Singapore’s SCID newborn screening programme safe alongside near-universal BCG vaccination

In newborn screening programmes for Severe Combined Immunodeficiency (SCID), patients found with transient T-cell lymphopaenia (TCL) without underlying immunodeficiencies can still safely receive Bacille-Calmette-Guerin (BCG) vaccines, according to a recent Singapore study. SCID newborn screening programmes can be feasibly implemented alongside almost universal BCG vaccination.

“Singapore has successfully implemented newborn screening for SCID in 2019 … as part of the Expanded Newborn Screening Program, while retaining the practice of concomitant routine BCG vaccination at birth,” the researchers said. “Our results provide evidence that patients with transient TCL and no significant underlying primary immunodeficiency are able to tolerate BCG vaccination with no short/medium-term complications.”

Between 10 October 2019 and 9 October 2020, a total of 35,888 neonates underwent newborn SCID screening using a T-cell receptor excision circle (TREC) assay. Those with low TREC were subjected to subsequent lymphocyte subset analysis and a full blood count to better assess the severity of lymphopaenia, as well as the likelihood of SCID.

Thirty-six infants showed non-normal or persistently inconclusive TREC results, including 13 (0.04 percent, 1 in 2,760 cases) who were referred for further immunological assessment. None of these patients had maternal histories of immunosuppression or familial histories of primary immunodeficiency cases. [Front Immunol 2022;12:794221]

Of these 13 infants, 54 percent (n=7) were diagnosed with secondary TCL, including two with sepsis, two with premature trisomy 21, two with extreme prematurity, and one with partial 22q11 Syndrome. The remaining six patients (46 percent) had idiopathic TCL with no obvious cause. Five of these cases were transient, with TCL resolving by 6 months; the remaining patient had idiopathic TCL persistent beyond 1 year. The resulting incidence of clinically significant non-SCID TCL was 1 in 11,962 newborns.

Notably, none of the patients were diagnosed with SCID. As confirmation, no hospital in Singapore reported a case of SCID in the next 10 months after data collection and up until the time of writing in August 2021. According to the researchers, this suggested “that the TREC screening was highly unlikely to have missed any cases of true SCID.”

Eleven of the 13 TCL infants received the BCG vaccine, while the remaining two died before the shots could be given. Despite low TREC counts at vaccination in eight patients, low initial CD3+ T cell counts in three, and persistent significant lymphopaenia in two, none developed short- to medium-term BCG-related complications for at least 10 months after recruitment.

“Inoculation of live BCG at birth in tuberculosis (TB)-endemic countries like Singapore poses a risk of disseminated BCG disease in the small number of SCID patients who are yet to be diagnosed,” the researchers said. “However, delayed BCG vaccination may have unintended consequences on the majority of the population.” [J Infect 2012;64:543-554; Front Immunol 2017;8:808]

The present study finds that an SCID newborn screening programme can be implemented alongside near-universal BCG vaccination without posing considerable risks, they added. “To our knowledge, we are the first country to implement a national newborn SCID screening algorithm in a setting of high TB endemicity and routine neonatal BCG vaccination.”

“Longer duration of TREC screening is needed to define the exact incidence of SCID in Singapore, and to determine if the transient TCL observed during the neonatal period has any long-term significance,” the researchers said.