Background: Public health newborn screening (NBS) programs continuously evolve, taking advantage of international shared learning. NBS for severe combined immunodeficiency (SCID) has recently been... Show moreBackground: Public health newborn screening (NBS) programs continuously evolve, taking advantage of international shared learning. NBS for severe combined immunodeficiency (SCID) has recently been introduced in many countries. However, comparison of screening outcomes has been hampered by use of disparate terminology and imprecise or variable case definitions for non-SCID conditions with T-cell lymphopenia.Objectives: This study sought to determine whether standardized screening terminology could overcome a Babylonian confusion and whether improved case definitions would promote international exchange of knowledge.Methods: A systematic literature review highlighted the diverse terminology in SCID NBS programs internationally. While, as expected, individual screening strategies and tests were tailored to each program, we found uniform terminology to be lacking in definitions of disease targets, sensitivity, and specificity required for comparisons across programs.Results: The study's recommendations reflect current evidence from literature and existing guidelines coupled with opinion of experts in public health screening and immunology. Terminologies were aligned. The distinction between actionable and nonactionable T-cell lymphopenia among non-SCID cases was clarified, the former being infants with T-cell lymphopenia who could benefit from interventions such as protection from infections, antibiotic prophylaxis, and live-attenuated vaccine avoidance.Conclusions: By bringing together the previously unconnected public health screening community and clinical immunology community, these SCID NBS deliberations bridged the gaps in language and perspective between these disciplines. This study proposes that international specialists in each disorder for which NBS is performed join forces to hone their definitions and recommend uniform registration of outcomes of NBS. Standardization of terminology will promote international exchange of knowledge and optimize each phase of NBS and follow-up care, advancing health outcomes for children worldwide. Show less
Severe combined immunodeficiency (SCID) is one of the most severe form of inborn errors of immunity characterized by the absence or dysfunction of T-lymphocytes affecting both cellular and humoral... Show moreSevere combined immunodeficiency (SCID) is one of the most severe form of inborn errors of immunity characterized by the absence or dysfunction of T-lymphocytes affecting both cellular and humoral immunity. Infants with SCID are asymptomatic at birth, but develop severe infections in the first months of life. Without curative treatment, in the form of allogeneic hematopoietic stem cell transplantation (HSCT) or gene therapy (GT), affected infants die within the first year of life. Early treatment, before the onset of infections, results in the best outcomes making SCID a suitable candidate for early detection via newborn screening (NBS). NBS for SCID is based on the detection of T-cell receptor excision circles (TRECs), a marker for thymic production of naïve T-cells. Since the introduction of the TREC assay 15 years ago, many countries have adopted SCID in their NBS programs leading to improved outcomes for SCID patients worldwide. There are several hurdles and challenges associated with the introduction of SCID into these complex, multifaceted NBS programs. This thesis highlights the many aspects that are associated with NBS for SCID addressing innovative societal and ethical implications, as well as technical aspects and cost-effectiveness within a prospective implementation pilot study. In the end, results presented in this thesis have led to the implementation of SCID in the Dutch NBS program on 1 January 2021. Show less
Blom, M.; Pico-Knijnenburg, I.; Imholz, S.; Vissers, L.; Schulze, J.; Werner, J.; ... ; Burg, M. van der 2021
Purpose Newborn screening (NBS) for severe combined immunodeficiency (SCID) is based on the detection of T-cell receptor excision circles (TRECs). TRECs are a sensitive biomarker for T-cell... Show morePurpose Newborn screening (NBS) for severe combined immunodeficiency (SCID) is based on the detection of T-cell receptor excision circles (TRECs). TRECs are a sensitive biomarker for T-cell lymphopenia, but not specific for SCID. This creates a palette of secondary findings associated with low T-cells that require follow-up and treatment or are non-actionable. The high rate of (non-actionable) secondary findings and false-positive referrals raises questions about the harm-benefit-ratio of SCID screening, as referrals are associated with high emotional impact and anxiety for parents. Methods An alternative quantitative TREC PCR with different primers was performed on NBS cards of referred newborns (N = 56) and epigenetic immune cell counting was used as for relative quantification of CD3 + T-cells (N = 59). Retrospective data was used to determine the reduction in referrals with a lower TREC cutoff value or an adjusted screening algorithm. Results When analyzed with a second PCR with different primers, 45% of the referrals (25/56) had TREC levels above cutoff, including four false-positive cases in which two SNPs were identified. With epigenetic qPCR, 41% (24/59) of the referrals were within the range of the relative CD3 + T-cell counts of the healthy controls. Lowering the TREC cutoff value or adjusting the screening algorithm led to lower referral rates but did not prevent all false-positive referrals. Conclusions Second tier tests and adjustments of cutoff values or screening algorithms all have the potential to reduce the number of non-actionable secondary findings in NBS for SCID, although second tier tests are more effective in preventing false-positive referrals. Show less
Ploeg, C.P.B. van der; Blom, M.; Bredius, R.G.M.; Burg, M. van der; Schielen, P.C.J.I.; Verkerk, P.H.; Akker-van Marle, M.E. van den 2019
Cytomegalovirus (CMV) infection is the most common congenital viral infection worldwide. The symptom of congenital CMV infection encountered most frequently is sensorineural hearing loss, which... Show moreCytomegalovirus (CMV) infection is the most common congenital viral infection worldwide. The symptom of congenital CMV infection encountered most frequently is sensorineural hearing loss, which will affect approximately one out of __ve congenitally infected newborns. Because of the late-onset nature of the hearing loss, up to half of the children with congenital CMV-related hearing loss may not be detected in the newborn hearing screening. This thesis addresses several aspects of congenital CMV infection in general and more specifically in the Netherlands, in order to determine the necessity and feasibility of newborn screening for congenital CMV. Show less
