The Natural History of Children with Severe Combined Immunodeficiency: Baseline Features of the First Fifty Patients of the Primary Immune Deficiency Treatment Consortium Prospective Study 6901

Abstract

The Primary Immune Deficiency Treatment Consortium (PIDTC) consists of 33 centers in North America. We hypothesized that the analysis of uniform data on patients with severe combined immunodeficiency (SCID) enrolled in a prospective protocol will identify variables that contribute to optimal outcomes following treatment. We report baseline clinical, immunologic, and genetic features of the first 50 patients enrolled, and the initial therapies administered, reflecting current practice in the diagnosis and treatment of both typical (n = 37) and atypical forms (n = 13) of SCID. From August 2010 to May 2012, patients with suspected SCID underwent evaluation and therapy per local center practices. Diagnostic information was reviewed by the PIDTC eligibility review panel, and hematopoietic cell transplantation (HCT) details were obtained from the Center for International Blood and Marrow Transplant Research. Most patients (92%) had mutations in a known SCID gene. Half of the patients were diagnosed by newborn screening or family history, were younger than those diagnosed by clinical signs (median 15 vs. 181 days; P = <0.0001), and went to HCT at a median of 67 days vs. 214 days of life (P = <0.0001). Most patients (92%) were treated with HCT within 1–2 months of diagnosis. Three patients were treated with gene therapy and 1 with enzyme replacement. The PIDTC plans to enroll over 250 such patients and analyze short and long-term outcomes for factors beneficial or deleterious to survival, clinical outcome, and T- and B-cell reconstitution, and which biomarkers are predictive of these outcomes.

Immune reconstitution and survival of 100 SCID patients post–hematopoietic cell transplant: a PIDTC natural history study

“…Briefly, patients in stratum A had typical SCID (CD3 , 300/mL or maternal engraftment present and response to phytohemagglutinin (PHA) ,10% of the lower limit of normal); patients in stratum B had either: (1) leaky SCID (CD3 , 1000/mL if ,2 years of age, CD3 ,800/mL if 2-4 years of age, or CD3 , 600/mL if .4 years of age, without maternal engraftment, and either response to PHA 10-30% of the lower limit of normal, absent a response to Candida or post-immunization tetanus toxoid, or a pathologic mutation in a known SCID gene); (2) Omenn syndrome (generalized skin rash, PHA response ,30% of the lower limit of normal, .80% T cells with the CD45RO phenotype and the absence of maternal engraftment or a genotype consistent with Omenn); or (3) RD (CD3 , 300/mL, PHA response ,10% of the lower limit of normal, sensorineural deafness, and either neutrophils , 200/mL despite administration of granulocyte-colony stimulating factor or a mutation in AK2). 13,14 Due to important biological differences, patients with RD were not included in the main analyses for this manuscript and are reported only descriptively. Patients who received ERT or GT were not analyzed in this report.…”

Newborn Screening for Severe Combined Immunodeficiency in Israel

“…If untreated, infants with SCID succumb early in life to severe and recurrent infections [8]. Recent estimates, based on the results of American SCID neonatal screening, indicate an SCID incidence of 1.7:100,000 in the general population [9], but it is substantially higher in some populations.…”

“…The most common SCID phenotype in the United States (and presumably worldwide) is T-B+NK-, caused in most instances by a mutation in Interleukin 2 Receptor γ Chain (IL2RG, X-linked SCID) [8]. In contrast, the most frequent type of SCID phenotype in Israel is autosomal-recessive T-B-, whereas X-linked SCID is rare [25].…”

“…ARTEMIS then opens this hairpin to allow for joining of the selected V (D) J segments [26]. Historically, ARTEMIS mutations are very rare compared to other causes of SCID [8]. This could result from under diagnosis due to the great phenotypic variability induced by ARTEMIS mutations, with some mutations correlating to leaky SCID or combined immunodeficiency (CID) presentations [27].…”

Clinical and Epidemiological Aspects of Primary Immunodeficiency Diseases (Pid) and Early Diagnosis Options

“…Тяжелые формы ПИДС приводят к леталь-ным исходам в первые два года жизни [23,54]. Менее тяжелые формы приводят к необратимым изменениям в организме, которые значительно снижают качество жизни человека.…”