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Immune reconstitution and survival of 100 SCID patients post-hematopoietic cell transplant: a PIDTC natural history
Jennifer Heimall1, Brent R Logan2, Morton J Cowan3
1Division of Allergy and Immunology, Children's Hospital of Philadelphia, Philadelphia, PA.
Insights
Severe combined immunodeficiency (SCID) patients undergoing hematopoietic cell transplantation (HCT) have a 90% survival rate. Preventing active infection before HCT is crucial for improving outcomes in SCID treatment.
Area of Science:
- Immunology
- Pediatrics
- Hematology
Background:
- Severe combined immunodeficiency (SCID) is a group of rare genetic disorders characterized by profound defects in cellular and humoral immunity.
- Allogeneic hematopoietic cell transplantation (HCT) is the primary curative treatment for SCID.
- The Primary Immune Deficiency Treatment Consortium (PIDTC) prospective natural history study aims to improve understanding and treatment of SCID.
Purpose of the Study:
- To analyze survival outcomes and factors influencing HCT success in children with SCID.
- To evaluate the impact of pre-HCT infection status and other clinical variables on survival.
- To assess immunologic reconstitution and identify predictors of poor outcomes post-HCT.
Main Methods:
- Analysis of 68 typical SCID and 32 leaky SCID/Omenn syndrome/reticular dysgenesis patients treated with HCT between 2010-2014.
- Data collection on diagnosis methods (newborn screening, family history), pre-HCT infection status, preparative chemotherapy, donor type, and immunologic parameters.
- Survival analysis and landmark analysis at day +100 post-HCT to identify predictors of mortality or need for second HCT.
Main Results:
- Overall 2-year survival was 90%. Patients infection-free at HCT had 95% survival vs. 81% with active infection (P = .009).
- Preparative chemotherapy improved CD4 counts and reduced IV immunoglobulin need but did not affect other reconstitution parameters.
- Post-HCT, low CD3, CD8, CD45RA counts, or restricted T-cell receptor repertoire predicted the need for a second HCT or death.
Conclusions:
- Active infection remains the most significant threat to survival in SCID patients undergoing HCT.
- Newborn screening effectively enables early SCID diagnosis, but strategies to ensure patients are infection-free pre-HCT are urgently needed.
- Further prospective trials are required to validate approaches for achieving infection-free HCT and optimize long-term outcomes.
Abstract:
The Primary Immune Deficiency Treatment Consortium (PIDTC) is enrolling children with severe combined immunodeficiency (SCID) to a prospective natural history study. We analyzed patients treated with allogeneic hematopoietic cell transplantation (HCT) from 2010 to 2014, including 68 patients with typical SCID and 32 with leaky SCID, Omenn syndrome, or reticular dysgenesis. Most (59%) patients were diagnosed by newborn screening or family history. The 2-year overall survival was 90%, but was 95% for those who were infection-free at HCT vs 81% for those with active infection (P = .009). Other factors, including the diagnosis of typical vs leaky SCID/Omenn syndrome, diagnosis via family history or newborn screening, use of preparative chemotherapy, or the type of donor used, did not impact survival. Although 1-year post-HCT median CD4 counts and freedom from IV immunoglobulin were improved after the use of preparative chemotherapy, other immunologic reconstitution parameters were not affected, and the potential for late sequelae in extremely young infants requires additional evaluation. After a T-cell-replete graft, landmark analysis at day +100 post-HCT revealed that CD3 < 300 cells/μL, CD8 < 50 cells/μL, CD45RA < 10%, or a restricted Vβ T-cell receptor repertoire (<13 of 24 families) were associated with the need for a second HCT or death. In the modern era, active infection continues to pose the greatest threat to survival for SCID patients. Although newborn screening has been effective in diagnosing SCID patients early in life, there is an urgent need to identify validated approaches through prospective trials to ensure that patients proceed to HCT infection free. The trial was registered at www.clinicaltrials.gov as #NCT01186913.
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