The diagnosis of severe combined immunodeficiency: Implementation of the PIDTC 2022 Definitions

Abstract

Background: Shearer et al in 2014 articulated well-defined criteria for the diagnosis and classification of severe combined immunodeficiency (SCID) as part of the Primary Immune Deficiency Treatment Consortium's (PIDTC's) prospective and retrospective studies of SCID.

Objective: Because of the advent of newborn screening for SCID and expanded availability of genetic sequencing, revision of the PIDTC 2014 Criteria was needed.

Methods: We developed and tested updated PIDTC 2022 SCID Definitions by analyzing 379 patients proposed for prospective enrollment into Protocol 6901, focusing on the ability to distinguish patients with various SCID subtypes.

Results: According to PIDTC 2022 Definitions, 18 of 353 patients eligible per 2014 Criteria were considered not to have SCID, whereas 11 of 26 patients ineligible per 2014 Criteria were determined to have SCID. Of note, very low numbers of autologous T cells (<0.05 × 10⁹/L) characterized typical SCID under the 2022 Definitions. Pathogenic variant(s) in SCID-associated genes was identified in 93% of patients, with 7 genes (IL2RG, RAG1, ADA, IL7R, DCLRE1C, JAK3, and RAG2) accounting for 89% of typical SCID. Three genotypes (RAG1, ADA, and RMRP) accounted for 57% of cases of leaky/atypical SCID; there were 13 other rare genotypes. Patients with leaky/atypical SCID were more likely to be diagnosed at more than age 1 year than those with typical SCID lacking maternal T cells: 20% versus 1% (P < .001). Although repeat testing proved important, an initial CD3 T-cell count of less than 0.05 × 10⁹/L differentiated cases of typical SCID lacking maternal cells from leaky/atypical SCID: 97% versus 7% (P < .001).

Conclusions: The PIDTC 2022 Definitions describe SCID and its subtypes more precisely than before, facilitating analyses of SCID characteristics and outcomes.

Keywords: Omenn syndrome; SCID; Severe combined immunodeficiency; leaky/atypical SCID; newborn screening; typical SCID.

FIG 1.

Flow diagram of patients with center-diagnosed SCID proposed for enrollment on PIDTC Protocol 6901. Stratum A: patients with typical SCID planned for allogeneic HCT; stratum B: patients with atypical SCID planned for allogeneic HCT; stratum C: patients with either typical or atypical SCID planned for GT or ERT.

FIG 2.

Age at first CD3 count in months (log-scale) by PIDTC 2022 Criteria subtype classification.

FIG 3.

Relationship of absolute CD3 count to total PBMCs proliferative response to PHA for typical vs leaky/atypical SCID. Quadratic trend (black line) of higher PBMCs proliferative response to PHA in patients with higher final (using second value, when available) CD3 counts, including only patients with negative testing result for TME and omitting patients with Omenn syndrome. The PIDTC 2022 Criteria consider patients with typical SCID to be those with final (using second value, when available) CD3 counts less than 0.05 × 10⁹/L, irrespective of proliferation; most (91.8%) cases also have poor proliferation (<10%) of PBMCs to PHA (P < .001); some (red-dotted box) have modest proliferation and would have been considered leaky/atypical SCID per PIDTC 2014 Criteria. Most patients (66.1%) with CD3 counts more than 0.05 × 10⁹/L have low/normal proliferation (>10%) of PBMCs to PHA, though some (blue-dotted box) have poor proliferation (<10%) and would have been considered typical SCID per PIDTC 2014 Criteria.