Integration of SCID Screening into the Dutch Newborn ......Pilot SCID screening in Sweden 4 Retrospective study with 2560 freshly collected, anonymized heelprick cards and 18 cards

Integration of SCID Screening into the Dutch Newborn Screening Program

Benefits and shortcomings of the available screening assays

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SCID screening in USA● About half of the states screens half of the newborns…

APHL-NBSGTS, St. Louis| 29.02.20162

https://www.newsteps.org

Presenter

Presentation Notes

Sean McGhee Sean McGhee Clinical Associate Professor, Pediatrics - Immunology and Allergy, Stanford medicine, Newborn screening symposium, Turku Finland 27-30 June 2015. https://www.newsteps.org/scid, status november 9, 2015 http://www.piduk.org/advocacy/involvementincampaigns/sciduknewbornscreeningprogramme http://www.piduk.org/advocacy/consultationresponses http://www.piduk.org/advocacy/supportforIPOPIpositionstatements http://legacy.screening.nhs.uk/scid

Meanwhile, on the continent..

3APHL-NBSGTS, St. Louis| 29.02.2016

Presenter

Presentation Notes

Almost no one… European actives… European initiative SCID screening…

Pilot SCID screening in Sweden

4

● Retrospective study with 2560 freshly collected,

anonymized heelprick cards and 18 cards of

SCID patients (and other (B-cell-related-)

immunodeficiencies)

● Combined TREC*/KREC** - in house PCR

● National Board of Health and Welfare works on

criteria for the evaluation of NBS diseases.

* T-cell receptor excision circles

**kappa-deleting recombination excision circles


Borte et al., Blood 2012, 119(11)

Presenter

Presentation Notes

Presentatie Von Döbeln There has not been a defined process The National Board of Health and Welfare has initiated work to establish a process Criteria for the evaluation have been defined Applications will be subject to an HTA, followed by evaluation by an expert group and finally a reference group will give a recommendation to the head of the National Board of Health and Welfare, who will decide 2560 freshly collected, anonymized Guthrie cards (903;GEHealthcare) and 28 stored original cards of patients diagnosed with SCID (n18), XLA (n4), ataxia-telangiectasia (AT; n4), or Nijmegen-breakage-syndrome (NBS; n2) were included. In addition, Guthrie card samples from patients with common variable immunodeficiency (CVID; n4), immunoglobulinAdeficiency (IgAD; n15), or X-chromosomelinked hyper-IgM-syndrome (X-HIGM, CD40L defect; n 2) served as disease controls.

Recommendation Newborn screening for SCID is not recommendedinsufficient information on: ● the epidemiology of the condition in the

UK ● the performance of the test ● the management and outcomes of

babies who are detected by screening but do not have SCID

● the clinical and cost effectiveness of screening compared to current practice


Pilot SCID screening in UK

Adams et al., J Clin Immunol (2014), 34, 323-330

Presenter

Presentation Notes

Adams et al: 5081 samples met een TREC assay. well designed evaluations to assess the impact of screening, and review in three years time Assessment on twenty screening criteria of which a number was not met. Decision was not to adopt SCID screening in the UK programme. Recommendation The UK NSC is asked to agree the policy position on newborn SCID screening as follows:- Newborn screening for SCID is not recommended outside of well designed evaluations to assess the impact of screening. At present there is insufficient information on: the epidemiology of the condition in the UK the performance of the test the management and outcomes of babies who are detected by screening but do not have SCID the clinical and cost effectiveness of screening compared to current practice 13. The UK NSC is asked to agree that the policy should be reviewed in three years time unless there is significant new peer reviewed evidence in the meantime. USA States in 2011 (staat in rapport 2013 NHS-NSC) lack of cost benefit information, budgetary concerns (cost estimates for technology infrastructure estimated at $500,000–$1 million), prior commitment to implement other screening tests mandated by State legislation, lack of the widespread availability of experts in immunodeficiency within a State for diagnosis and treatment, lack of an FDA approved or cleared assay 4. Pilots are being planned in Sweden and areas of Germany and a multicentre

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Neonatal Screening. New recommendations.Dutch Health Council, The Hague, Netherlands.April 8, 2015

Dutch Health council on SCID screening● Serious health problem

● Acceptable treatment (gene therapy or

haematopoetic stem cell therapy)

● Suitable test (TREC, or TREC/KREC)

● Note-unintended findings (e.g. DiGeorge, Down

syndrome, others)

● Note-cost-effectiveness study is needed


Presenter

Presentation Notes

The Health council Screening is for the benefit of the child. aandoeningen die in aanmerking komen voor opname • Neonatale screening voorkomt aanzienlijke, onherstelbare schade en/of levert aanmerkelijke gezondheidswinst op voor het kind • Er is een testmethode van bewezen kwaliteit Kosten baten analyse, indeling in categorie 1. De commissie vindt dit nadeel van onvermijdelijke nevenbevindingen niet opwegen tegen het zojuist genoemde voordeel van verbetering van de behandeling door vroege diagnose. De sceeningstest is weliswaar gecompliceerder en duurder dan de andere neonatale testmethoden, maar lijkt binnen aanvaardbare grenzen van doelmatigheid te blijven. Wel is volgens de commissie een precieze kostenbatenanalyse aangewezen als onderdeel van de uitvoeringstoets. De commissie deelt SCID in categorie 1 in en beveelt dus opname in het neonatale screeningsprogram

Distribution of SCID patients based on genetic diagnosis

7

Pagter et al., Eur J Pediatrics 2015


1998-2013; n=43

Presenter

Presentation Notes

Anne de Pagter… Distribution of SCID patients based on genetic diagnosis. Eur J Pediatr IL-2RG IL2 receptor subunit gamma ADA – SCID = adenosine deaminase deficiency DOI 10.1007/s00431-015-2518-4 Overview of 15-year severe combined immunodeficiency in the Netherlands: towards newborn blood spot screening Anne P. J. de Pagter1 & Robbert G. M. Bredius2 & Taco W. Kuijpers3 & Jelco Tramper1 & Mirjam van der Burg1,4 & Joris van Montfrans5 & Gertjan J. Driessen1,6 & on behalf of the Dutch Working Party for Immunodeficiencies

Fate of Dutch SCID patients


Pagter et al., Eur J Pediatrics 2015

Aims of Dutch retrospective SCID study● To get first experience with DNA-analysis in the screening laboratory with

two (commercially available) TREC (/KREC) assays

● To evaluate common SCID screening algorithms

● To get an idea of TREC in samples of premature births

● To align screening, diagnostic and treatment expertise

● To supply data for an extended prospective pilot screening with an analysis

of costs


Presenter

Presentation Notes

.. In anticipation of the Health Council report..

Samples● Anonymized fresh heel prick cards (n=1295) from the Dutch Newborn

Screening

● Filter paper cards with peripheral blood of 22 patients with a clinical, genetically confirmed, SCID diagnosis, (affected genes: ADA n=2, RAG1 n=6, RAG2 n=2, IL2Rg n=4, JAK3 n=2, XLF n=2, Artemis n=2, CD3E n=2) and of 27 patients with a primary immunodeficiency (PID), potentially SCID

● Reference samples of the Newborn Screening Translational Research Initiative (CDC, Atlanta, Georgia)


Presenter

Presentation Notes

Anonymized fresh heel prick cards (n=1295) from the Dutch Newborn Screening To get first experience with two (commercially available) TREC (/KREC) assays . Filter paper cards (PerkinElmer 226 paper, PerkinElmer, Shelton, USA) were spotted with peripheral blood from 22 patients with a clinical, genetically confirmed, SCID diagnosis, (affected genes: ADA n=2, RAG1 n=6, RAG2 n=2, IL2Rg n=4, JAK3 n=2, XLF n=2, Artemis n=2, CD3E n=2) and of 27 patients with a primary immunodeficiency (PID), potentially SCID, however not confirmed by genetic analysis. To align screening, diagnostic and treatment expertise Reference samples were kindly provided by the Newborn Screening Translational Research Initiative at the Center for Disease Control and Prevention (CDC, Atlanta, Georgia)

SCREEN-ID kit (TRM Leipzig*)● Quantitative analysis of TREC, KREC

and β-actin● Real-time multiplex PCR

EnLite Neonatal TREC kit (PerkinElmer)● Semi-quantitative analysis of TREC and β-

actin● End-point PCR

Methods


*Currently: Mabtech Diagnostics, Nacka Strand, Sweden

Presenter

Presentation Notes

25 mogelijke SCID-patiënten (n=7 mutaties bekend) 5 verse monsters uit het hielprikscreeningsprogramma TCD, BCD, TBCD controles Afkapwaarden TREC <8/μl KREC <4/μl β-actine Ct>35 http://www.mabtechdiagnostics.com/products.html

Screening scheme


Re-test: 1.62%

Second sample:about 0.1%)

Results EnLite assay – samples of premature births

155 NBS cards of premature births (birth weight below ≤2500 g andGA ≤ 36.0 weeks)

● Average TREC-values; 65 copies/µl (median: 55)

● Re-test rate = 29%

13

0

50

100

150

200

250

300

350

0 155

TREC

cop

ies

/ µ

l blo

od

premature sample nr


Results PE EnLite assay –SCID patients

• 22 confirmed SCID-patiënts (average TREC values: 0.47 copies/µl blood)

• 17 of 27 SCID-inconclusivediagnosis < cut off value of 40 copies/µl blood)

14

0

50

100

150

200

250

TREC

(co

pie

s/µ

l)

confirmedSCID patients

PID patientsdiagnosis

inconclusive


Results SCREEN-ID assay (KREC/TREC-assay)

15

log(

copi

es/µ

l blo

od)


What did we learn?

● Both assays work fine in the hands of experienced and well-trained technicians

● A basically equipped PCR laboratory is sufficient

● High throughput KREC analysis seems not feasible at this time (no commercial

supply)

● Screening protocol with cut off of 40 TREC copies/µl blood (re-test rate 1.62 %)

may be adapted, with adapted policy for premature newborns

● This became a joint project of screening laboratory and clinical immunological

specialists with focus on diagnosis and treatment


Presenter

Presentation Notes

SCREEN-ID kit Eenvoudiger protocol, minder pipetteerstappen Kwantitatieve analyse KREC-analyse EnLite Neonatal TREC kit Commercieel verkrijgbaar CE-marking en GMP Kwaliteitsbewaking

What next? “To supply data for an extended prospective pilot screening with a cost-analysis”

Prospective pilot screening in three laboratories (about 30.000 samples) to test

● ICT logistics

● High throughput prospective approach

● Referral of positive results (including into clinical diagnostic routine)

● Definition of applicable cut off values (also for samples of premature

newborns)

● 330.000 euro

● TREC assay



Lennart Hammerstrøm (email 27.02.2016)

• Pilot program for both TREC and KREC (first in the world) in Stockholm

• 70.000 children screened• Three severe PID children identified. • First one, a SCID, successfully transplanted• Request made for starting nationwide screening as of late this year.

Next (2018?) on the continent…



Next (2018?) on the continent…

Acknowledgements


Maartje Blom (RIVM/LUMC)

Erasmus University Medical Centre RotterdamMirjam van der Burg Ingrid Pico-Knijnenburg

Leiden University Medical Centre(LUMC)Robbert Bredius

Nat. Inst. Public Health and the Environment (RIVM)Maartje Blom

Academic Medical Centre AmsterdamAnita BoelenMarja van Veen-Sijne

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Editor-in-ChiefDr. Ralph Fingerhut Swiss Newborn Screening Laboratory, Zurich, Switzerland [email protected]

http://www.mdpi.com/journal/neonatalscreening

(ISSN 2409-515X)

International Journal of Neonatal Screening

The official journal of the International Society for Neonatal Screening (ISNS)


We recommend IJNS for your next publication…

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Integration of SCID Screening into the Dutch Newborn ......Pilot SCID screening in Sweden 4 Retrospective study with 2560 freshly collected, anonymized heelprick cards and 18 cards