Authors' objectives: Severe combined immunodeficiency is an inherited condition arising from mutations in at least 19 known genes. Severe combined immunodeficiency can be identified through screening, family history or clinical presentation. Severe combined immunodeficiency is usually asymptomatic at birth and presents, in infancy, as recurrent and frequently severe infections. Without treatment, severe combined immunodeficiency is usually fatal in the first year of life. To summarise the available evidence relevant to newborn screening for severe combined immunodeficiency in the UK NHS newborn blood spot screening programme. Three research questions, concerning the accuracy of screening tests, the efficacy of early treatment and the acceptability of screening, were developed to address this objective. Severe combined immunodeficiency (SCID) is an inherited form of severe primary immune deficiency, which arises from mutations in at least 19 known genes and hence has a large number of subtypes. The proportions of different SCID subtypes vary widely geographically. SCID is characterised by T-cell lymphopenia (TCL), that is absence or significant reduction in the number of functioning T cells. Hypomorphic mutations in SCID genes (mutations which result in reduced levels of activity of the gene product) result in particular forms of SCID known as atypical SCID and Omenn syndrome. Most subtypes of SCID have autosomal recessive inheritance. Severe combined immunodeficiency may be identified through screening, family history (FH) (cascade testing) or upon clinical presentation. SCID is usually asymptomatic at birth and presents, in infancy, as recurrent and frequently severe infections. In the absence of treatment, SCID is usually fatal in the first year of life. In addition to prompt initiation of treatment, early identification of SCID is important, because children with the condition should not receive live vaccinations. Immune reconstitution using allogeneic haematopoietic stem cell transplant (HSCT) is the primary treatment for SCID. Gene therapy may be an additional treatment option for some SCID subtypes. The most widely used method of newborn screening for SCID involves the quantification of T-cell receptor excision circles (TRECs). TRECs are a deoxyribonucleic acid (DNA) by-product, generated during normal T-cell maturation; blood levels of TRECs are a surrogate marker of thymic output of newly formed T cells, with an absence or low level of TREC being indicative of TCL. The TREC assay is performed using DNA extracted from a dried blood spot sample and involves the use of polymerase chain reaction. The results from a TREC assay are indicative of the presence or absence of TCL, for which there are a large number of possible causes. TREC-based screening for SCID is, therefore, different from the other tests and target conditions included in the UK NHS newborn blood spot (NBS) screening programme, in that it is associated with high rates of incidental findings (screen-positive results caused by conditions other than the target condition, SCID). A report for the Health Information and Quality Authority, Republic of Ireland, published in 2023, examined the rates of SCID and non-SCID TCL detected by implemented screening programmes. The report found that the ratio of SCID to non-SCID TCLs detected by screening programmes ranged from 1 : 2 to 1 : 38. There is currently a lack of established consensus guidelines or algorithms for the management of non-SCID TCL cases detected through screening programmes for SCID. This systematic review (SR) assessed the evidence to inform four UK National Screening Committee (NSC) criteria for a population screening programme. The criteria considered and the associated research questions were as follows: Criterion 4 – There should be a simple, safe, precise and validated screening test. Criterion 5 – The distribution of test values in the target population should be known and a suitable cut-off level defined and agreed. Research question 1: What is the accuracy of the TREC test in population studies of screening for SCID? Supplementary questions: What is the accuracy of the TREC test in subgroups: term babies, preterm babies and sick babies? What is the rate and type of incidental findings (non-SCID TCL) observed in population screening for SCID? Criterion 9 – There should be an effective intervention for patients identified through screening, with evidence that intervention at a pre-symptomatic phase leads to better outcomes for the screened individual compared with usual care. Evidence relating to wider benefits of screening, for example those relating to family members, should be taken into account where available. However, where there is no prospect of benefit for the individual screened, the screening programme should not be further considered. Research question 2: Does HSCT (or gene therapy or thymic transplant, if appropriate) in SCID cases detected during the asymptomatic period lead to improved outcomes? Criterion 6 – The test, from sample collection to delivery of results, should be acceptable to the target population. Research question 3: Is the experience of population screening for SCID acceptable to parents and carers of newborn babies?

Authors' results and conclusions: Most positive predictive values, calculated from reports of newborn blood spot screening programme experience, were between 3.6% and 26%. Screening algorithms incorporating repeat sampling in preterm babies appeared to reduce false positives due to prematurity. However, the large number of other conditions that can give rise to a positive screening result mean that the positive predictive value for severe combined immunodeficiency remains consistently poor. Two small studies reported that early diagnosis of severe combined immunodeficiency, via newborn blood spot screening or family history and following the introduction of newborn blood spot screening, respectively, was associated with non-statistically significant improvements in post-transplant survival. A third study analysed data on n = 902 United States patients with severe combined immunodeficiency collected over a 28-year period and reported the results of multivariable Cox regression analyses, adjusted for demographic disease-related and transplant-related variables found to be significant on univariate analysis, showing that diagnosis of severe combined immunodeficiency via newborn blood spot screening significantly improved survival compared to diagnosis via clinical presentation. Qualitative data from the publications included in this evidence summary were generally indicative of parental support for newborn blood spot screening for severe combined immunodeficiency, but was mainly derived from parents of healthy newborns. The current published evidence base alone is not adequate to fully support implementation of newborn blood spot screening for severe combined immunodeficiency. With respect to UK National Screening Committee population screening criteria, criterion 4 was partially met and there was insufficient evidence to adequately assess whether criterion 6 was met. The findings of this evidence summary should be considered alongside findings from the recent in-service evaluation of newborn screening for severe combined immunodeficiency conducted in the NHS in England and the results of cost-effectiveness modelling. Research question 1 Most (9/11) of the new studies included in this evidence summary were retrospective reports of experience from existing screening programmes. This evidence summary did not identify any new UK studies that met the inclusion criteria for question 1. Four of the reports of screening experience, included in the current evidence summary, either stated that no missed (screen-negative) cases SCID were identified during the reported period or that all screen-negative cases identified were late-onset SCID. These studies provide some indication that TREC-based screening, as implemented in existing NBS screening programmes, has high sensitivity for the target condition SCID. However, it should be noted that, given the apparent lack of a standardised approach to identifying and recording any cases missed by screening, it remains uncertain whether the apparently high sensitivity of implemented screening programmes is a reliable representation of the capture of SCID cases. Calculated positive predictive values (PPVs) were between 3.6% and 26%, with the exception of that for the Japanese screening programme (1.6%). The wide variation in calculated PPVs may be explained by differences in screening algorithms. Geographical variation in the prevalence of SCID and syndromic non-SCID TCLs may also account for some of the variation in observed PPVs. We did not identify any accuracy data for the specified subgroups (preterm babies and sick babies). However, the included reports of screening experience appear to indicate a growing use of screening algorithms that incorporate a repeat sampling step for preterm/low birthweight or sick babies with an initially abnormal TREC result. The numbers of reported cases of TCL of prematurity were generally highest in those screening programmes which did not include use of a repeat sample for premature babies. There was, therefore, some evidence to indicate that the use of screening algorithms incorporating repeat sampling (e.g. at term-adjusted gestational age) in preterm babies can markedly reduce false-positive (FP) results due to transient TCL of prematurity. However, even where FP results due to prematurity are reduced or eliminated, the large number of other conditions that can give rise to a low TREC value (positive screening result) mean that the PPV for SCID remains consistently poor. If both SCID and non-SCID TCLs are treated as target conditions for TREC-based NBS screening, then PPV increases to levels that may be regarded as acceptable. An in-service evaluation (ISE) of newborn screening for SCID has recently completed in English NHS services. At the time of writing, the findings of this ISE are not yet available. The ISE may provide more up-to-date information on test and cut-off values from a large UK sample. The ISE also has the potential to provide UK-specific insights into how incidental findings have been handled in practice, including care pathways and outcomes for these children and their families. The current published evidence base alone is not adequate to fully support implementation of NBS screening for SCID. The findings of this evidence summary should be considered alongside findings from the ISE of newborn screening for SCID conducted in the NHS in England and the results of cost-effectiveness modelling. Further work is needed to inform policy on how the identification of non-SCID TCL conditions by screening should be treated. Stakeholder dialogue and patient and public involvement activities may be helpful. In particular, the views of parents who have lived experience of a non-SCID (incidental) finding from NBS screening for SCID should be sought.

Authors' methods: Eleven bibliographic databases were searched for relevant studies from 2011 to April 2024. Separate inclusion criteria were specified for each research question. Study selection, data extraction and assessment of methodological quality followed standard systematic review methods. A narrative synthesis of results is presented, structured by research question. No meta-analyses were conducted. The systematic review component of this evidence summary was limited by a restriction to full publications in the English language. MEDLINE and Epub Ahead of Print, In-Process, In-Data-Review and Other Non-Indexed Citations and Daily, EMBASE, Cumulative Index to Nursing and Allied Health Literature, PsycInfo® (American Psychological Association, Washington, DC, USA), Cochrane Database of Systematic Reviews (CDSR), Cochrane Central Register of Controlled Trials, the International Health Technology Assessment Database and Kleijnen Systematic Reviews Ltd evidence were searched for relevant studies from 2011 to April 2024. Search results were screened for relevance independently by two reviewers. Full-text inclusion assessment, data extraction and quality assessment were conducted by one reviewer and checked by a second. The methodological quality of included was assessed using quality assessment of diagnostic accuracy studies-2, QUality In Prognosis Studies, a modified version of the Critical Appraisal Skills Programme checklist for cohort studies of treatment, as previously used in the 2017 UK NSC evidence summary, or Mixed Methods Appraisal Tool. A narrative synthesis of results is presented, structured by NSC criterion and key question. No meta-analyses were conducted. The uncertainty around how the identification of non-SCID TCL through screening should be handled is a key limitation of this evidence summary. For many non-SCID TCL conditions, treatment options remain limited and long-term prognosis unclear. This evidence summary employed standard SR methodology to ensure that the capture of relevant evidence was as complete as possible. In addition, to provide further context, this report includes vignettes of some non-SCID TCL conditions that may be identified by screening, a summary of the current status of NBS screening programmes for SCID internationally and findings from the results of horizon scanning for developments in gene therapy for SCID. The SR component of this evidence summary was limited by a restriction to full publications in the English language, specified by the UK NSC. Two full texts were excluded because they were not published in English. One was a SR, which was checked for relevant primary studies; all included studies had already been identified by our searches. The second was a French language publication, which reported a nationwide prospective study of neonatal screening of SCID in a population of 200,000 French newborns over a period of 2 years; it should be noted that, without the English language restriction, this study may have provided data relevant to research question 1.

Project Status: Completed

URL for project: https://www.journalslibrary.nihr.ac.uk/programmes/hta/NIHR168307

Year Published: 2026

URL for published report: https://www.journalslibrary.nihr.ac.uk/hta/GJMW5701

URL for additional information: English

English language abstract: An English language summary is available

Publication Type: Full HTA

Country: England, United Kingdom

DOI: 10.3310/GJMW5701

Organisation Name: NIHR Health Technology Assessment programme

Contact Address: NIHR Journals Library, National Institute for Health and Care Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK

Contact Name: journals.library@nihr.ac.uk

Contact Email: journals.library@nihr.ac.uk