilation at cloud-resolving scales is essential for advancing typhoon analysis and forecasting. This study focuses on Typhoon Linfa, the 10th Pacific Typhoon of 2015, and proposes T-TREC-IS (Typhoon Circulation Tracking Radar Echo by Correlations with Iterative Smoothing), an enhanced version of the T-TREC algorithm. The enhancement incorporates an iterative smoothing constraint into the T-TREC algorithm, which improves the continuity of the retrieved wind field and mitigates the effects of velocity aliasing in radar data, thereby increasing the operational feasibility of the method. Building on this improvement, we evaluate the effectiveness of assimilating the T-TREC-IS-retrieved wind field for analyzing and forecasting Typhoon Linfa. The results demonstrate that the iterative smoothing constraint effectively filters out velocity de-aliasing errors during radar data quality control, enhances wind field intensity near the typhoon core, and retrieves the typhoon circulation more accurately. The refined wind field exhibits improved consistency and continuity, resulting in superior performance in subsequent assimilation analyses and forecasts.

BackgroundLymphocyte neogenesis from primary lymphoid organs is essential for a successful reconstitution of immunity after allogeneic hematopoietic stem cell transplantation (HSCT). This single-center retrospective study aimed to evaluate T cell receptor excision circles (TREC) and kappa-deleting recombination excision circles (KREC) as surrogate markers for T and B cell recovery, as predictors for transplantation-related outcomes in adult acute myeloid leukemia (AML) patients.MethodsNinety adult patients diagnosed with AML and treated with HSCT between 2010 and 2015 were included in the study. TREC and KREC levels were measured by quantitative PCR at 1, 3, 6, and 12 months after transplantation.ResultsOverall, excision circle levels increased between 3 and 6 months post-HSCT for TREC (p = 0.005) and 1 and 3 months for KREC (p = 0.0007). In a landmark survival analysis at 12 months post-HSCT, TREC levels were associated with superior overall survival (HR: 0.52, 95% CI: 0.34 - 0.81, p = 0.004). The incidence of viral infections within the first 100 days after transplantation was associated with lower TREC levels at 6 months (p = 0.0002). CMV reactivation was likewise associated with lower TREC levels at 6 months (p = 0.02) post-HSCT. KREC levels were not associated with clinical outcomes in statistical analyzes.ConclusionsResults from the present study indicate that TREC measurement could be considered as part of the post-HSCT monitoring to identify AML patients with inferior survival after transplantation. Further prospective studies are warranted to validate these findings.

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. 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). 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. 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.

Severe combined immunodeficiency (SCID) can be detected at birth through T-cell receptor excision circles (TREC) analysis in dried blood spots. This study summarizes the results of the consolidated SCID newborn screening (NBS) program in Catalonia (Spain) during the first seven years of program implementation (2017-2023). Newborns were screened for SCID using the EnLite Neonatal TREC assay (cut-off: 20 copies/μL), with confirmatory immunological and genetic testing performed in screen-positive cases. Definitive SCID diagnosis was established according to PIDTC-2022 definitions, while final diagnostic classification followed the recommendations provided by Blom et al. Among 420,263 screened newborns, 105 screened positive (0.02%). SCID was diagnosed in eight infants and congenital athymia in one, corresponding to an overall incidence of 1:46,753 live births. Identified genetic defects included (n=3), (n=1), (n=2), (n=1), and (n=1) (one case remained genetically undefined). Six patients underwent early hematopoietic stem cell transplantation, achieving favorable outcomes in five patients, with one death due to post-transplant complications. In addition, gene therapy ( , ) and thymic transplantation ( ) resulted in successful outcomes in the three remaining patients. Overall and event-free survival reached 88%. Median age at diagnosis was 9 days and median age at initiation of definitive therapy was 3 months. In addition to SCID cases, 53 newborns were diagnosed with non-SCID T-cell lymphopenia (1:7,939), including syndromic, idiopathic, and reversible forms. During follow-up, patients with idiopathic T-cell lymphopenia did not develop significant infectious or autoimmune complications, except for one case of autoimmune neutropenia. Thirty-three cases were classified as false positives (0.008%). The Catalonian SCID newborn screening program demonstrated high clinical effectiveness, enabling early definitive treatment and excellent survival outcomes with a low false-positive burden. In addition, systematic follow-up of non-SCID T-cell lymphopenia identified through SCID screening appears warranted. These findings support the sustainability and clinical value of universal SCID screening programs.

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. Refining TREC cutoff values in newborn screening (NBS) for SCID: ROC analysis of a large testing cohort supports increasing the TREC threshold from 100 to 150–200 copies/105 cells, improving assay sensitivity and enabling earlier detection of SCID and other immunodeficiencies. Findings are based on validation cohort analysis and support the harmonization of TREC thresholds in NBS programs.

Background Population-based neonatal screening using T-cell receptor excision circles (TRECs) identifies infants with profound T lymphopenia, as seen in cases of severe combined immunodeficiency, and in a subgroup of infants with 22q11 deletion syndrome (22q11DS). Purpose To investigate the long-term prognostic value of low levels of TRECs in newborns with 22q11DS. Methods Subjects with 22q11DS and low TRECs at birth (22q11Low, N =10), matched subjects with 22q11DS and normal TRECs (22q11Normal, N= 10), and matched healthy controls (HC, N= 10) were identified. At follow-up (median age 16 years), clinical and immunological characterizations, covering lymphocyte subsets, immunoglobulins, TRECs, T-cell receptor repertoires, and relative telomere length (RTL) measurements were performed. Results At follow-up, the 22q11Low group had lower numbers of naïve T-helper cells, naïve T-regulatory cells, naïve cytotoxic T cells, and persistently lower TRECs compared to healthy controls. Receptor repertoires showed skewed V-gene usage for naïve T-helper cells, whereas for naïve cytotoxic T cells, shorter RTL and a trend towards higher clonality were found. Multivariate discriminant analysis revealed a clear distinction between the three groups and a skewing towards Th17 differentiation of T-helper cells, particularly in the 22q11Low individuals. Perturbations of B-cell subsets were found in both the 22q11Low and 22q11Normal group compared to the HC group, with larger proportions of naïve B cells and lower levels of memory B cells, including switched memory B cells. Conclusions This long-term follow-up study shows that 22q11Low individuals have persistent immunologic aberrations and increased risk for immune dysregulation, indicating the necessity of lifelong monitoring. Clinical Implications This study elucidates the natural history of childhood immune function in newborns with 22q11DS and low TRECs, which may facilitate the development of programs for long-term monitoring and therapeutic choices.