Newborn screening for severe combined immunodeficiency—Coming to a region near you soon

Abstract

The most profound of primary immunodeficiencies, severe combined immunodeficiency (SCID), presents in infancy. Infants appear healthy at birth, but they are unable to clear pathogens, particularly viruses, and present with recurrent infection, progressive pnueumonitis and failure to thrive due to enteric viral infection, often associated with persistent vaccine‐strain rotavirus. The administration of live vaccines is contraindicated in these infants, but most who are eligible receive bacillus Calmette–Guérin vaccination and the live rotavirus vaccine before the diagnosis of SCID is made, making treatment more complicated. Newborn infants with SCID can be screened using the newborn bloodspot to measure T lymphocyte receptor excision circles (TRECs), episomal DNA formed during T lymphocyte receptor development and very low or absent in SCID. Introduction of this programme in the United Kingdom will require the neonatal BCG vaccination programme to be altered, with vaccination at 28 days, once the SCID screening result is known. Although SCID newborn screening has been successfully introduced in other countries, the change in neonatal BCG vaccination requires the introduction of newborn screening to be carefully introduced. An evaluation of impact of screening on SCID diagnosis, treatment and outcomes, together with an evaluation of the technology used to detect TRECs, and the impact of screening and changes to the BCG programme on families will commence in six screening regions in England in September 2021 for 2 years – should the evaluation prove positive, it is likely that screening for this fatal disease will be introduced across the United Kingdom.

The most severe of primary immunodeficiencies, severe combined immunodeficiency (SCID), generally presents in infancy and, untreated, is fatal by 12–18 months. Infants appear healthy at birth but as they encounter pathogens, particularly viruses, and opportunistic pathogens such as Pneumocystis jirovecii, they are unable to clear them, and present to medical services with recurrent (usually persistent) infection, progressive pnueumonitis and failure to thrive due to enteric viral infection, often associated with persistent vaccine‐strain rotavirus [1]. The administration of live vaccines is contraindicated in these infants, but most who are eligible receive bacillus Calmette–Guérin vaccination and the live rotavirus vaccine before a diagnosis of SCID is made. This makes treatment of SCID more complicated [2]. Mutations in ~20 genes critical for T lymphocyte development (and, for some genes, B lymphocyte and/or natural killer cell development) are described in the majority of SCID patients, but for a small percentage the genetic defect has yet to be elucidated. For most genetic causes of SCID, haematopoietic stem cell transplantation (HSCT) is the treatment of choice and is curative [3] the first patients with SCID were transplanted in 1968, and remain alive and well. For adenosine deaminase (ADA)‐deficient SCID, enzyme replacement therapy with polyethylene glycol‐modified ADA can ameliorate acute inflammatory symptoms and temporally restore immunity, but definitive treatment with HSCT or gene therapy is recommended [4]. Gene therapy clinical trials are underway for other genetic forms of SCID, including interleukin (IL)‐2RG and recombination activating gene 1 (RAG1) deficiency. While a successful procedure is curative, mortality from HSCT is significant, with an increased risk in the presence of active infection or pre‐existing organ damage – survival of infants who are infection‐free is significantly better [5]. SCID meets the criteria for screening in the newborn period:

• It is serious, and lack of treatment results in early death

• Effective treatment is readily accessible at two national centres in London and Newcastle upon Tyne

• Treatment in the pre‐symptomatic period leads to improved outcomes compared to treatment of infants with established infection

Ideally, a reliable screening test with low false‐negative and ‐positive rates must be available and suitable to be carried out on all the neonatal population. In addition, the cost should be acceptable relative to the potential benefit of early diagnosis and treatment, ie the screening programme should be cost effective.

An initial diagnosis can be made on a full blood count, as the total lymphocyte count is usually, although not invariably, low and the repeated finding of a total lymphocyte count < 2.8 × 10⁹/l in a newborn infant should prompt further investigation with flow cytometry [6]. However, most newborn infants do not have a routine blood count. Mass spectrometry screening can pick up infants with ADA SCID, but this only detects approximately 12% of infants with SCID (depending upon the population being tested) [7]. During T lymphocyte receptor formation, unwanted receptor gene segment blocks are excised and stored as episomal DNA in the developing T lymphocytes – these are not replicated when the cell divides. The episomal DNA, known as a T lymphocyte receptor excision circle (TREC), is a marker for naive T lymphocyte development. Infants with SCID and associated Omenn syndrome and atypical SCID have no TRECs, and therefore this is a good biomarker for the presence of this disorder. TRECs can be detected by polymerase chain reaction (PCR) on the newborn blood spot taken 5 days after birth (Guthrie spot), and therefore their absence can be used as a cheap mass screening test to detect SCID [8]. Infants with a positive test (i.e. low or no TRECs detected on the bloodspot) can be referred for definitive lymphocyte phenotyping by flow cytometry and, if confirmed, transferred to a specialist centre for definitive treatment. The advantage of this is that most infants will still be asymptomatic, and so treatment is more likely to be successful and also cheaper, as there will be fewer complications and less requirement for prolonged and expensive therapies, including anti‐viral treatment and parenteral nutrition. It will also be less distressing for parents who may previously have visited health care facilities with recurrent infections and SCID not suspected.

First introduced in the United States [9], SCID screening programmes have now been rolled out in a number of countries around the world, including a growing number of European countries. A common theme upon introduction of newborn screening for SCID is that the incidence rises from that previously estimated from the number of referrals for treatment, strongly suggesting that, in unscreened areas, infants are dying from a disease that can be cured before a diagnosis is made.

Initiating a new screening program into a region is rarely as simple as introducing the screening and diagnostic tests. Particular features about a population may differ from area to area, meaning that unforeseen complications may be introduced upon introduction of the screening programme. The introduction of newborn screening for SCID presents some challenges. It is the first screening programme to use PCR techniques in the initial screening step, and thus requires introduction of a different technology into the screening laboratory – there is more than one PCR technology for this screening and the available products do not give identical results, so the introduction of a national programme requires careful planning. This is also the first screening programme to analyse DNA as the initial screening test (albeit, what is actually measured is an absence of a particular segment of DNA) – this may require careful consultation with the public to allay fears of mass DNA screening. However, not only is SCID the first primary immunodeficiency to be screened for, it is the only screened disorder for which there is curative treatment, meaning that identified patients will not need to take lifelong medication.

The United States, on whose experience most of our knowledge is based, unlike the United Kingdom, does not have a programme of neonatal BCG vaccination – a live vaccine contraindicated in SCID. Thus, the introduction of such a screening programme in the United Kingdom requires a change in the neonatal BCG vaccination policy to avoid vaccinating infants who are subsequently confirmed as having SCID through the newborn screening programme.

While it is highly likely that the introduction of newborn screening for SCID in the United Kingdom will provide similar benefits, as seen when introduced in other countries, this is not certain. Therefore, the National Screening Committee has tasked Public Health England with overseeing an evaluation in six screening regions in England to confirm cost‐effectiveness and assess the impact of moving neonatal BCG vaccination. In addition, at least two different PCR screening methods will be used. Experience shows that the TREC assay has a very high sensitivity, but there are infants detected by the assay who do not have SCID – some have other immunodeficiencies, including DiGeorge syndrome, dedicator of cytokinesis (DOCK8) deficiency and ataxia–telangiectasia or secondary immunodeficiencies due to maternal immunosuppression or others, including intestinal lymphangiectasia. Extreme prematurity can also lead to low TREC values. Idiopathic CD4⁺ lymphocytopenia may also be detected – how important it is to screen for this condition is unclear, and detected infants will need long‐term follow‐up to determine their outcome [10]. In addition, there will be babies who have a positive screening test, but on further assessment, have no evidence of disease: ‘false‐positives’. It is important to reduce the number of these as far as possible, as it can cause distress to parents. Data from this evaluation will be collected nationally, as well as in European databases such as the European Society of Immunodeficiencies registry. Following a delay due to the SARS‐Cov‐2 pandemic, the evaluation will commence in September 2021 and run for 24 months. It is likely that you will hear about it from several sources: more information about the programme can be found at https://phescreening.blog.gov.uk/tag/scid/ and https://www.gov.uk/topic/population‐screening‐programmes/newborn‐blood‐spot.

In step with the evaluation, a research project will look at the effect of the screening programme on the families involved, whether or not their babies have SCID.

The planning of the evaluation has involved a wide range of stakeholders, including professionals and public, without whom it would not have been possible. While complicated to implement, it is hoped that the evaluation will be positive and that a national screening programme will be implemented subsequently throughout England and the devolved nations. Newborn screening is a fantastic public health success story and we are delighted that the immunology community can be part of that narrative and that the future for UK‐born infants with SCID is looking brighter.

CONFLICTS OF INTEREST

The authors declare no competing interests.

DATA AVAILABILITY STATEMENT

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

AUTHOR CONTRIBUTIONS

DACE and ARG conceived and wrote the article and approved the final version

Elliman DAC, Gennery AR. Newborn screening for severe combined immunodeficiency—Coming to a region near you soon. Clin Exp Immunol. 2021;205:343–345. 10.1111/cei.13642