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HTA of the addition of severe combined immunodeficiency (SCID) to the National Newborn Bloodspot Screening Programme

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Health Technology Assessment of the addition of SCID to the National Newborn Bloodspot Screening Programme
Health Technology Assessment of the addition of SCID to the National Newborn Bloodspot Screening Programme Banner

At the request of the National Screening Advisory Committee (NSAC), the Health Information and Quality Authority (HIQA) agreed to undertake a health technology assessment (HTA) of the addition of severe combined immunodeficiency (SCID) to the National Newborn Bloodspot Screening Programme (NNBSP). The findings of this HTA were presented to NSAC to inform its recommendation to the Minister for Health.

Background

SCID is a rare, but serious inherited condition which is almost uniformly fatal in the first year of life without appropriate treatment. The condition is characterised by a low or absent T-cell count resulting in a reduced ability to fight infection. Allogeneic haematopoietic stem cell transplant (HSCT) is the primary treatment and is potentially curative. 

In Ireland, cases of SCID are currently identified by family history (typically a sibling previously diagnosed) or through clinical presentation (typically through the development of infections), and, since May 2022, through screening for ADA-SCID (one specific subtype of SCID that may be screened for using existing laboratory technology). Newborn bloodspot screening (NBS) is provided in Ireland through the NNBSP. NBS for SCID is possible through the quantification of T-cell receptor excision circles (TRECs). This form of screening has been added to a growing number of NBS programs internationally and aims to enable the earlier identification of those previously diagnosed on the basis of symptomatic presentation, thereby facilitating earlier disease management and treatment.

Methodology

This research was carried out in accordance with HIQA’s guidelines for the conduct of HTA. In summary:

  • The Terms of Reference of the HTA were agreed between HIQA and the Department of Health.
  • An Expert Advisory Group (EAG) was convened by HIQA comprising representation from relevant stakeholders. These included the Department of Health, the Health Service Executive (HSE), the National Immunisation Advisory Committee, the National Newborn Bloodspot Screening Programme (NNBSP), the National Newborn Bloodspot Screening Laboratory (NNBSL), clinicians with specialist expertise in paediatric immunology, public health, haematology, and clinical genetics, patient and public representatives (Irish Primary Immunodeficiencies Association, 22q11 Ireland, and Cuidiú), methodological experts and international screening experts. An Evaluation Team was appointed comprising HIQA staff.
  • The current NNBSP was described, along with descriptions of the diagnostic and treatment pathways for SCID and the mechanism, and international use, of TREC-based screening for SCID.
  • The epidemiology of SCID in Ireland and internationally was described.
  • Systematic reviews of the accuracy of TREC-based newborn screening for SCID, the impact of early versus late diagnosis and or HSCT for the treatment of SCID, and the cost effectiveness of newborn screening for SCID were performed.
  • The resource and budget implications of introducing newborn screening for SCID in Ireland were estimated.
  • Wider organisational, ethical, and societal implications that newborn screening for SCID may have for children, their families, the general public, and the healthcare system in Ireland were described.
  • A draft report summarising the findings of this HTA was produced and was circulated to the EAG for review. This was subsequently amended, where appropriate. 
  • The final draft of the HTA was submitted to the Board of HIQA for approval. Following its approval, the finalised HTA was submitted to NSAC for consideration and published on the HIQA website.

Advice to the National Screening Advisory Committee

SCID is a rare, but serious inherited condition which is almost uniformly fatal in the first year of life without appropriate treatment. Compared with international data, the estimated prevalence of diagnosed SCID in Ireland is relatively high at 1 in 39,760 births, with 27 patients diagnosed from 2005 to 2020. 

National and international evidence consistently suggests that earlier identification, and earlier treatment, for SCID results in better clinical outcomes for the child in terms of reduced morbidity and mortality. Children with SCID should not receive live vaccines. Early identification of infants with SCID through screening is important in order to avoid harms and to maintain confidence and trust in the national immunisation programme. 

Screening for ADA-SCID (which accounts for approximately half of SCID cases in Ireland) was implemented as part of the NNBSP in May 2022. SCID is also currently identified through risk-based detection at birth (for infants with a family history) or, later, through clinical presentation. 

The addition of TREC-based screening for SCID would enable the earlier detection of infants that will otherwise present clinically. Such screening could also detect infants that would otherwise experience early mortality prior to diagnosis. 

While considered sensitive, TREC-based screening is not specific to SCID. Other T-cell lymphopenias (TCLs) would also be identified, and it is likely that the incidence of these non-SCID TCLs detected through screening would be higher than that of SCID.

The incremental budget impact of adding TREC-based screening was estimated at €3.66 million over five years. This estimate was driven largely by the cost of the TREC test kit, new equipment, laboratory staff, and the potential for an increase in post-screening prevalence. 

There are a number of key operational challenges and considerations relevant to any decision to implement screening. These include:

  • the need to establish and verify the testing method and screening algorithm in terms of the defined screening target and the population in Ireland
  • the timing of implementation, given the scheduled move of the NNBSL to the new children’s hospital. 

From an ethical and social perspective, the benefits of screening for children with SCID, their families and the broader health system should be weighed against the potential for harm in the context of instances of false positives and the non-SCID TCLs detected through screening (not all of which would be clinically relevant or will benefit from earlier detection). 

The NNBSP has an established quality assurance programme. If TREC-based screening for SCID is implemented, consideration should be given to monitoring and evaluating the continuing relevance of screening for ADA-SCID alongside TREC-based screening.