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Severe combined immunodeficiency (SCID) results from defects in the differentiation of hematopoietic stem cells into mature T lymphocytes, with additional lymphoid lineages affected in particular genotypes. In 2014, the Primary Immune Deficiency Treatment Consortium published criteria for diagnosing SCID, which are now revised to incorporate contemporary approaches. Patients with typical SCID must have less than 0.05 × 109 autologous T cells/L on repetitive testing, with either pathogenic variant(s) in a SCID-associated gene, very low/undetectable T-cell receptor excision circles or less than 20% of CD4 T cells expressing naive markers, and/or transplacental maternally engrafted T cells. Patients with less profoundly impaired autologous T-cell differentiation are designated as having leaky/atypical SCID, with 2 or more of these: low T-cell numbers, oligoclonal T cells, low T-cell receptor excision circles, and less than 20% of CD4 T cells expressing naive markers. These patients must also have either pathogenic variant(s) in a SCID-associated gene or reduced T-cell proliferation to certain mitogens. Omenn syndrome requires a generalized erythematous rash, absent transplacentally acquired maternal engraftment, and 2 or more of these: eosinophilia, elevated IgE, lymphadenopathy, hepatosplenomegaly. Thymic stromal defects and other causes of secondary T-cell deficiency are excluded from the definition of SCID. Application of these revised Primary Immune Deficiency Treatment Consortium 2022 Definitions permits precise categorization of patients with T-cell defects but does not imply a preferred treatment strategy. [ABSTRACT FROM AUTHOR]

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. Because of the advent of newborn screening for SCID and expanded availability of genetic sequencing, revision of the PIDTC 2014 Criteria was needed. 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. 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). The PIDTC 2022 Definitions describe SCID and its subtypes more precisely than before, facilitating analyses of SCID characteristics and outcomes. [ABSTRACT FROM AUTHOR]

With >36 years of data collected, PIDTC prospective (6901) and retrospective (6902) natural history studies provide an unprecedented opportunity to study hematopoietic cell transplantation (HCT) outcomes for SCID over time. Patients in this 6901/6902 analysis met PIDTC diagnostic criteria for SCID and underwent HCT. Categorial variables were analyzed between decades (a) 1982-89 (b) 1990-99 (c) 2000-09 (d) 2010-18 using the chi-square test. Continuous outcomes were compared using the Kruskal-Wallis test. Kaplan-Meier method was used for estimates of overall survival (OS). 896 children with typical (n=742) and atypical (n=154) SCID requiring HCT between 1982-2018 were enrolled. Diagnosis of SCID for reasons other than family history or newborn screening was common (60%) in early cohorts (a-c) dropping to 30% in cohort (d). Distribution of SCID genotypes changed over time (Fig 1), and novel/unknown genotypes also decreased from (a) 53% to (d) 13%, p<0.001. Due to the rise of gene therapy, there were fewer patients with adenosine deaminase deficient SCID receiving HCT in cohort (d) compared to prior decades. Median age at HCT has decreased, from 193 to 112 days of life, p<0.001. While marrow was the most common stem cell source in the 1980's (95%), currently peripheral blood stem cells and cord blood are given to 46% of patients (p<0.001). The increased use of unrelated donors parallels a decrease in mismatched related donors (Fig 2a; p<0.001). In univariate analysis, use of conditioning has increased from 12% in the 1980's to 65% currently (Fig 2b, p<0.001); contributing factors that will be evaluated in upcoming multivariate analyses include genotype, typical vs atypical SCID, and donor type. Day +100 cumulative incidence of grades 3-4 acute graft-versus-host disease (GVHD) has dropped, from 9.6% to 5.9% (p=0.02). OS has markedly improved in the last decade (Fig 3a), with 1- and 5-year OS being 90 and 87%, respectively (p=0.02). In particular, gains have been made in OS when using alternative donors (p=0.02) (Fig 3c,d) while OS for matched sibling HCT remains high (Fig 3b). This longitudinal data set, spanning the implementation of NBS and advancements in diagnostics and supportive care, highlights improved OS after HCT for SCID, including alternative donors. Exploration of decreased toxicity approaches that maintain high OS and engraftment are warranted. [ABSTRACT FROM AUTHOR]