Ten Years of Newborn Screening for Severe Combined Immunodeficiency (SCID) in Massachusetts

Abstract

To examine the outcomes of population newborn screening (NBS) for severe combined immunodeficiency (SCID) by using T-cell receptor excision circles (TRECs) after the first decade of implementation in Massachusetts.Infants born in Massachusetts screened through the New England Newborn Screening Program between February 1, 2009, and January 31, 2019.The authors present a population cohort of infants receiving NBS for SCID, both before and after mandatory NBS implementation in 2016.Of 720 038 infants screened, normal TRECs were identified in 99.71%. At least 1 abnormal specimen was identified in 2072 infants (0.29% of those screened). Of these infants, 1771 had an additional TREC result, which was normal, and were released from the screening program (83.8% of those with an abnormal TREC result before confirmatory flow cytometry and 1.7% after further lymphocyte phenotyping). Further evaluation by flow cytometry occurred in 237 infants (11.4% of those with at least 1 abnormal TREC result), and low naïve T-cell percentages were associated with a greater risk of a combined immunodeficiency. A total of 9 infants were diagnosed with SCID or leaky SCID, 7 were diagnosed with other combined immunodeficiencies, and 3 were diagnosed with athymia (0.4%, 0.3%, and 0.1%, respectively. of those with an abnormal TREC screen). The incidence of SCID or leaky SCID was reported as ∼1 in 80 000; however, more broadly, the incidence of severe T-cell lymphopenia for which definitive treatment was indicated was ∼1 in 50 000 infants. All patients with SCID or leaky SCID underwent hematopoietic cell transplant or gene therapy for which survival was 100%, and 1 patient with athymia underwent a successful thymus transplant. With NBS, the researchers successfully identified all known cases of SCID. Compared with survival before NBS by TREC, survival improved significantly for infants with SCID or leaky SCID (100% [n = 9] vs 57% [n = 7]. Of 162 infants with T-cell counts <2500 but above 1500 µL, no cases of SCID were identified, but 8 infants were diagnosed with partial DiGeorge syndrome.NBS of TREC levels is highly sensitive and specific, with the ability to improve early diagnosis of SCID. When compared with historical rates of SCID diagnosis and management before TREC evaluation by NBS, screening can reduce the time to transplant (3.4 months versus 6.5 months) and improve outcomes for infants with SCID.Screening for SCID has been a significant addition to NBS programs across the country, and multiple studies have suggested this to be a cost-effective strategy. As of December 2018, all 50 states have begun to screen for SCID at birth. SCID is often unrecognized in early life, but survival improves with early diagnosis. With this study, the authors provide long-term outcomes and highlight the benefit of these programs, suggesting a 43% reduction in mortality from a condition that can be successfully treated when identified early. From these data, the sensitivity, specificity, negative predictive value, and positive predictive value can be calculated (100%, 99.7%, 100%, and 0.91%, respectively). Notably, despite high sensitivity and specificity, a population prevalence of ∼1:50 000 to 80 000 lowers the positive predictive value of screening. Although early referral to an immunologist is important in infants with abnormal TREC results, these data also suggest the absolute risk of SCID in these infants is low (<1%). Thus, when counseling families of infants with an abnormal TREC screen, there is room for cautious optimism, pending results of definitive testing. More work is needed to better understand the short- and longer-term psychosocial impacts of a false-positive NBS result for SCID on families with unaffected infants after a positive screening test result.