The case for severe combined immunodeficiency (SCID) and T cell lymphopenia newborn screening: saving lives one at a time.

Severe combined immunodeficiency (SCID) is a group of syndromes resulting from genetic defects causing severe deficiency in T cell and B cell function. These conditions are life-threatening and result in susceptibility to serious infections. SCID is often fatal in the first year of life if not detected and properly treated. SCID and related T cell lymphopenias can be detected in newborns by a simple screening test, the T cell receptor excision circle (TREC) assay, using the same dried blood spot samples already collected from newborns to screen for other genetic disorders. The TREC assay facilitates the earliest possible identification of cases of SCID before opportunistic infections, irreversible organ damage, or death, thus allowing for the possibility of curative treatment through hematopoietic stem cell transplant and gene therapy. Infants receiving hematopoietic stem cell transplant in the first few months of life, after being identified through screening, have a high probability of survival (95-100%), along with lower morbidity. The TREC assay has proven to have outstanding specificity and sensitivity to accurately identify almost all infants with SCID (the primary targets) as well as additional infants having other select immunologic abnormalities (secondary targets). The TREC assay is inexpensive and has been effectively integrated into many public health programs. Without timely treatment, SCID is a fatal disease that causes accrual of exorbitant healthcare costs even in just 1 year of life. The cost of care for just one infant with SCID, not diagnosed through newborn screening, could be more than the cost of screening for an entire state or regional population. Continued implementation of TREC screening will undoubtedly enhance early diagnosis, application of treatment, and healthcare cost savings. The Jeffrey Modell Foundation helped initiate newborn screening for SCID in the USA in 2008 and continues its efforts to advocate for SCID screening worldwide. Today, all 50 states and Puerto Rico are screening for SCID and T cell lymphopenia, with 27 million newborns screened to date, and hundreds diagnosed and treated. Additionally, there are at least 20 countries around the world currently conducting screening for SCID at various stages. Newborn screening for SCID and related T cell lymphopenia is cost-effective, and most importantly, it is lifesaving and allows children with SCID the opportunity to live a healthy life.

Clinical and economic aspects of newborn screening for severe combined immunodeficiency: DEPISTREC study results.

PURPOSE: Severe combined immunodeficiency (SCID) refers to a group of genetic disorders characterized by greatly compromised cellular and humoral immunity. Children with SCID are asymptomatic at birth, but they die from infections within the first months of life if not treated. Quantification of T-cell receptor excision circles is an extremely sensitive screening method for detecting newborns who may have SCID.The goal of the DEPISTREC study was to evaluate the feasibility of nationwide newborn screening for severe T-cell lymphopenia in France as well as its economic and clinical utility. METHODS: The test universally used for neonatal screening for SCID was the quantification of TRECs on Guthrie cards. We compared a group of 190,517 babies from 48 maternities across the country who underwent newborn SCID screening with a control group of 1.4 million babies out of whom 28 were diagnosed with SCID without such screening during the course of the study. RESULTS: Within the screening group, 62 babies were found to be lymphopenic, including three with SCID. The cost of screening ranged from 4.7€ to €8.15 per newborn. The average 18-month cost was €257,574 vs €204,697 in the control group. CONCLUSIONS: In this large-scale study, we demonstrate that routine SCID screening is feasible and effective. This screening offers the additional benefit of aiding in the diagnosis of non-SCID lymphopenia. Economic evaluation allowed us to calculate the cost per test. Newborn screening may also prevent death by SCID before any curative treatment can be administered. The difference in cost between screened and control children could not be ascertained because of the very low numbers and death of one of the children tested.

Newborn screening for severe combined immune deficiency (technical and political aspects).

PURPOSE OF REVIEW: Newborn screening for severe combined immune deficiency (SCID) has been implemented in more than half of the states in the United States. Despite the success of these programs, numerous challenges remain for implementing newborn screening. The present review will focus on technical, programmatic, and political aspects pertinent to newborn screening for SCID. (Figure is included in full-text article.) RECENT FINDINGS: Recent data from newborn screening in 11 U.S. programs suggest that the birth prevalence of SCID is higher than previous estimates. In addition, a large number of other conditions causing T-cell lymphopenia have been detected. Several European countries have initiated pilot screening for SCID. Significant cost savings for treatment of infants with SCID detected at birth, compared with later in life, has been demonstrated. Published evidence of the favorable cost-benefit ratio for screening supports implementation of universal SCID newborn screening. SUMMARY: SCID fulfills criteria for a condition that should be included in routine newborn screening. Data presented from multiple newborn screening programs in the United States and Europe have shown that high throughput screening of all newborns is cost-effective. Screening improves early detection of this life-threatening condition and follow-up studies have shown a clear improvement in survival for early treatment.

Systematic neonatal screening for severe combined immunodeficiency and severe T-cell lymphopenia: Analysis of cost-effectiveness based on French real field data.

BACKGROUND: The inclusion of severe combined immunodeficiency (SCID) in a Europe-wide screening program is currently debated. OBJECTIVE: In making a case for inclusion in the French newborn screening program, we explored the costs incurred and potentially saved by early management of SCID. METHODS: For test costs, a microcosting study documented the resources used in a laboratory piloting a newborn screening test on Guthrie cards using the T-cell receptor excision circle quantification method. For treatment costs, patients with SCID admitted to the national reference center for primary immunodeficiency in France between 2006 and 2010 were included. Costs of admission were estimated from actual national production costs. We estimated the costs for patients who underwent early versus delayed hematopoietic stem cell transplantation (HSCT; age, ≤3 vs. >3 months, respectively). RESULTS: The unit cost of the test varied between €4.69 and €6.79 for 33,800 samples per year, depending on equipment use and saturation. Of the 30 patients included, 27 underwent HSCT after age 3 months. At 1 year after HSCT, 10 of these had died, and all 3 patients undergoing early transplantation survived. The medical costs for HSCT after 3 months were €195,776 (interquartile range, €165,884-€257,160) versus €86,179 (range, €59,014-€272,577) when performed before 3 months of age. In patients undergoing late transplantation, active infection contributed to high cost and poor outcome. CONCLUSION: Early detection of SCID could reduce the cost of treatment by €50,000-100,000 per case. Assuming a €5 unit cost per test, the incidence required to break even is 1:20,000; however, if the survival advantage of HSCT before 3 months is confirmed, universal screening is likely to be cost-effective.

Assessment of thiopurine methyltransferase enzyme activity is superior to genotype in predicting myelosuppression following azathioprine therapy in patients with inflammatory bowel disease.

BACKGROUND: Myelosuppression occurs in 2-7% of inflammatory bowel disease (IBD) patients treated with azathioprine, and can be associated with reduced activity of thiopurine methyltransferase (TPMT) in some patients. It has been proposed that pretreatment assessment of TPMT status reduces the incidence of toxicity and is cost-effective. AIMS: To determine if screening for TPMT status predicts side-effects to azathioprine in patients with IBD and to ascertain whether screening by TPMT enzyme activity or genotype is superior. METHODS: Sequential IBD patients were identified and azathioprine tolerance recorded. Blood was collected for measurement of TPMT activity and TPMT*3C, TPMT*3A and TPMT*2 genotypes. RESULTS: Of 130 patients, 25% stopped azathioprine because of toxicity. Four patients experienced severe myelosuppression (WCC < 2). Eleven of 17 patients with reduced TPMT activity were heterozygotes, including one patient with marked TPMT deficiency who experienced severe myelosuppression. There was no association between intermediate TPMT deficiency and any side-effect. CONCLUSIONS: Moderate reduction of TPMT activity in heterozygotes was not associated with toxicity, but very low TPMT activity caused severe myelosuppression in one patient. This would have been predicted by measuring TPMT activity but not by genotyping. Measurement of TPMT activity may therefore be superior to genotype in predicting severe myelosuppression.