Reviews and feature article
The Wisconsin approach to newborn screening for severe combined immunodeficiency

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Severe combined immunodeficiency (SCID) is a life-threatening disease of infants that is curable with hematopoietic cell transplantation if detected early. Population-based screening for SCID using the T-cell receptor excision circle (TREC) assay began in Wisconsin in 2008; 5 infants with SCID or other forms of severe T-cell lymphopenia (TCL) have been detected, and no infants with SCID have been missed. This review will provide an overview of the TREC screening assay and an update of the findings from Wisconsin on all infants screened from January 1, 2008, until December 31, 2010. Importantly, we give practical recommendations regarding newborn population-based screening using the TREC assay, including the evaluation and care of infants detected.

Section snippets

Results of 3 years of NBS in Wisconsin

During the first 3 years of screening in Wisconsin, 207,696 infants were screened with the TREC assay.11 In total, 72 full-term infants (0.035%) had an abnormal TREC assay result (low TREC counts and normal β-actin levels) during the first 3 years of testing, which included 63 infants found to have abnormal results on initial testing and 9 infants reclassified as having abnormal results after repeat testing because of prematurity or low β-actin levels. Of the abnormal results, 38 infants had

The TREC assay in premature infants

Early in the implementation of the NBS program for SCID, it became apparent that the numbers of abnormal (ie, low TREC counts and normal β-actin levels) or inconclusive (ie, low TREC counts and low β-actin levels) TREC assay results were higher in premature infants (adjusted gestational age [AGA] ≤ 37 weeks) compared with those seen in full-term infants.9, 11 In 3 years of screening, 63 (0.03%) full-term infants were classified as having abnormal results, and 51 (0.025%) had inconclusive

Pitfalls and dilemmas

It is generally accepted that a diagnosis of SCID can be made with a T-cell count of less than 200 cells/μL and particularly with mitogenic responses of less than 10% of control values, even in the absence of a molecular cause. This definition, however, would have only applied to 2 infants detected in Wisconsin, highlighting that the TREC assay detects known and unknown causes of SCID/TCL. The infant with a de novo mutation in the RAC2 gene had relatively normal T-cell counts and T-cell

Anticipatory guidance of infants detected with SCID/TCL

With the inception of NBS for SCID, newborns with SCID/sTCL are being identified within the first few weeks of life, before the onset of illness or infections. We have developed a multidisciplinary program, with input from both the clinical immunology and bone marrow transplantation services, to manage infants with high suspicion for SCID/sTCL. Our primary goal is to prevent infections that could predispose infants to end-organ damage and transplant-related mortality. We have also developed

Where should patients be managed? The decision of inpatient versus outpatient care

Infants suspected of SCID but without infectious symptoms are cared for at home, and we use several guidelines to prevent infection (Table III). We also require that the infant live within 1 hour’s drive of our hospital or another appropriate hospital well versed in taking care of sick children from which transfer to our hospital would occur. Infants whose social surroundings, home surroundings, or both are worrisome for poor care, follow-up, or family’s lack of understanding of the prophylaxis

Prophylaxis of infectious disease and other management issues

The infectious diseases department is consulted, and all newborns with possible SCID undergo a panel of PCR tests to evaluate for viral disease (Table IV). If results of these PCR assays are negative, surveillance PCR assays are repeated monthly or bimonthly during the pretransplantation period. The frequency of PCR surveillance increases based on clinical suspicion of new infection (eg, fever or irritability) or if the initial PCR result is positive. Other laboratory studies (eg, lumbar

Conclusion

NBS for SCID/sTCL with the TREC assay is the first step in the early identification and treatment of SCID and other severe immunodeficiencies that present with TCL. Since the initiation of NBS for SCID/sTCL in 2008, there has been considerable progress in implementing nationwide screening. Outcomes to date have been extremely encouraging because all infants given a diagnosis of SCID/sTCL by means of existing NBS have been successfully treated and there have been no missed cases of SCID in the

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Supported by the Children’s Hospital of Wisconsin, the Jeffrey Modell Foundation, the Wisconsin State Laboratory of Hygiene, and the Centers for Disease Control and Prevention (U01 EH000365).

Disclosure of potential conflict of interest: J. Verbsky has received honoraria from Baxter, Illumina, and the Jeffrey Modell Foundation. M. Thakar declares that she has no relevant conflicts of interest. J. Routes has received research support from the National Institutes of Health.

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