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.

Craniospinal irradiation with concomitant and adjuvant temozolomide--a feasibility assessment of toxicity in patients with glioblastoma with a PNET component.

There is no standard treatment for glioblastoma with elements of PNET (GBM-PNET). Conventional treatment for glioblastoma is surgery followed by focal radiotherapy with concurrent temozolomide. Given the increased propensity for neuroaxial metastases seen with GBM-PNETs, craniospinal irradiation (CSI) with temozolomide (TMZ) could be a feasible treatment option but little is known regarding its toxicity. The clinical records of all patients treated at two UK neuro-oncology centres with concurrent CSI and TMZ were examined for details of surgery, radiotherapy, chemotherapy and toxicities related to the CSI-TMZ component of their treatment. Eight patients were treated with CSI-TMZ, the majority (6/8) for GBM-PNET. All patients completed radiotherapy to the craniospinal axis 35-40 Gy in 20-24 daily fractions with a focal boost to the tumour of 14-23.4 Gy in 8-13 daily fractions. Concurrent TMZ was administered at 75 mg/m(2) for seven of the cohort, with the other patient receiving 50 mg/m(2). The most commonly observed non-haematological toxicities were nausea and vomiting, with all patients experiencing at least grade 2 symptoms of either or both. All patients had at least grade 3 lymphopaenia. Two patients experience grade 4 neutropaenia and grade 3 thrombocytopaenia. Three of the eight patients required omission of TMZ for part of their chemoradiotherapy and 3/8 required hospital admission at some point during chemoradiotherapy. The addition of TMZ to CSI did not interrupt radiotherapy. Principal toxicities were neutropaenia, lymphopaenia, thrombocytopaenia, nausea and vomiting. Treatment with CSI-TMZ merits further investigation and may be suitable for patients with tumours at high-risk of metastatic spread throughout the CNS who have TMZ-sensitive pathologies.

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.

An analysis and decision tool to measure cost benefit of newborn screening for severe combined immunodeficiency (SCID) and related T-cell lymphopenia.

Severe combined immunodeficiency (SCID) is a group of syndromes resulting from genetic defects causing absence in T-cell and B-cell function, leading to serious and life-threatening infections. SCID is often fatal in the first 2 years of life if not identified and properly treated. While additional laboratory methods are being developed, the current T-cell receptor excision circle assay has proven to have outstanding specificity and sensitivity to accurately identify infants with SCID and other T-cell lymphopenia. The Jeffrey Modell Foundation (JMF) has a long history of advocacy and continues to promote newborn screening for SCID to be implemented in the United States and worldwide. Based on reports provided by California, New York, Texas, and Wisconsin on the results of their population based newborn screening programs, the overall incidence of SCID averaged 1:33,000 and T-cell lymphopenia averaged 1:6,600. JMF has developed a working algorithm or "decision tree", validated by peer-reviewed scientific literature, to be used by Public Health Departments and Health Ministries in states, countries, and regions throughout the world. This decision tool allows for local or regional data to be applied to measure the threshold and economic impact of implementing newborn screening for SCID and T-cell lymphopenia.

A Markov model to analyze cost-effectiveness of screening for severe combined immunodeficiency (SCID).

OBJECTIVE: To evaluate the cost-effectiveness of universal neonatal screening for T cell lymphocytopenia in enhancing quality of life and life expectancy for children with severe combined immunodeficiency (SCID). METHODS: Decision trees were created and analyzed to estimate the cost, life years, and quality adjusted life years (QALYs) across a population when universal screening for lack of T cells is used to detect SCID, as implemented in five states, compared to detection based on recognizing symptoms and signs of disease. Terminal values of each tree limb were derived through Markov models simulating the natural history of three cohorts: unaffected subjects; those diagnosed with SCID as neonates (early diagnosis); and those diagnosed after becoming symptomatic and arousing clinical suspicion (late diagnosis). Models considered the costs of screening and of care including hematopoietic cell transplantation for affected individuals. Key decision variables were derived from the literature and from a survey of families with children affected by SCID, which was used to describe the clinical history and healthcare utilization for affected subjects. Sensitivity analyses were conducted to explore the influence of these decision variables. RESULTS: Over a 70-year time horizon, the average cost per infant was $8.89 without screening and $14.33 with universal screening. The model predicted that universal screening in the U.S. would cost approximately $22.4 million/year with a gain of 880 life years and 802 QALYs. Sensitivity analyses showed that screening test specificity and disease incidence were critical driving forces affecting the incremental cost-effectiveness ratio (ICER). Assuming a SCID incidence of 1/75,000 births and test specificity and sensitivity each at 0.99, screening remained cost-effective up to a maximum cost of $15 per infant screened. CONCLUSION: At our current estimated screening cost of $4.22/infant, universal screening for SCID would be a cost effective means to improve quality and duration of life for children with SCID.