NEWBORN SCREENING FOR PRIMARY … · Antibiotics, Antifungal, Antivirus Anti BCG Intravenous immunoglobulin Enzyme replacement (ADA) as indicated Hematopoietic stem cell transplantation

NEWBORN SCREENING FOR PRIMARY IMMUNODEFICIENCIES

PILOT PROGRAMS IN SÃO PAULO AND CURITIBA - BRASIL

Sponsorship:Partners:

ANTONIO CONDINO-NETO, MD, PHD, FAAAAI

DEPARTMENT OF IMMUNOLOGY - INSTITUTE OF BIOMEDICAL SCIENCES

UNIVERSITY OF SAO PAULO

THE JEFFREY MODELL CENTER SÃO PAULO

A group of ~ 350 monogenic diseases presenting with:

recurrent infections, autoimmunity, inflammation,

allergy, and susceptibility to cancer

90% PID without diagnosis

Diagnosis delay 7 - 10 years

▪ Severe Combined Immunodeficiency

▪ Most severe form of PID

▪ Newborns usually healthy at birth

▪ Absence or low number of T cells deficiency in B and/or NK function

▪ Recurrent infections

▪ Frequent diarrhea and failure to thrive

▪ Severe, sometimes fatal reactions to vaccination

▪ Fatal without immune reconstitution

Severe Combined Immunodeficiency

SCID: Molecular / functional defects

Kelly et al, 2013. Clin Epidemiol.16;5:363-9

Klebsiela pneumoniae

SCID – Pediatric Emergency




JPL: received BCG twice


JPL

SCID – Pediatric EmergencySCID – Pediatric Emergency


Sind. Omenn / SCID

Obito pre- transplante

Sd Omenn / SCID - Pre Transplant


Post-transplant


Complications BCG/ SCID


Complications BCG/ SCID

Leaky SCID Moluscum


SCID / Death Post-transplant

JPL: BCG was found in lungs, brain and bone marrow


SCID PRE x POST TRANSPLANT

SCID – Pediatric EmergencySCID – Pediatric Emergency



Term, Birth weight 1220g, Height 35cm,

cephalic perimeter 28cm


240 SCID transplanted

2000 - 2009

25 centers

(Pai et al., 2014)

SCID: A Pediatric Emergency


2000 - 2009

25 centers

(Pai et al., 2014)



2000 - 2009

25 centers

(Pai et al., 2014)



2000 - 2009

25 centers

(Pai et al., 2014)



Treatment

▪ Antibiotics, Antifungal, Antivirus

▪ Anti BCG

▪ Intravenous immunoglobulin

▪ Enzyme replacement (ADA) as indicated

▪ Hematopoietic stem cell transplantation

▪ Gene therapy

▪ 2005: Chan and Puck described TREC quantification as a technique for NBS for SCID

▪ 2007: SCID was nominated for addition to the screening panel in the USA

▪ 2008: first NBS pilot for SCID in Wisconsin

▪ 2010: start of NBS pilot in São Paulo

▪ 2014: start of NBS pilot in Curitiba (Parana, Rondonia, RJ and SP)

▪ 2016 start of NBS PRONAS SABARA / PENSI / USP

Newborn screening for SCID

(Dorsey & Puck, 2017)

Today: Brazil (private market), USA; in part Canada, United Kingdom,

France, Italy, Sweden, Germany, pilot Iran, Taiwan, and others.

NewbornScreening

Test

Brasil 2011

2.913.000 live births

~100 SCID cases

São Paulo 2011

610.000 live births

~ 20 SCID cases

SCID incidence in São Paulo

~1/30.000 live births

How does newborn screening test for scid work?

Serana et al., 2013

T cell Receptor Excision Circles

3,2mm

PunchDNA

elution

Analysis

Healthy

newborn

Healthy adult

or

DiGeorge

newbornSCID

newborn

▪ K-deleting recombination excision circles

Van Zelm et al., 2011. Frontiers in Immunol.

KRECs

TREC and KREC> 25/ul

TREC and/or KREC< 25/ul

ALGORITHM



Normal result

ALGORITHM



Normal resultTRECKREC

B-actin

ALGORITHM




B-actin

T and K >25B-actin > 8000

ALGORITHM




B-actin

T and K >25B-actin > 8000

T and/or K <25B-actin < 8000

New Sample

ALGORITHM




B-actin

T and K <25B-actin > 8000

T and/or K <25B-actin > 8000

T and/or K <25B-actin < 8000

IMMUNOLOGIST New Sample

ALGORITHM

Valores de TRECs e KRECs para 4.490 amostras.

0.1 1 10 100 1000 100000.1

1

10

100

1000

10000Ataxia-telangiectasia

Amostras encaminhadas

Agamaglobulinemia

SCID

Hipogamaglobulinemia

TRECs/L

KR

EC

s/

L

TRECs x KRECs


Multisyndromes with Variable T-cell Deficiency

DiGeorge / 22q11.2 deletion 57%

Trisomy 21 13%

Ataxia Telangectasia 3%

CHARGE syndrome 2%

NewbornScreening

Test


Secondary T Lymphopenia

Congenital cardiac anomalies 25%

Other congenital anomalies 38%

Vascular leakage, 3rd space, hydrops 13%

Neonatal leukemia 3%

Maternal immunosuppressive medications 3-5%

Extreme preterm birth

NewbornScreening

Test

Van Zelm et al., 2011. Frontiers in Immunol.

▪ Early diagnosis;

▪ Early HSCT – better outcome;

▪ Cost-effectiveness – estimated costs:

▫ Early HCT: $120,000

▫ Late HCT: $360,000

▪ Detection of other T cell lymphopenia.

Newborn screening for SCID

TREC

8715 newborns

3 hospitals in Sao Paulo

1 hospital in Belém

49 <30 copies/ul

4 <20 copies/ul

1 premature 27w 3 normal cell count

TREC and KREC

6881 newborns

4 hospitals in Sao Paulo

1 hospital in Belém

1 hospital in Porto Alegre

1 TREC/ul and 211 KREC/ul: died at 6 days of

life, complications during pregnancy.

157 TREC/ul and 10 KREC/ul: lost follow-up

after 1st medical appointment.

Carolina Prando, MD, PhD

Maternidade

81 hospitals

545 professionals

Acre and Rondonia

State Secretary of Health

USP / PENSI / SABARA

(Dr Antonio Condino)

UFMT

UFRJHUCFF/UFRJ

Sta Casa Vitória

UFUberlandia

UEPiaui

Unicamp

UFBAC.Pediátrico Prof. Hosanah de Oliveira

HCPOAUniv Passo Fundo

H.inf Albert Sabin

CESUPA

FMRPFMSJRP

Sta Casa SPF.med ABCICB_USPFMSantosH. DiademaUNIFESP

UFRN

UFPRPequeno Principe

UFPE

Hosp Univ Brasilia

H.Infantil sec estado

UFSE

www.bragid.org.br

Centros de Referência IDPs Brasil

~30 centros / ~120 médicos

www.lasid.orgwww.bragid.org.br

[email protected]

[email protected]

Antonio Condino-Neto, MD, PhD, FAAAAI

Department of Immunology – Institute of Biomedical Sciences

University of São Paulo

The Jeffrey Modell Center São Paulo

Brazil

Agradecimentos:

Dr Jose Luiz Egydio Setubal

Dra Fatima Fernandes

Carla, Clarice e toda equipe PENSI

http://www.lasid.org/

http://www.bragid.org.br/

mailto:[email protected]

mailto:[email protected]

Documents

NEWBORN SCREENING FOR PRIMARY … · Antibiotics, Antifungal, Antivirus Anti BCG Intravenous immunoglobulin Enzyme replacement (ADA) as indicated Hematopoietic stem cell transplantation