The US Advisory Committee on Heritable Disorders in Newborns and Children was established in part to work toward uniform, evidence-based newborn screening in what has previously been a patchwork of individual state programs [3
]. The Advisory Committee solicits nominations of conditions to be added to newborn screening, commissions an independent review of evidence, and gathers input from stakeholders; upon arriving at a determination, it reports to the Department of Health and Human Services (DHHS) Secretary. SCID was first nominated in 2008, and evidence was assembled and reported in 2009 and 2010, at which time it was considered strong enough to merit a formal recommendation [4**
]. Secretary of DHHS Kathleen Sibelius endorsed SCID screening in May, 2010.
SCID includes more than 10 genetic disorders characterized by profound defects in both cellular immunity and specific antibody production, and is estimated to occur in 1/50,000 to 1/100,000 births. All SCID infants have absent or extremely low production of antigenically naïve T cells from their thymus. The combined defects of T and B cells, plus absent NK cells in some forms of SCID, severely compromise an infant’s ability to resist infections. Thus, it has long been clinically identified as infants without HIV infection who present with Pneumocystis jiroveci pneumonia and other bacterial, fungal and viral infections and failure to thrive, which is most often due to persistent enteric infection.
The rationale for SCID newborn screening, outlined in , centers on the facts that SCID is potentially treatable, but is infrequently recognized effectively prior to onset of devastating infections. SCID infants do not survive unless provided with functional immunity, but this can be achieved by hematopoietic cell transplantation (HCT) from a healthy donor [5*
], by enzyme replacement in cases of adenosine deaminase (ADA) deficiency [6
], and (although still experimental) by gene therapy for X-linked and ADA deficient SCID [7*
] (see article by Booth and Thrasher in this issue). Infants with SCID are healthy at birth and initially protected by transplacentally derived maternal IgG antibodies, but typically develop severe and opportunistic infections by age 4 to 7 months. Repeated observations have shown superior outcomes in SCID infants diagnosed at a young age, particularly those fortunate enough to have an affected relative to alert health providers of the diagnosis [8
Rationale for newborn screening for SCID.
The first suggestion that screening infants for lymphopenia could identify SCID in time for lifesaving treatment was by Buckley et al
. in 1997 [8*
]. Further retrospective analysis of cases treated by Dr. Buckley at Duke [11
], and in England [12**
], underlined the better survival of SCID infants diagnosed before developing infections. While the above studies from transplant centers showed a clear benefit for early diagnosis, a family based survey by the Immune Deficiency Foundation and Chan et al
. found even more striking differences due to higher mortality of SCID infants not recognized at birth: Half of the deceased infants were either not diagnosed pre-mortem, or were too ill to be transferred to a tertiary center for specialized treatment [13*
]. Furthermore, confirmation that >80% of SCID infants were the first known to be affected in their family indicated that family history taking would not be helpful in diagnosing most cases of SCID. Additional rationale for the pursuit of newborn screening came from mathematical modeling by two methods, which showed that a sensitive, specific, and economical newborn screening test for SCID would be likely to be cost-effective [14
Another important development was the institution, beginning in 2006, of live attenuated rotavirus vaccination of infants at 6 weeks to 2 months of age. Infants affected with SCID whose diagnosis was not recognized received the vaccination and developed severe diarrheal disease due to vaccine-strain rotavirus [16
]. While the vaccine is specifically contraindicated in immunodeficient infants, there is no way to know whether a healthy-appearing infant at that age has SCID, other than by performing an immunological blood test. Newborn screening for SCID thus became an important consideration to balance the public health benefit of protection from rotavirus-induced diarrhea against the harm of vaccine-strain rotavirus infection caused in rare infants lacking adaptive immunity.