1 / 27

Newborn Screening for SCID and Other PIDs INGID 2012

Newborn Screening for SCID and Other PIDs INGID 2012. PID Classification International Union of Immunologic Societies, 2009. Combined T and B Immunodeficiencies - 27 Include all forms of SCID Predominantly Antibody Deficiencies - 21 Other well defined PIDs – 21

vlad
Download Presentation

Newborn Screening for SCID and Other PIDs INGID 2012

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Newborn Screening for SCID and Other PIDs INGID 2012

  2. PID ClassificationInternational Union of Immunologic Societies, 2009 • Combined T and B Immunodeficiencies - 27 • Include all forms of SCID • Predominantly Antibody Deficiencies - 21 • Other well defined PIDs – 21 • WAS, DiGeorge s., AT

  3. Challenges of Prompt Diagnosis of SCID • Rare disease (estimated 100 born annually in U.S.) • Sporadic cases or family history unrecognized • Generally, patients appear normal • Early infections may be indistinguishable from normal infections in infants • Early mortality from infections • Prenatal diagnosis is possible only if family history and SCID genotype is known

  4. Importance of Early Diagnosis of SCID • Provide protective isolation • Avoid acquisition of life-threatening and chronic infections • Avoid live vaccines (rotavirus, BCG) • Afford time to prepare safest and most effective immune reconstituting therapy

  5. Early vs. Late Diagnosis of SCID* • Survey of IDF patient database in 2009 • Specified SCID diagnosis • Diagnosed by expert center • Autopsy diagnosis consistent with SCID • 126 families (158 individuals) • 61 deaths confirmed * Chan et al, 2010

  6. a b aThese infants became symptomatic prior to diagnosis of their SCID. In some of these families a positive family history was ultimately recognized retrospectively. bDefinitive treatments in these infants included transplantation or enzyme replacement. Chan. Clin. Immunol. 2011

  7. Percentage of families citing particular reasons for not receiving definitive therapy among patients who were diagnosed with SCID, but died without being treated (n=14). Chan. Clin. Immunol. 2011

  8. Composition of mortality in SCID patients surveyed. Of the 61 deaths, "Not Diagnosed" were cases of SCID "Not Diagnosed" pre-mortem (dark gray); Diagnosed cases were separated into those who received (white) and those who did not receive (light gray) transplantation or enzyme replacement. Chan. Clin. Immunol. 2011

  9. Time After Treatment (months) Time After Treatment (months) Survival of treated SCID patients. (A) Patients grouped by birth year. All treated patients, solid line (81.4%, n=93); born pre-1995, dashed/dotted line (78.6%, n=28); born 1995–1999 dashed, (75%, n=24); born in 2000 or later, with no difference pre or post 2004, dotted (87.2%, n=41). (B) Patients grouped by treatment type (includes only patients reporting a single treatment, since the order of different treatments was not available); HLA matched sibling HSCT, long-dashed line (93%, n=16); haploidentical T-depleted parent HSCT, short dashed (84%, n=50); adult matched unrelated HSCT, dotted (67%, n=9); matched unrelated cord blood, solid (67%, n=9); and PEG-ADA dashed/dotted (80%, n=5). Chan. Clin. Immunol. 2011

  10. Comparison of infant mortality between those groups of neonates who were not tested (n=138, left) and tested (n=20, right) for SCID. Testing was performed only if an affected relative's SCID diagnosis had made parents and medical providers aware of the risk. Proportion of deceased infants is shaded in each pie chart. Chan. Clin. Immunol. 2011

  11. Flow chart showing survival outcomes in the 48 proband and 60 sibling cohorts. Brown. Blood. 2011

  12. Criteria for Newborn Screening • Important health problem • Detectable at birth • Early treatment improves outcomes • Benefits outweigh risks • Costs balanced against risks

  13. Programmatic criteria considered by the Wisconsin NBS Advisory Committee in evaluating the addition of SCID screening to its NBS test panel * NBS=newborn screening SCID= severe combined immunodeficiency TREC= T-cellreceptor excision circle Baker. Public Health Rep. 2010

  14. SCID Detection Assay • A small punch is taken from the blood spot on a standard Guthrie card used for other NBS • DNA is extracted from the 3.2 mm punch • T cell receptor excision circles are enumerated by RT-qPCR (TRECs) • TRECs cannot replicate, therefore they serve as a biomarker of naïve T cells that have recently emigrated from the thymus • One specific TREC is produced in approximately 70% of T cells which express the alpha/beta T cell receptor

  15. SCID Detection Assay Puck. J Allergy ClinImmunol. 2012

  16. TRECs reflect functional T cells • If TREC (or KREC) is detected , it is highly likely that the cell (T or B) has successfully created a template for a productive (and unique) T cell receptor or immunoglobulin • This process underlies the diversity of functional T and B lymphocytes

  17. SCID NBS Assay • TRECs are profoundly reduced in all forms of SCID • Including cases with maternal engraftment • TRECS are also reduced in other disorders with poor T cell production (e.g. severe DiGeorge s.)

  18. Results of initial RT-qPCR TREC assay conducted by the Wisconsin NBS Program on 5,766 NBS cards during the 2007 SCID-screening pilot studya,b aBakerMW, Grossman WJ, Laessig RH, Hoffman GL, Brokopp CD, Kurtycz DF, et al. Development of a routine newborn screening protocol for severe combined immunodeficiency. J Allergy ClinImmunol 2009;124:522-7. Reproduced with permission. b(A) TREC distribution, where the mean is 827 TRECs/3.2-mm DBS and the median is 708 TRECs/3.2-mm DBS; and (B) number of samples with ≤150 TRECs/3.2-mm DBS RT-qPCR = real-time quantitative polymerase chain reaction TREC = T-cell receptor excision circle NBS = newborn screening SCID = severe combined immunodeficiency mm = millimeter DBS = dried-blood spot Baker. Public Health Rep. 2010

  19. SCID Detection Assay • TREC assay not reliable in premature infants • TREC assay not reliable if drawn from heparinized catheter • Follow up of deceased premature infants in Wisconsin with abnormal TREC levels revealed that CODs were generally related to congenital malformations or complications of prematurity

  20. Sample newborn blood screening (NBS) algorithm. Chase. Ann. N.Y. Acad. Sci. 2011

  21. Wisconsin Newborn Screening Program severe combined immunodeficiency screening results, 2008 (n=71,000) Baker. Public Health Rep. 2010

  22. Summary of California TREC screening experience in the first year Puck. Ann. N.Y. Acad. Sci. 2011

  23. Figure 1 TREC and KREC copy numbers in dried blood spot samples (DBSS) from anonymized Guthrie cards and retested samples and in patients diagnosed with SCID, XLA, AT, NBS, X-HIGM, CVID, or IgAD. Borte. Blood. 2012

  24. NBS in U.S. • Every state has its own Dept. of Health which determines NBS • Financial considerations • (equipment is expensive: >$ 300,000 for Ohio) • Priorities • U.S. Secretary Sibelius (HHS) supports NBS for SCID • Ten states currently screening and 5 others to start early 2013

  25. Management of Patients with SCID identified by NBS(Sullivan,Puck,Routes,Filipovich*) • Issue 1: Low TRECs in prematures • Repeat until> 37 weeks • If replicate low refer for flow cytometry • Issue 2: Ideal time interval from abnormal TRECs to immunologic assessment • Less than 2 weeks • Caution family to prevent ill contacts and avoid live vaccines * J. ClinImmunol, 2012

  26. Management of Patients with SCID identified by NBS(Sullivan,Puck,Routes,Filipovich) • Issue 3: Ideal time from diagnosis to HCT • 2 wks. to 4 mos; as soon as dx is confirmed and donor is identified; 3-6 mos. • Issue 4: If gene defect not known is HCT plan modified to accommodate possible DNA repair defects • Radiation sensitivity testing is available in California • Reduced Intensity Conditioning * J. ClinImunol 2012

More Related