Inherited deficiencies of the adaptive immune system are rare diseases, but the consequences of such diseases are grave because affected infants and children are rendered susceptible to life-threatening infections. Among the inherited immunodeficiency syndromes, severe combined immunodeficiency (SCID) presents particularly complex diagnostic and therapeutic challenges because the syndrome is diverse at both the genetic and cellular levels. Transplantation of allogeneic hematopoietic stem cells has long been known to be curative in children for whom a suitably matched allograft is available. Outcomes for recipients of unrelated grafts and older children appeared to be less successful than those observed for patients who have a matched sibling donor; however, the rarity of the condition, in conjunction with the variability of transplantation approaches used in clinical studies, compromised the quality of evidence on which such impressions were based.
Now, by retrospectively analyzing transplantation outcomes in 240 children treated at 25 North American centers, Dr. Sung-Yun Pai and colleagues, on behalf of the Primary Immune Deficiency Consortium, provide compelling data that can be used to guide more rationally the management of patients with SCID. Predictably, patients in the study were genetically diverse and heterogeneous in terms of donor source, conditioning regimen, and graft-versus-host disease (GVHD) prophylaxis. Nonetheless, the authors found that the presence of prior infections and older age at the time of transplantation were key factors that predicted for shorter survival. The authors suggested that because infants younger than 3.5 months at the time of transplantation had less time and fewer opportunities to develop invasive infections and resulting organ compromise, they fared best, with a 94 percent overall survival at five years, regardless ofdonor type. This interpretation was supported by the observation that children who were older but without a history of infection did nearly equally well (90% five-year survival). Other noteworthy findings included the relationship between immune reconstitution and graft source (more favorable for matched sibling donors) and the impact of pretransplant conditioning (more favorable for reduced-intensity or myeloablative). The genetic subtype of SCID affected the quality of CD3+T-cell recovery but not of survival. Together, the findings of this study suggest that transplants from donors other than matched siblings are associated with excellent survival among infants with SCID identified before the onset of infection, and that all available graft sources are expected to lead to excellent survival among asymptomatic infants.
The impact of early diagnosis and prompt treatment on survival is particularly exciting when considered alongside a recent report on the results of newborn screening for primary immunodeficiency diseases. Dr. Antonia Kwan and colleagues reported on the results of a SCID screening program that included 3 million infants from 10 states and the Navajo Nation. Those investigators found that molecular testing for T-cell receptor excision circles provides a cost-effective screening tool that can be efficiently combined with flow-cytometry when necessary for validation of selected cases. Using this approach, the study found that the incidence of SCID (one in 58,000 births) is higher than generally thought. Remarkably, no cases of SCID were missed in the target population, nor did this strategy result in false-positive assignment of disease. These results clearly illustrate that there are currently available cost-effective diagnostic techniques that can reliably identify SCID patients based on analysis of postnatal blood spots. This study also validates the U.S. Department of Health and Human and Services’s 2010 recommendation to expand SCID testing in newborn screening panels beyond the 23 states currently participating in the program.
The value of disease screening is ultimately tied to the effectiveness of available therapeutic interventions, and, when considered together, these two timely studies make a compelling case for nationwide SCID screening. Dr. Kwan and colleagues acknowledge that the molecular techniques used for screening must be standardized, and they emphasize the importance of improving existing administrative infrastructure to allow for more efficient and timely referral of patients.
In Brief
Collaborative group studies such as these can provide unique insights into the natural history of rare diseases. Together, the studies of Dr. Kwan and colleagues and Dr. Pai and colleagues show that genetic screening can identify patients with inherited immunodeficiencies, enabling the opportunity for expedited referral at a time when stem-cell transplantation serves as an effective, and almost uniformly successful treatment option. While the high cost of the transplantation procedure cannot be ignored, the upfront cost of transplantation compares favorably with the cumulative cost of noncurative approaches that merely address the downstream complications of primary immunodeficiencies. Disease prevention remains the most clinically beneficial and cost-effective strategy for long-term health improvement in the population. Avoiding much of the medical, emotional, and financial burden currently facing patients and their families should be more than sufficient motivation to implement nationwide screening and preemptive treatment programs for SCID and other well-characterized inherited diseases.
Competing Interests
Drs. Nemecek and Kurre indicate no relevant conflicts of interest.
