Newborn Screening for Primary Immunodeficiency Diseases – Past, Present and Future

A special issue of International Journal of Neonatal Screening (ISSN 2409-515X).

Deadline for manuscript submissions: closed (15 April 2017) | Viewed by 61330

Special Issue Editors


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Guest Editor
Department of Clinical Immunology, Karolinska University Hospital Huddinge, SE-14186 Stockholm, Sweden
Interests: primary immunodeficiency; genetics; newborn screening

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Guest Editor
Department of Laboratory Medicine (LABMED), H5, Division of Clinical Immunology, Karolinska Universitetssjukhuset, Huddinge F79, 14186 Stockholm, Sweden
Interests: primary immunodeficiency; pediatrics; genetics; newborn screening

Special Issue Information

Dear Colleagues,

Newborn screening for primary immunodeficiency is coming of age! Following the seminal paper by Jenifer Puck and her group in 2005, describing the T Cell Receptor Excision Circle assay (TREC), screening of newborns using this assay started in Wisconsin a few years later. During 2017, it is expected that all states in the US will be screening for T cell lymphopenia (as a sign of SCID). National screening using the TREC assay has also been implemented in Taiwan and Israel and pilot trials are ongoing in many additional countries.

The KREC assay, using a similar technology but analyzing B cells (Kappa Receptor Excision Circle assay) was published in 2011 and has been used to identify children with B cell lymphopenia. Subsequently, a combined assay (TREC/KREC/beta actin) was developed for the simultaneous detection of both T and B cell lymphopenia.

Further development of assays for detection of newborn children with various forms of primary immunodeficiency were developed in the following years and discussions on the appropriare use of next generation sequencing methods are currently underway.

This Special Issue (by invitation only) of the International Journal of Neonatal Screening, devoted to “Newborn Screening for primary immunodeficiency diseases – Past, Present and Future”, will thus consider where we have been, where we are, and where we might be going.

Best regards

Lennart Hammarström and Stephan Borte

Prof. Dr. Lennart Hammarström
Dr. Stephan Borte
Guest Editors

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Published Papers (9 papers)

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Research

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644 KiB  
Article
Newborn Screening for Primary T- and B-Cell Immune Deficiencies—A Prospective Study in Andalucía
by Beatriz De Felipe, Peter Olbrich, Walter Goycochea-Valdivia, Carmen Delgado-Pecellin, Paula Sanchez-Moreno, Berta Sánchez, José Manuel Lucena, Araceli Ferrari-Cortes, Joséfa Salguero Martin De Soto, Josefina Marquez, Carmen Salamanca, Carlos Jimenez Contreras and Olaf Neth
Int. J. Neonatal Screen. 2017, 3(4), 27; https://doi.org/10.3390/ijns3040027 - 07 Oct 2017
Cited by 3 | Viewed by 4477
Abstract
Background: Quantification of T-cell-receptor-excision circles (TRECs) and kappa-deleting-recombination-excision circles (KRECs) from dried blood spots (DBS) allows detection of neonates with severe T-cell and/or B-cell lymphopenia that are potentially affected by severe combined immunodeficiency (SCID), as well as X-linked agammaglobulinemia (XLA). Methods: Determination of [...] Read more.
Background: Quantification of T-cell-receptor-excision circles (TRECs) and kappa-deleting-recombination-excision circles (KRECs) from dried blood spots (DBS) allows detection of neonates with severe T-cell and/or B-cell lymphopenia that are potentially affected by severe combined immunodeficiency (SCID), as well as X-linked agammaglobulinemia (XLA). Methods: Determination of TRECs and KRECs using a triplex RT-PCR (TRECS-KRECS-β-actin) assay from prospectively collected DBS between February 2014 and December 2016 in three hospitals in Seville, Spain. Cut-off levels were TRECs < 6/punch, KRECs < 4/punch and b-actin > 700/punch. Internal (SCID, XLA, ataxia telangiectasia) and external controls (CDC) were included. Results: A total of 8943 DBS samples obtained from 8814 neonates were analysed. Re-punching was necessary in 124 samples (1.4%) due to insufficient β-actin values (<700 copies/punch). Preterm neonates (GA < 37 weeks) and neonates with a BW < 2500 g showed significantly lower TRECs and KRECs levels (p < 0.001). Due to repeated pathological results, ten neonates were re-sampled (0.11%), of which five neonates (0.055%) confirmed the pathological results: one case was a fatal chromosomopathy (TRECs 1/KRECs 4); two were extreme premature newborns (TRECs 0/KRECs 0 and TRECs 1/KRECs 20 copies/punch); and 2 neonates were born to mothers receiving azathioprine during pregnancy (TRECs 92/KRECs 1 and TRECs 154/KRECs 3 copies/punch). All controls were correctly identified. Conclusions: Severe T- and B-cell lymphopenias were correctly identified by the TRECS-KRECS-β-actin assay. Prematurity and low BW are associated with lower TREC and KREC levels. Extreme prematurity and maternal immune suppressive therapy can cause false positive results of TRECs and KRECs values. Full article
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455 KiB  
Article
Newborn Screening for Severe Combined Immunodeficiency in Taiwan
by Yin-Hsiu Chien, Hsin-Hui Yu, Ni-Chung Lee, Hui-Chen Ho, Shu-Min Kao, Meng-Yao Lu, Tang-Her Jaing, Wen-I Lee, Kuei-Wen Chang, Chi-Chang Shieh, Jiann-Shiuh Chen, Shu-Chuan Chiang, Chen-Chen Liu and Wuh-Liang Hwu
Int. J. Neonatal Screen. 2017, 3(3), 16; https://doi.org/10.3390/ijns3030016 - 23 Jun 2017
Cited by 38 | Viewed by 7896
Abstract
A study of newborn screening for severe combined immunodeficiency (SCID) by detecting the T-cell receptor excision circle (TRECs) copy number in dried blood spots (DBSs) collected from newborns 3 days of age began in 2010 in Taiwan, and SCID screening was subsequently implemented [...] Read more.
A study of newborn screening for severe combined immunodeficiency (SCID) by detecting the T-cell receptor excision circle (TRECs) copy number in dried blood spots (DBSs) collected from newborns 3 days of age began in 2010 in Taiwan, and SCID screening was subsequently implemented country-wide in 2012. A total of 920,398 newborns were screened during a period of 78 months. Of these, 175 newborns (0.02%) were requested to undergo an immune function survey, and 136 cases (1 in 6768 newborns) were ultimately diagnosed as having T cell lymphopenia. The screening detected seven cases of typical SCID, with an incidence of 1 in 131,485 newborns (95% confidence interval, 1/63,693~1/271,434). Hematopoietic stem cell transplantation was performed in six patients before overt infection occurred, and the survival rate was 100%. The screening also detected eight cases of SCID variants and 20 cases of 22q11.2 deletion syndrome. Other etiologies of T lymphopenia were identified, and those newborns were evaluated and managed according to their immunological status. Owing to the introduction of newborn screening by measuring the TREC copy number, early administration of treatments became possible for newborns with conditions that put them at risk of primary or secondary immunodeficiency. Full article
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501 KiB  
Article
Newborn Screening for Primary Immune Deficiencies with a TREC/KREC/ACTB Triplex Assay—A Three-Year Pilot Study in Sweden
by Rolf H. Zetterström, Michela Barbaro, Annika Ohlsson, Stephan Borte, Susanne Jonsson, Jacek Winiarski, Ulrika Von Döbeln and Lennart Hammarström
Int. J. Neonatal Screen. 2017, 3(2), 11; https://doi.org/10.3390/ijns3020011 - 19 May 2017
Cited by 15 | Viewed by 6577
Abstract
Background: Screening newborns for severe combined immunodeficiency (SCID) has become essential, since efficient methods to identify infants with these disorders exist and early stem cell transplantation is life-saving. Method: We performed a three-year screening trial in Stockholm comprised of 89,462 newborn [...] Read more.
Background: Screening newborns for severe combined immunodeficiency (SCID) has become essential, since efficient methods to identify infants with these disorders exist and early stem cell transplantation is life-saving. Method: We performed a three-year screening trial in Stockholm comprised of 89,462 newborn infants. The number of T-cell receptor excision circle (TREC)/kappa-deleting recombination excision circle (KREC)/β-actin (ACTB) copies were quantified simultaneously by real time polymerase chain reaction (PCR) in 3.2 mm punches from dried blood samples taken in the regular neonatal screening program. Results: Five patients with immune deficiencies were identified: two with SCID caused by mutations in the Artemis- and adenosine deaminase gene, respectively, one with ataxia telangiectasia and two with reversible agammagloblinemia, which so far, is of unknown cause. This points to an incidence of SCID at the same level as in other studies (around 1:50,000). In 19 recalled infants, low KREC levels and in one case, also low TREC levels, were caused by immunosuppressive treatment of the mother during pregnancy. The levels normalized within a month in all these infants. The total recall rate was 0.10%, and 40% of the recalled infants were born prematurely (<37 weeks gestation). Among 69 patients with inborn errors of metabolism screened retrospectively, only two, who were severely ill with organic acidemias when the sample was taken, and two with mitochondrial disorders, screened positive. Full article
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Review

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10 pages, 1210 KiB  
Review
Introducing Newborn Screening for Severe Combined Immunodeficiency (SCID) in the Dutch Neonatal Screening Program
by Maartje Blom, Robbert G.M. Bredius, Gert Weijman, Eugènie H.B.M. Dekkers, Evelien A. Kemper, M. Elske Van den Akker-van Marle, Catharina P.B. Van der Ploeg, Mirjam Van der Burg and Peter C.J.I. Schielen
Int. J. Neonatal Screen. 2018, 4(4), 40; https://doi.org/10.3390/ijns4040040 - 12 Dec 2018
Cited by 27 | Viewed by 5765
Abstract
The implementation of newborn screening for severe combined immunodeficiency (SCID) in the Netherlands is a multifaceted process in which several parties are involved. The Dutch Ministry of Health adopted the advice of the Dutch Health Council to include SCID in the Dutch newborn [...] Read more.
The implementation of newborn screening for severe combined immunodeficiency (SCID) in the Netherlands is a multifaceted process in which several parties are involved. The Dutch Ministry of Health adopted the advice of the Dutch Health Council to include SCID in the Dutch newborn screening program in 2015. As newborn screening for SCID is executed with a new, relatively expensive assay for the Dutch screening laboratory, an implementation pilot study is deemed instrumental for successful implementation. A feasibility study was performed in which the practicalities and preconditions of expanding the newborn screening program were defined. Cost-effectiveness analysis (CEA) indicated that SCID screening in the Netherlands might be cost-effective, recognizing that there are still many uncertainties in the variables underlying the CEA. Data and experience of the pilot study should provide better estimates of these parameters, thus enabling the actualization of CEA results. Prior to the implementation pilot study, a comparison study of two commercially available SCID screening assays was performed. A prospective implementation pilot study or so-called SONNET study (SCID screening research in the Netherlands with TRECs) started in April 2018 and allows the screening for SCID of all newborns in three provinces of the Netherlands for one year. Based on the results of the SONNET study, the Dutch Ministry of Health will make a final decision about national implementation of newborn screening for SCID in the Netherlands. Full article
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171 KiB  
Review
A Practical Guide to Implementing Population Newborn Screening (NBS) for Severe Combined Immunodeficiency (SCID)
by H. Bobby Gaspar
Int. J. Neonatal Screen. 2017, 3(4), 29; https://doi.org/10.3390/ijns3040029 - 10 Nov 2017
Cited by 5 | Viewed by 3642
Abstract
This review should be seen as a practical tool, one which we hope illustrates potential routes to follow when seeking to implement or lobby for severe combined immunodeficiency newborn screening (SCID NBS) at a national or regional level. Experience has shown that there [...] Read more.
This review should be seen as a practical tool, one which we hope illustrates potential routes to follow when seeking to implement or lobby for severe combined immunodeficiency newborn screening (SCID NBS) at a national or regional level. Experience has shown that there are country- and region-wide variations in terms of awareness of the need for SCID NBS and the processes required to demonstrate and prove the importance of SCID NBS. This guide therefore aims to share experiences and equip readers with evidence while also directing them to key further reading and resources that provide support, data, and existing frameworks that are relevant to making the case for mandatory NBS for SCID. Full article
362 KiB  
Review
Newborn Screening for Primary Immunodeficiency Diseases: The Past, the Present and the Future
by Jovanka King, Jonas F. Ludvigsson and Lennart Hammarström
Int. J. Neonatal Screen. 2017, 3(3), 19; https://doi.org/10.3390/ijns3030019 - 03 Aug 2017
Cited by 16 | Viewed by 8326
Abstract
Primary immunodeficiency diseases (PID) are a heterogeneous group of disorders caused by inborn errors of immunity, with affected children presenting with severe, recurrent or unusual infections. Over 300 distinct genetic molecular abnormalities resulting in PID have been identified, and this number continues to [...] Read more.
Primary immunodeficiency diseases (PID) are a heterogeneous group of disorders caused by inborn errors of immunity, with affected children presenting with severe, recurrent or unusual infections. Over 300 distinct genetic molecular abnormalities resulting in PID have been identified, and this number continues to rise. Newborn screening for PID has been established in many countries, with the majority of centers using a PCR-based T cell receptor excision circle (TREC) assay to screen for severe combined immunodeficiency (SCID) and other forms of T cell lymphopenia. Multiplexed screening including quantitation of kappa-recombining exclusion circles (KREC) has also been described, offering advantages over TREC screening alone. Screening technologies are also expanding to include protein-based assays to identify complement deficiencies and granulocyte disorders. Given the rapid advances in genomic medicine, a potential future direction is the application of next-generation sequencing (NGS) technologies to screen infants for a panel of genetic mutations, which would enable identification of a wide range of diseases. However, several ethical and economic issues must be considered before moving towards this screening strategy. Full article
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1529 KiB  
Review
Newborn Screening for Severe Combined Immunodeficiency in the US: Current Status and Approach to Management
by Morna Dorsey and Jennifer Puck
Int. J. Neonatal Screen. 2017, 3(2), 15; https://doi.org/10.3390/ijns3020015 - 21 Jun 2017
Cited by 31 | Viewed by 11215
Abstract
In the US, the assay of T cell receptor excision circles (TRECs) in newborn dried blood spot specimens to detect severe combined immunodeficiency (SCID) was first piloted in 2008 in the state of Wisconsin. It has been rapidly adopted with 49 states and [...] Read more.
In the US, the assay of T cell receptor excision circles (TRECs) in newborn dried blood spot specimens to detect severe combined immunodeficiency (SCID) was first piloted in 2008 in the state of Wisconsin. It has been rapidly adopted with 49 states and Puerto Rico now either routinely screening all newborns or planning to do so in 2017. Advances in SCID NBS over the last 9 years have revolutionized the ability to detect SCID and has led to profound improvement in outcomes of affected children. Full article
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1148 KiB  
Review
Newborn Screening for Severe Combined Immunodeficiency-A History of the TREC Assay
by Mary T. Bausch-Jurken, James W. Verbsky and John M. Routes
Int. J. Neonatal Screen. 2017, 3(2), 14; https://doi.org/10.3390/ijns3020014 - 18 Jun 2017
Cited by 9 | Viewed by 7628
Abstract
Infants born with T cell lymphopenias, especially severe combined immunodeficiency (SCID) are at risk for serious, often fatal infections without intervention within the first year or two of life. The majority of these disorders can be detected through the use of the T [...] Read more.
Infants born with T cell lymphopenias, especially severe combined immunodeficiency (SCID) are at risk for serious, often fatal infections without intervention within the first year or two of life. The majority of these disorders can be detected through the use of the T cell recombination excision circle assay (TREC assay.) The TREC assay detects the presence of non-replicating, episomal DNA that is formed during T cell development. This assay initially developed to measure thymic output during aging and HIV infection, has undergone modifications for the purpose of newborn screening (NBS) for SCID. To meet the requirements for inclusion on NBS panels, the assay needed to utilize blood from dried blood spots on NBS cards, and be both sensitive and specific, avoiding the costs of false positives. Currently, the assay relies upon real time, quantitative PCR (RT-qPCR) to detect TRECs in punches taken from dried blood spots. This review seeks to highlight some of the early work leading up to the initial implementation of the TREC assay for SCID detection, and the subsequent revisions made to optimize the assay. Full article
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213 KiB  
Review
Newborn Screening for Severe Combined Immunodeficiency in Israel
by Erez Rechavi, Atar Lev, Talia Saraf-Levy, Amos Etzioni, Shlomo Almashanu and Raz Somech
Int. J. Neonatal Screen. 2017, 3(2), 13; https://doi.org/10.3390/ijns3020013 - 17 Jun 2017
Cited by 23 | Viewed by 5169
Abstract
Newborn screening (NBS) programs for severe combined immunodeficiency (SCID), the most severe type of primary immunodeficiency, are being implemented in more and more countries with every passing year. Since October 2015, SCID screening via T cell receptor excision circle (TREC) quantification in dried [...] Read more.
Newborn screening (NBS) programs for severe combined immunodeficiency (SCID), the most severe type of primary immunodeficiency, are being implemented in more and more countries with every passing year. Since October 2015, SCID screening via T cell receptor excision circle (TREC) quantification in dried blood spots (DBS) has been part of the Israeli NBS program. As an NBS program in its infancy, SCID screening is still evolving, making gathering input from the various programs crucial for compiling an ideal screening algorithm. The relatively high rate of consanguineous marriages in Israel, especially among non-Jews, correlates with an increased incidence of SCID. The Israeli algorithm uses a commercial kit and consists of a two-Guthrie card confirmation system prior to referral to a national immunology center. Preliminary data from the first year and a half of SCID screening in Israel has identified a surprisingly high prevalence of DNA cross-link repair protein 1c (DCLRE1C; ARTEMIS) mutations as the cause of SCID in Israel. The clinically unbiased nature of SCID screening helps unearth mild/leaky SCID phenotypes, resulting in a better understanding of true SCID prevalence and etiology. Full article
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