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Immune Cellular Evaluation Following Newborn Screening for Severe T In this issue: Clinical flow cytometry in 2019 This is a Platinum Open Access Journal distributed under the terms of the Creative Commons Attribution Non-Commercial License which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Immune cellular evaluation following newborn screening for severe T and B cell lymphopenia Johannes Wolf1,2, Karolin Dahlenburg3, Stephan Borte2,4 1 Municipal Hospital St. Georg Leipzig, Academic Teaching Hospital of the University Leipzig, Department of Laboratory Medicine and Microbiology, Leipzig, Germany 2 Immuno Deficiency Center Leipzig (IDCL) at Hospital St. Georg Leipzig, Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiency Diseases, Leipzig, Germany 3 Faculty of Medicine, University Leipzig, Germany 4 Municipal Hospital St. Georg Leipzig, Academic Teaching Hospital of the University Leipzig, Department of Pediatrics, Leipzig, Germany ARTICLE INFO ABSTRACT Corresponding author: Newborn screening (NBS) for severe T and/or B cell Stephan Borte, MD, PhD Immuno Deficiency Center Leipzig (IDCL) lymphopenia to identify neonates with severe com- Hospital St. Georg Leipzig bined immunodeficiencies (SCID) or agammaglob- Delitzscher Strasse 141 ulinemia rapidly after birth has paved its way into D-04129 Leipzig clinical practice. Debate exists on the concept and Germany Phone: +49 341 909 4478 strategy for rapid verification and stratification of the E-mail: [email protected] cellular immune status of positively screened infants. We provide impulses for harmonization of flow cyto- Key words: newborn screening, T cell lymphopenia, metric approaches to allow rapid integration in the B cell lymphopenia, severe combined growing number of immunological laboratories in- immunodeficiency volved in follow-up and subdivision of SCID and non- Acknowledgement: SCID entities. All authors declare no conflicts of interest. Page 396 eJIFCC2019Vol30No4pp396-406 Johannes Wolf, Karolin Dahlenburg, Stephan Borte Immune cellular evaluation following newborn screening for severe T and B cell lymphopenia INTRODUCTION Severe combined immunodeficiency (SCID) is the most severe form of inherited primary im- The purpose of neonatal screening programs is munodeficiency and is a pediatric emergency. the early recognition of treatable genetic dis- Delay in recognizing and detecting SCID can eases that manifest with a high rate of morbid- have fatal consequences and also reduces the ity and mortality. While the implementation of chances of successful hematopoietic stem cell newborn screening tests for metabolic disorders transplantation (HSCT) [1]. traces back to the mid-1960s, suitable technolo- gies to identify severe inborn errors of immune Screening for SCID at birth would prevent chil- function have emerged only in recent years. dren from dying before HSCT can be attempted and would increase the success of HSCT. There The estimated incidence of primary immunode- is strong evidence to show that SCID fulfills the ficiency diseases (PID) that would require imme- internationally-established criteria for a condi- diate treatment ranges from 2 to 8 per 100,000 tion to be screened for at birth [2]. live births, making high demands on the effec- tiveness and availability of screening tests [3]. Severe combined immunodeficiency In comparison with metabolic diseases, the iden- – a life-threatening group of disorders tification of sensitive and traceable biomarkers SCID is a group of life-threatening immune disor- poses a challenge due to the genetic diversity of ders arising from a variety of genetic defects that pediatric PID patients. lead to the absence of lymphocyte development Figure 1 T/B/NK-cellular classification of SCID entities Page 397 eJIFCC2019Vol30No4pp396-406 Johannes Wolf, Karolin Dahlenburg, Stephan Borte Immune cellular evaluation following newborn screening for severe T and B cell lymphopenia and function [3]. Nearly all patients with SCID DIAGNOSTIC CONCEPT AND STRATEGY have absent T-cells, and are further grouped by Newborn screening algorithm the absence or presence of B-cells and NK-cells (Figure 1). Normal T-cell development requires produc- tion of precursor T-cells in the bone marrow and Thus, the absence or severe reduction of func- subsequent processing of T-cells in the thymus. tional naïve T and/or B cells at birth would be the Although SCID can arise from a variety of genetic preferable biomarker for newborn screening of defects, there is an abnormality of T-cell devel- SCID [4]. opment in the thymus in all cases. During nor- The diagnosis of SCID is a pediatric emergency, mal thymic processing, T cells undergo recep- given that most affected children exhibit ex- tor gene splicing and rearrangement, leading to treme susceptibility to bacterial, viral, fungal intracellular accumulation of DNA by-products and opportunistic infections, which are fatal known as T-cell receptor excision circles (TRECs). in the first 1-2 years of life without curative When used in NBS assays, TRECs are a surro- treatment. gate marker of newborns’ capability to produce In most cases, children with SCID appear well at T cells, which is severely hampered in SCID pa- birth and present with recurrent severe infec- tients [4]. tions and failure to thrive at 3-6 months as pas- TRECs do not replicate in dividing cells and are sively transferred protective maternal immuno- diluted out upon cellular division. They are globulins are diminishing. therefore only found in recent thymic emigrant Figure 2 Spectrum of neonatal T cell lymphopenia Page 398 eJIFCC2019Vol30No4pp396-406 Johannes Wolf, Karolin Dahlenburg, Stephan Borte Immune cellular evaluation following newborn screening for severe T and B cell lymphopenia Figure 3 Representative distribution of TREC and KREC copy numbers in neonatal dried blood spot samples Page 399 eJIFCC2019Vol30No4pp396-406 Johannes Wolf, Karolin Dahlenburg, Stephan Borte Immune cellular evaluation following newborn screening for severe T and B cell lymphopenia naïve T-cells. This aspect is important, as in cer- single TREC assay, the addition of other screen- tain conditions such as engraftment of maternal ing markers such as kappa-deleting recombina- T-cells or expansion of a few oligoclonal T-cells tion excision circles (KREC), which detect de- in Omenn syndrome, a substantial amount of fects of B-cell development, has been proposed T-cells can be found in an infant with SCID. As and might be considered helpful (Figure 2) [4]. these T-cells have undergone multiple rounds Screening for severe T-cell lymphopenia by of cell division, TRECs are diluted and the TREC TRECs is not standardized and employs differ- value is low despite high numbers of T-cells in ent methods, leading to marked differences in peripheral blood. cut-offs for the number of newly formed T-cells As some leaky, variant, or delayed-onset forms in the ongoing screening programs in various of SCID will not be detected at birth based on a countries. This, in turn, has resulted in significant Figure 4 Proposed flow-chart for the follow-up of positive newborn screening results for TRECs and KRECs Page 400 eJIFCC2019Vol30No4pp396-406 Johannes Wolf, Karolin Dahlenburg, Stephan Borte Immune cellular evaluation following newborn screening for severe T and B cell lymphopenia difference in the number of patient recalls and of the significance of the test results, if they diagnostic procedures, including flow cytometry are abnormal again, will be provided only at a and other cellular testing stages. Typical testing specialized immunodeficiency center. The par- results in a large cohort of healthy newborn us- ents will be directed to such a center in the area ing a commercially available screening kit for (Stage 2), and the center will be informed about TRECs and KRECs are depicted in Figure 3 [5]. the patient to be expected. To ensure adequate follow-up of infants with Subsequently, a specialized treatment center likely SCID identified by TREC screening and to should be selected that is close to home: in limit the number of false-positive results at the the case of suspected severe naive T- and/or same time, algorithms have been designed by B-lymphopenia, intensive hygiene measures screening centers together with clinical immu- and possibly early, strict isolation to prevent op- nologists [5]. In most cases this will include the portunistic infections are necessary steps to be following (Figure 4): All infants undergo screen- taken. In order to perform HSCT or gene thera- ing by the TREC (and KREC) assay. If normal, py, a transfer to a specialized transplant center no further intervention is recommended. In may be necessary. infants with TREC levels below the cut-off, the first screening card will be retested for TREC as Flow cytometric analyses well as DNA amplification by quantifying beta- in Stage 1 and Stage 2 actin levels. If the beta-actin level is normal and Screening for neonatal T and/or B cell lymphope- TRECs are still below the cut-off the primary nia reveals not only patients with SCID or agam- care provider is contacted for two scenarios: maglobulinemia, but also genetic, metabolic 1) an emergency scenario - if TRECs are unde- and other medical conditions associated with tectable (~1 in 20.000 cases), the infant needs low TREC and/or KREC copies in the dried blood urgent confirmatory testing by flow cytometry spot card. Whereas the most common reasons and treatment by a clinical immunologist; 2) an for low TREC/KREC copies refer to neonates with intermediate scenario – if TRECs are detectable, preterm birth, 22q11 microdeletion syndrome yet below the established local cut-off value, re- and Trisomy 21, radiosensitivity disorders such as testing of a second screening card is performed: Ataxia telangiectasia (ATM) or Nijmegen break- Tracking of newborns is thus initiated in case of age syndrome, chylothorax or spina bifida, there repeated abnormal test results for TREC and/ is also a fraction of newborns found resulting or KREC copy numbers after examination of at from side-effects of maternal medication during least three independent dried blood punches of pregnancy (i.e.
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