Newborn screening (NBS) program experience for severe combined immunodeficiency (SCID ... · 2018-12-01 · Newborn screening (NBS) program experience for severe combined immunodeficiency
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Newborn screening (NBS) program experience for severe combined immunodeficiency (SCID) diagnostic in catalonia Andrea Martín Nalda Pediatric Infectious Diseases and Immunodeficiencies Unit. Hospital Universitari Vall d'Hebron. Barcelona 1 1
Newborn screening (NBS) program experience for severe combined
immunodeficiency (SCID) diagnostic in catalonia
Andrea Martín NaldaPediatric Infectious Diseases and Immunodeficiencies Unit. Hospital
Universitari Vall d'Hebron. Barcelona
11
440.000 births/yearNewborn screening in Spain
Ongoing since 1968Different programs according to each autonomous community:
from 2 to 23 disorders!
2
Why SCID for newborn screening?
“Is a disease without
specific early symptoms that
cause a severeand irreversible damage and
with an effective therapy”
3Chinn IK, Shearer WT. Immunol Allergy Clin North Am.2015
NBS criteria SCIDSevere disease All patients die before
1y age
Disease not detected with physical examination
Newborn babies areasymptomatic at bird
Frecuency:Carnitine deficiency
1:100.000
Frecuency:SCID: 1.40.000
Confirmatory test Lymphocyte count(flow cytometry)
Early treatment improvessurvival
Survival >90% withtherapy
Curative therapy Stem cell trasplantation, gene
therapy
Newborn screening costeffective
TRECs assay
Adaptation of Wilson and Jungner.World health organization.1968 3
Before the diagnosis…
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Pai SY et al.N Engl J Med. 2014
Brown L. Blood.20114
Moderador
Notas de la presentación
Data collected by the Primary Immune Deficiency Treatment Consortium demonstrate survival rates of 94 % for those treated with hematopoietic stem cell transplantation in the first 3.5 months of life, 90 % in older infants without infections, and 82 % in those with resolved infections. In contrast, survival of infants older than 3.5 months with active infection during transplant was only 50 %, indicating that early diagnosis of SCID improves outcome Chan et al.11 reported an infant mortality rate of 42% for 138 neonates who were not tested at birth compared to a 15% mortality rate for 20 neonates who were tested at birth. Moreover, early diagnosis of SCID was also proved to be relatively cost-effective in spite of the low incidence of the disease.
Before the diagnosis…
Best survival rates in SCIDpatients are achieved with
early diagnosis beforeinfections
5
Pai SY et al.N Engl J Med. 2014
Brown L. Blood.20115
Moderador
Notas de la presentación
Data collected by the Primary Immune Deficiency Treatment Consortium demonstrate survival rates of 94 % for those treated with hematopoietic stem cell transplantation in the first 3.5 months of life, 90 % in older infants without infections, and 82 % in those with resolved infections. In contrast, survival of infants older than 3.5 months with active infection during transplant was only 50 %, indicating that early diagnosis of SCID improves outcome Chan et al.11 reported an infant mortality rate of 42% for 138 neonates who were not tested at birth compared to a 15% mortality rate for 20 neonates who were tested at birth. Moreover, early diagnosis of SCID was also proved to be relatively cost-effective in spite of the low incidence of the disease.
The adecuate screening test?
The dried blood spot samples
already collected for
routine newborn screening (NBS)
for other conditions
Robert R. Guthrie (1916-1995)
6Guthrie R and Susi A.Pediatrics.1963
The only assay with adequate sensitivity and specificity as well as cost
effective method for SCID NBS
NBS06.Newborn Blood Spot Screening for Severe Combined Immunodeficiency by Measurement of T-cell Receptor Excision Circles, 1st Edition
Chan K et al. J Allergy Clin Immunol 2005
T-cell receptor excision circle (TREC) assay
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Moderador
Notas de la presentación
In 1958, a 15-month-old girl was diagnosed with phenylketonuria (PKU), a potentially life-threat-ening metabolic disease. A few years later, her uncle, Dr Robert Guthrie, an American microbiologist, published his seminal paper on the feasibility of mass screening for PKU, using a bacterial inhibition assay and dried blood spot (DBS) samples. This innovation can be regarded as the birth of newborn screening (NBS). Over the last 50 years, NBS has been an acclaimed success, and many thousands of children have been saved from devastating effects of severe inborn metabolic disorders, congenital endo-crinopathies, hemoglobinopathies, and other genetic disorders because of early diagnosis of their conditions. Many countries across the globe have made NBS mandatory The addition of KREC based screening would allow identification of concurrent B cell lymphopenia, including patients with delayed-onset ADA-SCID, however a systematic evaluation of the effectiveness of additional KREC screening is not available yet. Con la SCID se criban 24 enfermedades en la prueba del talon en catalunya
LAST UPDATE – AUGUST 2018
which countries have SCID NBS?
77
2008
2017
Study protocol for these
patients in our hospital
SCID-NBS in Catalonia (January 2017)
88
Moderador
Notas de la presentación
Estudio OLAF. Continuación: Inicialmente, se emplearon puntos de corte conservadores con TRECS < 15/l, KRECS < 10/l. Con estos límites, el 0,75% de las muestras testadas resultaron patológicas en nuestra población. Otros grupos han comunicado cifras de 0,08-4,1%, dependiendo del punto de corte usado13,20,21. Estudios poblaciones con un número elevado de muestras patológicas serían inviables, puesto que para nuestra área de salud (25.000 partos/ano) ˜ esta tasa se traduciría en la necesidad de repetir el ensayo a 188 muestras al ano. ˜ Tres motivos pueden contribuir a encontrar esta elevada tasa re-test: a) la baja calidad de muestras de sangre seca pre-análisis; b) la curva de aprendizaje de metodología y el uso apropiado de la infraestructura establecida, y finalmente, c) puntos de corte conservadores. Al repetir las muestras patológicas, todas menos una presentaron valores por encima de los puntos de corte iniciales (0,09%). Esta tasa re-call es considerada adecuada para este tipo de estudio19. Considerando unos puntos de corte más restrictivos (TRECS < 8/l y KRECS < 4/l), se observó que todas las muestras mostraban resultados normales (no patológico). Datos recientes publicados por el grupo británico de Gaspar et al. y el grupo de Borte et al. (comunicación personal) son similares e indican la necesidad de determinar el punto de corte específico para cada laboratorio y población. El objetivo final tiene que ser la disminución de la tasa de re-test. Para ello es importante cuidar y mejorar la calidad de las muestras y hallar el punto de corte adecuado para la población espanola. ˜ Esto implica una comunicación estrecha con los centros de salud asociados. Así se reducen tanto gastos como ansiedad familiar innecesarios y, en casos aislados, evita la necesidad de extraer una nueva muestra en el recién nacido (re-call). Neonatos prematuros pueden presentar con mayor frecuencia resultados falsos positivos en el ensayo y requieren, por lo tanto, un manejo diferente, tal como se detalla en la figura 1.
TRECs≤ 34 copies/µL
Repetition of the same sample in duplicate
> 20 copies/µLin 2 of 3 TREcs results
≤ 20 copies/µLIn 2 of 3 TREcs results
Term newborn (≥ 37 weeks) Preterm newborn (< 37 weeks)
-T CD4+ and CD8+ (HLA-DR)-TCR repertoire (αβ/γδ TCR)-Lymphoproliferation assay
-IgG, IgA,IgM and IgECMV urine
POSITIVE DETECTION
No lymphopeniaNormal ImmunophenotypeNormal TRECs at 3-6 months
Lymphopenia without SCID criteria SCID suspicion
Stop Follow -up
Array (22q11)AFP (>12m)
Normal
PID genepanel
323 genes including ATM
+ Psychologist
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STUDY PERIOD 01.01.2017à28.02.2018Analyzed samples 81.040Re study 1ª sample 2,76%Request 2ª sample 0,14% Positive result 0,03% (n=19)“Non SCID babies” 89% (n=17)
STUDY PERIOD 01.01.2017à31.08.2018Confirmed SCID babies
