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Clinical Immunology (2011) 139, 360–362

Letter to the Editor

Early versus delayed diagnosis of SCID:Triumph versus tragedy

As Chan et al. [1] demonstrate in a family survey-basedevaluation of detection and outcome of severe combinedimmunodeficiency (SCID) patients in the US, there is asignificant discrepancy between outcomes of North AmericanSCID patients based on age of diagnosis. This discrepancy wasalso described by Brown et al. [2] showing differences inoutcomes between first-in-family SCID patients and later-bornaffected members at two UK centers. These excellent reviewsdocument the disparity of outcomes between children bornwith SCID and other serious T cell disorders whose diagnosiswas delayed as compared to those children diagnosed in thefirst few weeks of life. Definitive therapy with hematopoieticstem cells from various donors is life-saving in most cases ofSCID when given within the first 3.5 months of life [3]. Forexample, for infants tested for SCID near birth, 85% surviveafter stem cell transplant, whereas with those children withdelayed diagnosis, only 58% survived [1]. Debilitating in-fections acquired prior to stem cell transplant are amajor partof this lower percent survival [4–6]. Development of the T cellreceptor excision circle (TREC) assay for documentation of lownumbers of T cells at birth has been a major step toward thegoal of universal screening of neonates for SCID and otherserious T cell disorders [7]. Currently, Wisconsin, Massachu-setts, California, NewYork, Louisiana, and Puerto Rico providefor universal SCID screening. Other states have voted forsimilar programs but have not implemented them. Withlooming state budget shortfalls, it is important to keep thisissue at the forefront of public concern. To this aimwe presentthe divergent outcomes of a sister–brother pair with SCIDdiagnoses at 10 months and 1 month, respectively, thatpoignantly illustrate the need for the earliest application oftranslational science to children, the future of the world.

After an uneventful neonatal period, a female first-borninfant in a Mennonite community with immigration histories ofGermany to Canada (1820s), Mexico (1920s), and USA (1980s)became ill at 3 months of age with chronic diarrhea, vomiting,and failure to thrive, despite previous well baby care androutine immunizations. The infantwas seen in rural outpatientclinics and hospital emergency rooms for periods of vomitinganddiarrheaunchangedby formula adjustments. At 10 monthsof age she worsened with significant cough necessitatingadmission to the pediatric intensive careunit at a local hospitaland subsequently to Texas Children's Hospital. The child

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equired mechanical ventilation for severe pneumonia andhest tube placements for repeated pneumothoraces. Lowerng and blood cultures contained Enterobacter sp. anderratia sp., cytomegalovirus, and HHV6 virus by culture orCR assay. Rotavirus particles were found in the stool. She waslaced on appropriate antibacterial and antiviral medications.munological studies revealed a child with T-B + NK + SCID.fter clinical stabilization at 12 months of age the childeceived a mild preconditioning regimen and a paternal,aploidentical, T-cell-depleted peripheral blood stem cellransplant. Because of failure to engraft, at 13 months of age,he child was more rigorously conditioned and received aecond paternal bone marrow transplant followed by severeraft-versus-host disease. Despite all attempts to rescue thehild, respiratory and gastrointestinal complications pro-ressed and the child expired 4 months later.Because of the history of SCID in a previous sibling, themale

ibling, born 3 years later was tested on day one of life,evealing a T-B + NK + SCID phenotype. At 5 days of life, thehildwas transferred toTexasChildren's Hospitalwhere hewaslacedon reverse isolation in the bonemarrow transplant unit.ene sequencing studies on the child's bloodmononuclear cellsPHA-unresponsive) and on EBV-transformal B cells of his sistererformed in the Department of Immunology and Allergy atick Children's Hospital, Toronto, revealed CD3δ SCID defi-iency in both children. At the time of preconditioning withusulfan, cyclophosphamide, and fludarabine, the brotherwashriving and had gained 3 kg of weight and was withoutfection (Fig. 1). Hewas then successfully transplantedwith a/6 matched umbilical cord blood sample. Subsequently, hexperienced 100% donor cell engraftment (day +13) andature T development and significantmitogenic and antigenicmpho-proliferation (day +42) post-placental stem cellransplantation. Mild GVHD of the skin and transient throm-ocytopenia have been his only complications to date.The opportunity for early definitive treatment of SCID was

iscordant in this brother–sister pair. The sister was delayed inoming to a diagnosis because primary care personnel were notufficiently educated about the signs and symptoms of a seriousmune deficiency and there was no newborn screening for

CID in the state in which she was born. By the time a correctiagnosis had beenmade for the sister, several life-threateningfections had taken hold, including possibly that from anttenuated rotavirus vaccine [8], rendering reconstitution byonemarrow stemcells difficult. In contrast, a diagnosis of SCIDasmade in the brother before 1 month of life and hewas givencord blood stem cell transplant without the simultaneous

need to treat severe infections. Although the success of the

.

Figure 1 5 week old boy with CD3δ SCID 1 week prior tohematopoietic stem cell transplantation.

361Letter to the Editor

brother's transplant cannot be determined so soon aftertransplant (currently 2 months) and depends upon many otherconditions such as HLA-matching and type of donor, his chancesfor a favorable outcome are considerably enhanced comparedto those of his sister. This contrast of opportunity by earlydiagnosis and definitive treatment is a powerful argument foruniversal neonatal screening for T cell deficiencies.

Without treatment, SCID is a life threatening immunode-ficiency with 100% mortality due to infection and failure tothrive. The diagnosis of SCID is a critical step in theirdefinitive treatment of affected children as signs andsymptoms of SCID may be missed by primary physicians ormay not be present. The case for newborn screening for SCIDhas been made several times, e.g., Baker et al. [9] and Haleet al. [10], for the majority of states in the US that are notcurrently participating in this newborn screening. Thisexample of two siblings with CD3δ deficiency, one withearly diagnosis, the other with delayed diagnosis because oflack of awareness of the signs and symptoms of SCID, offers aclear teaching example of the need to educate the publicand medical communities alike of the critical need for auniversal neonatal screening program for SCID.

Acknowledgments

We thank the parents of the family of the two patients in thisreport. The NIAID funded Primary Immune DeficiencyTransplant Consortium (AI082978) supported this research.

The authors have no conflicts of interest with regards tothe contents of this article.

References

[1] A. Chan, C. Scalchunes, M. Boyle, J. Puck, Early vs. delayeddiagnosis of severe combined immunodeficiency: a familyperspective survey, Clin. Immunol. 138 (2011) 3–8.

[2] L. Brown, J. Xu-Bayford, Z. Allwood, M. Slatter, A. Cant, E.Graham Davies, P. Veys, A.R. Gennery, H.B. Gaspar, Neonataldiagnosis of severe combined immunodeficiency leads tosignificantly improved survival outcome: the case for newbornscreening, Blood (2010)8 2010-08-300384v1. (2011).

[3] R.H. Buckley, Molecular defects in human severe combinedimmunodeficiency and approaches to immune reconstitution,Annu. Rev. Immunol. 22 (2004) 625–644.

[4] N.C. Patel, J. Chinen, H.M. Rosenblatt, I.C. Hanson, R.A. Krance,M.E. Paul, S.L. Abramson, L.M.Noroski, C.M.Davis, F.O. Seeborg,S.B. Foster, K.S. Leung, B.S. Brown, J. Ritz, W.T. Shearer,Outcomes of severe combined immunodeficiency patientstreated with hematopoietic stem cell transplantation with andwithout preconditioning, J. Allergy Clin. Immunol. 124 (2009)1062–10698 E1-4.

[5] M.D. Railey, Y. Lokhnygina, R.H. Buckley, Long-term clinicaloutcome of patients with severe combined immunodeficiencywho received related donor bone marrow transplants withoutpre-transplant chemotherapy or post-transplant GVHD prophy-laxis, J. Pediatr. 155 (2009) 834–840.

[6] A.R. Gennery, M.A. Slatter, L. Grandin, P. Taupin, A.J. Cant, P.Veys, P.J. Amrolia, H.B. Gaspar, E.G. Davies, W. Friedrich, M.Hoenig, L.D. Notarangelo, E. Mazzolari, F. Porta, R.G.M. Bredius,A.C. Lankester, N.M. Wulffraat, R. Seger, T. Gungor, MD, A.Fasth, P. Sedlacek, B. Neven, S. Blanche, A. Fischer, M.Cavazzana-Calvo, P. Landais, on behalf of members of the InbornErrorsWorking Party of the European Group for Blood andMarrowTransplantation and European Society for ImmunodeficiencyNewcastle Upon Tyne and London, United Kingdom, Paris,France, Ulm, Germany, Brescia, Italy, Leiden and Utrecht, TheNetherlands, Zurich, Switzerland, Goteborg, Sweden, andPrague, Czech Republic, Transplantation of hematopoietic stemcells and long-term survival for primary immunodeficiencies inEurope: entering a new century, do we do better? J. Allergy Clin.Immunol. 3 (2010) 602–610.

[7] K. Chan, J. Puck, Development of population-based newbornscreening for severe combined immunodeficiency, J. AllergyClin. Immunol. 115 (2005) 391–398.

[8] R.L. Werther, N.W. Crawford, K. Boniface, C.D. Kirkwood, J.M.Smart, Rotavirus vaccine induced diarrhea in a child withsevere combined immune deficiency, J. Allergy Clin. Immunol.124 (2009) 600.

[9] M.W. Baker, R.H. Laessig, M.L. Katcher, J.M. Routes, W.J.Grossman, J. Verbsky, D.F. Kurtycz, C.D. Brokopp, Implement-ing routine testing for severe combined immunodeficiencywithin Wisconsin's newborn screening program, Public HealthRep. 125 (Suppl2) (2010) 88–95.

[10] J.E. Hale, F.A. Bonilla, S.Y. Pai, J.L. Gerstel-Thompson, L.D.Notarangelo, R.B. Eaton, A.M. Comeau, Identification of aninfant with severe combinedimmunodeficiency by newbornscreening, J. Allergy Clin. Immunol. 126 (2010)8 Letters to theEditor 1073–1074.

Sarah NicholasDepartment of Pediatrics, Baylor College of Medicine &

Section of Allergy and Immunology,Texas Children's Hospital, 1102 Bates, Suite 330,

Houston, TX 77030, USACorresponding author at: Texas Children's Hospital,

Section of Allergy and Immunology, 1102 Bates, Suite 330(FC330), Houston, TX 77030, USA. Fax: +1 832 825 7131.

E-mail address: sknichol@bcm.edu.

Robert A. KranceDepartment of Pediatrics and Section of Hematology-

Oncology and Center for Cell and Gene Therapy, BaylorCollege of Medicine & Pediatric Stem Cell Transplant

Program, Texas Children's Hospital,1102 Bates, TXFC-163014, Houston, TX 77030, USA

E-mail address: rkrance@bcm.edu.

362 Letter to the Editor

I. Celine HansonJavier Chinen

Department of Pediatrics, Baylor College of Medicine &Section of Allergy and Immunology,

Texas Children's Hospital, 1102 Bates, Suite 330,Houston, TX 77030, USA

E-mail addresses: ichanson@texaschildrens.org(I.C. Hanson), jxchinen@texaschildrens.org (J. Chinen).

Robert J. MamlokTexas Tech School of Medicine & Allergy and AsthmaAssociates of Lubbock, 5424 19th Street, Suite #311,

Lubbock, TX 79407, USAE-mail address: robertmam@gmail.com.

Chaim M. RoifmanHospital for Sick Children, Division of Immunology/

Allergy and Infection, Immunity, Injury andRepair Program, 555 University Avenue, Toronto,

Ontario, Canada, M5G 1X8E-mail address: chaim.roifman@sickkids.ca.

William T. ShearerDepartment of Pediatrics, Baylor College of Medicine &

Section of Allergy and Immunology,Texas Children's Hospital, 1102 Bates, Suite 330,

Houston, TX 77030, USA⁎Corresponding author at: Texas Children's Hospital,

Section of Allergy and Immunology, 1102 Bates, Suite 330(FC330), Houston, TX 77030, USA. Fax: +1 832 825 7131.

E-mail address: wtsheare@texaschildrens.org

10 March 2011