Implementation of Universal Newborn Screening for Severe Combined Immunodeficiency in Singapore While Continuing Routine Bacille-Calmette-Guerin Vaccination Given at Birth.

Su-Wan Bianca Chan,Ee Shien Tan,Kai Liang Teh,Woei Kang Liew,Jian Yi Soh,Michaela Seng,Youjia Zhong,Chia Yin Chong,Sherry Poh,Thaschawee Arkachaisri,Soon Chuan James Lim,Koh Cheng Thoon

doi:10.3389/fimmu.2021.794221

Abstract

IntroductionSevere Combined Immunodeficiency (SCID) is generally fatal if untreated; it predisposes to severe infections, including disseminated Bacille-Calmette-Guerin (BCG) disease from BCG vaccination at birth. However, delaying BCG vaccination can be detrimental to the population in tuberculosis-endemic regions. Early diagnosis of SCID through newborn screening followed by pre-emptive treatment with anti-mycobacterial therapy may be an alternative strategy to delaying routine BCG vaccination. We report the results of the first year of newborn SCID screening in Singapore while continuing routine BCG vaccination at birth.MethodNewborn screening using a T-cell receptor excision circle (TREC) assay was performed in dried blood spots received between 10 October 2019 to 9 October 2020 using the Enlite Neonatal TREC kit. Patients with low TREC had lymphocyte subset analysis and full blood count performed to determine the severity of lymphopenia and likelihood of SCID to guide further management.ResultsOf the 35888 newborns screened in 1 year, no SCID cases were detected, while 13 cases of non-SCID T-cell lymphopenia (TCL) were picked up. Using a threshold for normal TREC to be >18 copies/μL, the retest rate was 0.1% and referral rate to immunologist was 0.04%. Initial low TREC correlated with low absolute lymphocyte counts (ALC), and subsequent normal ALC corresponded with increases in TREC, thus patients with normal first CD3+ T cell counts were considered to have transient idiopathic TCL instead of false positive results. 7/13 (54%) had secondary TCL (from sepsis, Trisomy 21 with hydrops and stoma losses or chylothorax, extreme prematurity, or partial DiGeorge Syndrome) and 6/13 (46%) had idiopathic TCL. No cases of SCID were diagnosed clinically in Singapore during this period and for 10 months after, indicating that no cases were missed by the screening program. 8/9 (89%) of term infants with abnormal TREC results received BCG vaccination within the first 6 days of life when TREC and ALC were low. No patients developed BCG complications after a median follow-up of 17 months.ConclusionNewborn screening for SCID can be implemented while continuing routine BCG vaccination at birth. Patients with transient TCL and no underlying primary immunodeficiency are able to tolerate BCG vaccination.

Highlights

Severe Combined Immunodeficiency (SCID) is generally fatal if untreated; it predisposes to severe infections, including disseminated Bacille-Calmette-Guerin (BCG) disease from BCG vaccination at birth
In infants where the T-cell receptor excision circle (TREC) assay was repeated simultaneously with the eventual lymphocyte subsets done by flow cytometry, TREC count became normal when CD3+ T cell counts were normal in 3 patients (Patient 4, 8 and 11) and TREC counts were low where CD3+ counts T cell counts were low in 3 patients (Patient 3, 6 and 12)
These findings indicated to us that the TREC counts were reflective of contemporaneous CD3+ T cell counts; we considered the patients with abnormal TREC screening but eventually normal CD3+ lymphocyte counts on flow cytometry 7 to 20 days later, to have had transient idiopathic T cell lymphopenia (TCL) that spontaneously resolved, rather than “false positive results” as referred to in earlier studies [11]

Summary

Introduction

Severe Combined Immunodeficiency (SCID) is generally fatal if untreated; it predisposes to severe infections, including disseminated Bacille-Calmette-Guerin (BCG) disease from BCG vaccination at birth. The production of a commercial Enlite TREC screening kit by PerkinElmer has facilitated implementation [9] by circumventing the logistical barrier of de novo development and validation of an in-house TREC assay This Enlite TREC kit has been consistently effective in achieving early diagnosis of SCID in newborn screening programs in California [10], Catalonia [11], France [12] and Abbreviations: BCG, Bacille-Calmette-Guerin; CDC, Centers for Disease Control and Prevention; HSCT, Hematopoietic Stem Cell Transplant; NBS, Newborn Screening; NGS, Generation Sequencing; PID, Primary Immunodeficiency Disease; SCID, Severe Combined Immunodeficiency; SD, Standard Deviation; TB, Tuberculosis; TCL, T-cell Lymphopenia; TREC, T-cell Receptor Excision Circle; USA, United States of America

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