Severe Combined Immunodeficiency · SCID

Description

Severe combined immunodeficiency, SCID, is a group of inherited disorders defined by the absence or profound dysfunction of T lymphocytes, with variable effects on B and natural killer cells. Without functional T cells, an infant cannot mount adaptive immune responses, and routine childhood infections, live vaccines, and opportunistic organisms become life-threatening. Untreated typical SCID is fatal in the first one to two years of life.

More than a dozen genes cause SCID. The most common form is X-linked SCID from pathogenic variants in IL2RG, which encodes the common gamma chain shared by several cytokine receptors; IL2RG accounts for roughly 40 to 50 percent of cases and affects boys. Adenosine deaminase deficiency, ADA-SCID, from variants in ADA, is the next most common form and is autosomal recessive. RAG1 and RAG2 variants disrupt V(D)J recombination and produce SCID without functional T or B cells. Other causes include IL7R, JAK3, DCLRE1C (Artemis), CD3 chain genes, and several rarer loci. Pooled live-birth incidence in U.S. newborn screening data is approximately 1 in 58,000, reported by Kwan and colleagues in JAMA in 2014 from the first multistate cohort.

Detection is by newborn screening on the dried blood spot using the T-cell receptor excision circle assay. The TREC assay quantifies recent thymic emigrants; SCID infants have absent or markedly low TREC counts. The condition was added to the Recommended Uniform Screening Panel in May 2010 after Wisconsin began statewide TREC screening in 2008. Universal U.S. screening was complete by 2018. A low TREC result triggers urgent referral to a pediatric immunologist for confirmatory flow cytometry, lymphocyte function testing, and gene panel sequencing. Pre-symptomatic identification, isolation from infectious exposures, withholding of live vaccines, and Pneumocystis prophylaxis change the clinical course before any definitive therapy.

Treatments to date

Allogeneic hematopoietic stem cell transplant is the established curative therapy for typical SCID. Outcome data from the Primary Immune Deficiency Treatment Consortium published by Pai and colleagues in the New England Journal of Medicine in 2014 show 5-year survival above 90 percent for infants transplanted before 3.5 months of age, before any active infection, regardless of donor type. Survival drops with later transplant and active infection at the time of conditioning. Pre-symptomatic identification through TREC screening is the mechanism that delivers infants to transplant inside this window.

Enzyme replacement therapy is available for ADA-SCID. PEG-ADA, pegademase bovine, was approved by the FDA in 1990 and provides systemic enzyme that supports lymphocyte recovery. Elapegademase-lvlr, a recombinant pegylated bovine ADA, was approved by the FDA in 2018. ERT is typically used as a bridge before definitive cellular therapy.

Gene therapy programs target the genetic SCID subtypes. Strimvelis, an autologous CD34-positive cell product transduced with a gamma-retroviral vector carrying ADA, was approved by the European Medicines Agency in 2016 for ADA-SCID and is delivered at a single center in Italy. Strimvelis was not pursued through FDA approval. Lentiviral vector gene therapy for ADA-SCID developed at UCLA and the NIH has reported sustained immune reconstitution across multiple cohorts. A lentiviral gene therapy for X-linked SCID developed at St. Jude Children's Research Hospital reported sustained T, B, and NK cell reconstitution in infants in studies published by Mamcarz and colleagues in the New England Journal of Medicine in 2019. Current FDA approval status of any specific SCID gene therapy product should be verified before claims are repeated.

Supportive care from the time of suspected diagnosis includes protective isolation, intravenous immunoglobulin, antimicrobial prophylaxis, avoidance of live vaccines, and irradiated, CMV-negative, leukoreduced blood products. Long-term immunology follow-up tracks immune reconstitution, infections, and late effects of conditioning chemotherapy.