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ABSTRACT: Severe combined immunodeficiency (SCID) is a life-threatening disease of infants that is curable with hematopoietic cell transplantation if detected early. Population-based screening for SCID using the T-cell receptor excision circle (TREC) assay began in Wisconsin in 2008; 5 infants with SCID or other forms of severe T-cell lymphopenia (TCL) have been detected, and no infants with SCID have been missed. This review will provide an overview of the TREC screening assay and an update of the findings from Wisconsin on all infants screened from January 1, 2008, until December 31, 2010. Importantly, we give practical recommendations regarding newborn population-based screening using the TREC assay, including the evaluation and care of infants detected.
The Journal of allergy and clinical immunology 03/2012; 129(3):622-7. · 9.17 Impact Factor
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ABSTRACT: Newborn screening for early identification of T-cell lymphopenia and severe combined immunodeficiency has recently been recommended as an addition to the newborn screening programs in all states. This article will review the evidence supporting the use of this newborn screening test, and will outline the barriers to nationwide implementation, which include issues specific to this test and controversies regarding newborn screening in general.
Expert Review of Clinical Immunology 11/2011; 7(6):761-8. · 2.07 Impact Factor
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ABSTRACT: During the first 2 years of newborn screening (NBS) for severe combined immunodeficiency (SCID), 39 infants with an abnormal or inconclusive newborn screening test for SCID died prior to assessment of immune function. We investigated if SCID or primary T-cell lymphopenia likely contributed to the death of these neonates.
This study is a detailed retrospective chart review.
Medical records were available in all 39 infants. Three neonates were full-term infants whose deaths were due to congenital anomalies. Thirty-three infants were born <33 weeks estimated gestational age, and the majority of these infants died from complications of prematurity. Six infants died from sepsis: two due to maternal chorioamnionitis, two due to necrotizing enterocolitis, one due to early onset group B strep sepsis, and one from a likely nosocomial infection.
There was no evidence that SCID contributed to the cause of death in neonates with an abnormal of inconclusive NBS test for SCID.
Journal of Clinical Immunology 09/2011; 31(6):962-7. · 3.08 Impact Factor
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Journal of pediatric gastroenterology and nutrition 08/2011; 55(2):218-20. · 2.18 Impact Factor
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Deborah Accetta,
Grant Syverson,
Benedetta Bonacci,
Sreelatha Reddy,
Christine Bengtson,
Jill Surfus,
Ronald Harbeck,
Anna Huttenlocher,
William Grossman,
John Routes, James Verbsky
The Journal of allergy and clinical immunology 02/2011; 127(2):535-538.e1-2. · 9.17 Impact Factor
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ABSTRACT: Chemotaxis assays are essential tools for the study of gradient sensing and directed cell migration, and have the potential to aid in the diagnosis and characterization of patients with immune disorders. Current methods are limited in their ability to meet the more demanding requirements for clinical applications. Because patient samples have a short lifespan and sometimes a limited volume (e.g. pediatrics), the operational requirements for an efficient chemotaxis assay are increased in the clinical setting. Here we describe a microscale assay platform for gradient generation that overcomes these limitations. Passive fluidic methods are leveraged to provide a reliable microfluidic gradient generation device, operable in only three pipetting steps. In addition, arrayed imaging and advanced cell tracking algorithms enabled a 50-fold increase in throughput over current methods. These methods were employed to aid in the diagnostic evaluation of an infant who presented with severe, recurrent bacterial infections. Analysis of the infant's neutrophils revealed impaired cell polarization and chemotaxis in a gradient of the chemoattractant fMLP. The patient was subsequently diagnosed with an inhibitory mutation in the Rho GTPase, Rac2. The approach also enabled a microenvironmental screen of human primary neutrophil chemotaxis on fibronectin, fibrinogen and laminin with results suggesting that fibronectin, although commonly used, may not be the most appropriate matrix protein for chemotaxis assays. Together, these findings demonstrate the use of arrayed micro-devices to aid in the diagnosis of a primary immunodeficiency disorder, and illustrate the capability for increased throughput microenvironmental studies and screening targeted to specific human diseases.
Integrative Biology 11/2010; 2(11-12):630-8. · 4.51 Impact Factor
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ABSTRACT: A newborn blood screening (NBS) test that could identify infants with a profound deficiency of T cells may result in a reduction in mortality.
To determine if quantitating T-cell receptor excision circles (TRECs) using real-time quantitative polymerase chain reaction on DNA extracted from dried blood spots on NBS cards can detect infants with T-cell lymphopenia in a statewide program.
Between January 1 and December 31, 2008, the Wisconsin State Laboratory of Hygiene screened all infants born in Wisconsin for T-cell lymphopenia by quantitating the number of TRECs contained in a 3.2-mm punch (approximately 3 microL of whole blood) of the NBS card. Flow cytometry to enumerate the number of T cells was performed on full-term infants and preterm infants when they reached the equivalent of at least 37 weeks' gestation with TREC values of less than 25/microL. Infants with T-cell lymphopenia were evaluated by a clinical immunologist.
The number of infants with TREC values of less than 25/microL with T-cell lymphopenia confirmed by flow cytometry.
Exactly 71,000 infants were screened by the TREC assay. Seventeen infants aged at least 37 weeks' gestation had at least 1 abnormal TREC assay (TREC values < 25/microL), 11 of whom had samples analyzed by flow cytometry to enumerate T cells. Eight infants demonstrated T-cell lymphopenia. The causes of the T-cell lymphopenia included DiGeorge syndrome (n = 2), idiopathic T-cell lymphopenia (n = 2), extravascular extravasation of lymphocytes (n = 3), and a Rac2 mutation (n = 1). The infant with the Rac2 mutation underwent successful cord blood transplantation.
In a statewide screening program, use of the TREC assay performed on NBS cards was able to identify infants with T-cell lymphopenia.
JAMA The Journal of the American Medical Association 12/2009; 302(22):2465-70. · 30.03 Impact Factor
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ABSTRACT: We describe a patient with an autoinflammatory disease in which the main clinical features are pustular rash, marked osteopenia, lytic bone lesions, respiratory insufficiency, and thrombosis. Genetic studies revealed a 175-kb homozygous deletion at chromosome 2q13, which encompasses several interleukin-1 family members, including the gene encoding the interleukin-1-receptor antagonist (IL1RN). Mononuclear cells, obtained from the patient and cultured, produced large amounts of inflammatory cytokines, with increasing amounts secreted after stimulation with lipopolysaccharide. A similar increase was not observed in peripheral-blood mononuclear cells from a patient with neonatal-onset multisystem inflammatory disorder (NOMID). Treatment with anakinra completely resolved the symptoms and lesions.
New England Journal of Medicine 07/2009; 360(23):2438-44. · 53.30 Impact Factor
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ABSTRACT: Severe combined immunodeficiency (SCID) is the result of genetic defects that impair normal T-cell development. SCID babies typically appear normal at birth, but acquire multiple life-threatening infections within a few months. Early diagnosis and treatment with a bone-marrow transplant markedly improves long-term outcomes. On January 1, 2008, the newborn screening (NBS) program in Wisconsin became the first in the world to routinely test all newborns for SCID. A realtime quantitative polymerase chain reaction assay measures T-cell receptor excision circles (TRECs), which are formed during the maturation of normal T-cells. A lack or very low number of TRECs is consistent with T-cell lymphopenia. The development and validation of the TREC assay and the results of the first year of screening have been published. This article describes the process used to add SCID to the NBS panel, the establishment of follow-up capacity, and the integration of SCID screening into routine NBS workflows. The development of this expanded NBS program is described so that other states might benefit from the processes used in Wisconsin.
Public Health Reports 125 Suppl 2:88-95. · 1.27 Impact Factor
