SCID Prevalence Double Previous Estimates

Diana Phillips

August 19, 2014

Twice as many infants may be affected by severe combined immunodeficiency (SCID) than previously believed, a study has shown.

The findings, published in the August 20 issue of JAMA, support the view that the group of rare, heritable immune disorders has previously been underdiagnosed in infants with fatal infections and suggest that population-wide newborn screening for SCID, as per national guidelines, is an effective mechanism for altering the course of the potentially life-threatening syndrome.

In a combined analysis of more than 3 million infants screened for SCID in 10 states and the Navajo Nation, Antonia Kwan, PhD, from the Department of Pediatrics and the Benioff Children’s Hospital, University of California, San Francisco, and colleagues identified 52 SCID cases. The overall incidence was 1 in 58,000 births, which is almost double the previous estimates of 1 in 100,000 babies, the authors report.

Caused by any of multiple different genetic defects that contribute to a combined absence of T-lymphocyte and B-lymphocyte function, SCID renders immune systems vulnerable to potentially fatal infections. Early identification, such as bone marrow transplant, enzyme replacement, or gene therapy, however, can prompt interventions to restore the immune system before the development of life-threatening infections, the authors explain.

To this end, newborn screening using the T-cell receptor excision circle (TREC) assay followed by confirmatory flow cytometry, which identifies most forms of SCID and some other conditions caused by low T-lymphocytes, was added to the nationally recommended newborn screening panel in 2010.

At this time, 23 states, the District of Columbia, and the Navajo Nation conduct population-wide newborn SCID screening. As of July 31, 2013, 11 active programs with sufficient data provided information for the current study.

Of the participating programs, 8 set the TREC assay cut-off for SCID at less than 40 TREC/μL, and 3 set it at less than 252 TREC/μL, according to an accompanying editorial by Neil A. Holtzman, MD, MPH, from the Department of Pediatrics, Johns Hopkins Medical Institutions, Baltimore, Maryland. Excluding the Navajo Nation, in which a founder effect mutation in the DCLRE1C gene increased the incidence of SCID to 1 in 3500, the ratio of total TREC-positive results to SCID infants detected by confirmatory tests was 91.1 in the programs with the most stringent cutoffs compared with 170.5 in the programs with more inclusive cutoffs, the authors report.

Of the 52 SCID cases, 42 were classified as typical SCID (fewer than 300 autologous T cells/μL), 9 were classified as "leaky" SCID (incomplete mutation in a typical SCID gene, T cells ranging from 300 to 1500/μL), and 1 was classified as Omenn syndrome, the authors report. In addition, screening identified non-SCID T-cell lymphopenia in 411 infants.

Of the 52 infants detected with SCID in the first weeks of life, 49 received immunity-restoring therapies, including hematopoietic cell transplantation (44), gene therapy (4), and adenosine deaminase enzyme replacement therapy (2).

Overall survival among the treated infants was 92%, according to the authors. Posttreatment deaths were caused by cytomegalovirus infection acquired early postnatally (n = 1), pretransplant respiratory compromise (1), and hepatic sinusoidal obstructive disease secondary to pretransplant busulfan treatment (2).

Only 4 of the 411 infants with non-SCID T-cell lymphopenia were treated; thus, the usefulness of detection of these lymphopenias by the same screening "remains to be determined," the authors conclude.

"The ability to improve outcomes is a cardinal criterion for screening and there is no doubt that newborn SCID screening has saved lives and improved their quality," Dr. Holtzman writes. "Without early detection by screening, some of the survivors most likely would have died, some of them without a diagnosis."

He continues, "Infants born with SCID in the 27 states that do not screen for SCID have a greater chance of not being detected promptly, or at all, and are at increased risk of dying, compared with those born in the 23 states that do screen for SCID." However, before screening becomes universal in the United States, "agreement is needed on what constitutes a positive TREC screening test, on ensuring referrals to physicians competent to make a diagnosis, and on providing definitive therapy to every infant detected with SCID in every state."

The authors have disclosed no relevant financial relationships.

JAMA. 2014;7:701-702, 729-738.


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