Screening For Severe Combined Immunodeficiency Research Articles

Implementation of screening for severe combined immunodeficiency in the neonatal screening program of the community of Madrid

Implementation of screening for severe combined immunodeficiency in the neonatal screening program of the community of Madrid

Survival After Hematopoietic Stem Cell Transplantation in Severe Combined Immunodeficiency (SCID): A Worldwide Review of the Prognostic Variables.

This study aims to perform an extensive review of the literature that evaluates various factors that affect the survival rates of patients with severe combined immunodeficiency (SCID) after hematopoietic stem cell transplantation (HSCT) in developed and developing countries. An extensive search of the literature was made in four different databases (PubMed, Embase, Scopus, and Web of Science). The search was carried out in December 2022 and updated in July 2023, and the terms such as "hematopoietic stem cell transplantation," "bone marrow transplant," "mortality," "opportunistic infections," and "survival" associated with "severe combined immunodeficiency" were sought based on the MeSH terms. The language of the articles was "English," and only articles published from 2000 onwards were selected. Twenty-three articles fulfilled the inclusion criteria for review and data extraction. The data collected corroborates that early HSCT, but above all, HSCT in patients without active infections, is related to better overall survival. The universal implementation of newborn screening for SCID will be a fundamental pillar for enabling most transplants to be carried out in this "ideal scenario" at an early age and free from infection. HSCT with an HLA-identical sibling donor is also associated with better survival rates, but this is the least common scenario. For this reason, transplantation with matched unrelated donors (MUD) and mismatched related donors (mMRD/Haploidentical) appear as alternatives. The results obtained with MUD are improving and show survival rates similar to those of MSD, as well as they do not require manipulation of the graft with expensive technologies. However, they still have high rates of complications after HSCT. Transplants with mMRD/Haplo are performed just in a few large centers because of the high costs of the technology to perform CD3/CD19 depletion and TCRαβ/CD19 depletion or CD34 + selection techniques in vitro. The new possibility of in vivo T cell depletion using post-transplant cyclophosphamide could also be a viable alternative for performing mMRD transplants in centers that do not have this technology, especially in developing countries.

A new neonatal BCG vaccination pathway in England: a mixed methods evaluation of its implementation

IntroductionThe introduction of a national evaluation of newborn screening for Severe Combined Immunodeficiency (SCID) in England triggered a change to the selective Bacillus Calmette-Guerin (BCG) vaccination programme delivery pathway, as this live attenuated vaccine is contraindicated in infants with SCID. The neonatal BCG vaccination programme is a targeted programme for infants at increased risk of tuberculosis and used to be offered shortly after birth. Since September 2021 the BCG vaccine is given to eligible infants within 28 days of birth, when the SCID screening outcome is available. We explore the experiences of those implementing the new pathway, and how they made sense of, engaged with, and appraised the change.MethodsA mixed-methods evaluation was conducted between October 2022 and February 2023. This involved national online surveys with BCG commissioners and providers and qualitative semi-structured interviews with commissioners, providers, and Child Health Information System stakeholders in two urban areas. Survey data was analysed using descriptive statistics and interview data was analysed thematically. The data was triangulated using Normalization Process Theory as a guiding framework.ResultsSurvey respondents (n = 65) and qualitative interviewees (n = 16) revealed that making sense of the new pathway was an iterative process. Some expressed a desire for more direction on how to implement the new pathway. The perceived value of the change varied from positive, ambivalent, to concerned. Some felt well-prepared and that improvements to data capture, eligibility screening, and accountably brought by the change were valuable. Others were concerned about the feasibility of the 28-day target, reductions in vaccination coverage, increased resource burden, and the outcome of the SCID evaluation. New collaborations and communities of practice were required to facilitate the change. Three main challenges in implementing the pathway and meeting the 28-day vaccination target were identified: appointment non-attendance; appointment and data systems; and staffing and resourcing. Feedback mechanisms were informal and took place in tandem with implementation.ConclusionThe new NHS neonatal BCG service specification has created an effective structure for monitoring and managing the BCG vaccination programme, but further work is required to support delivery of the 28-day vaccination target and improve uptake rates.

Newborn Screening for Severe Combined Immunodeficiency: Lessons Learned from Screening and Follow-Up of the Preterm Newborn Population.

Newborn screening (NBS) for Severe Combined Immunodeficiency (SCID) by measurement of T-cell receptor excision circles (TRECs) successfully identifies newborns with SCID and severe T-cell lymphopenia, as intended. At the same time, NBS programs face the challenge of false positive results, with a disproportionately high number in the premature newborn population. This study evaluates TREC values and SCID screening outcomes in premature newborns and elucidates evidence-based SCID screening practices that reduce unnecessary follow-up activities in this population. De-identified individual SCID newborn screening data and aggregate SCID screening data were obtained from seven states across the US for babies born between 2018 and 2020. Relevant statistics were performed on data pooled from these states to quantify screening performance metrics and clinical impact on various birth and gestational age categories of newborns. The data were normalized using multiples-of-the-median (MoM) values to allow for the aggregation of data across states. The aggregation of NBS data across a range of NBS programs highlighted the trajectory of TREC values over time, both between and within newborns, and provides evidence for improved SCID screening recommendations in the premature and low birth weight population.

Newborn screening for severe combined immunodeficiency and inborn errors of immunity.

Severe combined immune deficiency (SCID) is the most devastating genetic disease of the immune system with an unfavorable outcome unless diagnosed early in life. Newborn screening (NBS) programs play a crucial role in facilitating early diagnoses and timely interventions for affected infants. SCID marked the pioneering inborn error of immunity (IEI) to undergo NBS, a milestone achieved 15 years ago through the enumeration of T-cell receptor excision circles (TRECs) extracted from Guthrie cards. This breakthrough has revolutionized our approach to SCID, enabling not only presymptomatic identification and prompt treatments (including hematopoietic stem cell transplantation), but also enhancing our comprehension of the global epidemiology of SCID. NBS is continuing to evolve with the advent of novel diagnostic technologies and treatments. Following the successful implementation of SCID-NBS programs, a call for the early identification of additional IEIs is the next step, encompassing a broader spectrum of IEIs, facilitating early diagnoses, and preventing morbidity and mortality.

Impact of newborn screening for SCID on the management of congenital athymia

Newborn screening (NBS) programs for severe combined immunodeficiency facilitate early diagnosis of severe combined immunodeficiency and promote early treatment with hematopoietic stem cell transplantation, resulting in improved clinical outcomes. Infants with congenital athymia are also identified through NBS because of severe T-cell lymphopenia. With the expanding introduction of NBS programs, referrals of athymic patients for treatment with thymus transplantation have recently increased at Great Ormond Street Hospital (GOSH) (London, United Kingdom). We studied the impact of NBS on timely diagnosis and treatment of athymic infants with thymus transplantation at GOSH. We compared age at referral and complications between athymic infants diagnosed after clinical presentation (n= 25) and infants identified through NBS (n= 19) who were referred for thymus transplantation at GOSH between October 2019 and February 2023. We assessed whether age at time of treatment influences thymic output at 6 and 12 months after transplantation. The infants referred after identification through NBS were significantly younger and had fewer complications, in particular fewer infections. All deaths occurred in the group of those who did not undergo NBS, including 6 patients before and 2 after thymus transplantation because of preexisting infections. In the absence of significant comorbidities or diagnostic uncertainties, timely treatment was achieved more frequently after NBS. Treatment when younger than age 4 months was associated with higher thymic output at 6 and 12 months after transplantation. NBS contributes to earlier recognition of congenital athymia, promoting referral of athymic patients for thymus transplantation before they acquire infections or other complications and facilitating treatment at a younger age, thus playing an important role in improving their outcomes.

Newborn screening for severe combined immunodeficiency: changing the landscape of post-transplantation survival

Severe combined immunodeficiency (SCID) represents a group of rare monogenic immune disorders resulting from defects of the adaptive immune system. Affected patients have a high risk of fatal outcome in infancy mainly due to early overwhelming infections. 1 Tangye SG Al-Herz W Bousfiha A et al. Human inborn errors of immunity: 2022 update on the classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol. 2022; 42: 1473-1507 Crossref PubMed Scopus (134) Google Scholar Hence, timely diagnosis and therapeutic interventions shortly after birth are vital. The gold standard of treatment for SCID is allogeneic haematopoietic stem cell transplantation (HSCT), which can provide a functional immune system and is lifesaving. Measuring the effect of newborn screening on survival after haematopoietic cell transplantation for severe combined immunodeficiency: a 36-year longitudinal study from the Primary Immune Deficiency Treatment ConsortiumPopulation-based newborn screening has facilitated the identification of infants with SCID early in life, in turn leading to prompt HCT while avoiding infections. Public health programmes worldwide can benefit from this definitive demonstration of the value of newborn screening for SCID. Full-Text PDF

Measuring the effect of newborn screening on survival after haematopoietic cell transplantation for severe combined immunodeficiency: a 36-year longitudinal study from the Primary Immune Deficiency Treatment Consortium

Severe combined immunodeficiency (SCID) is fatal unless durable adaptive immunity is established, most commonly through allogeneic haematopoietic cell transplantation (HCT). The Primary Immune Deficiency Treatment Consortium (PIDTC) explored factors affecting the survival of individuals with SCID over almost four decades, focusing on the effects of population-based newborn screening for SCID that was initiated in 2008 and expanded during 2010-18. We analysed transplantation-related data from children with SCID treated at 34 PIDTC sites in the USA and Canada, using the calendar time intervals 1982-89, 1990-99, 2000-09, and 2010-18. Categorical variables were compared by χ2 test and continuous outcomes by the Kruskal-Wallis test. Overall survival was estimated by the Kaplan-Meier method. A multivariable analysis using Cox proportional hazards regression models examined risk factors for HCT outcomes, including the variables of time interval of HCT, infection status and age at HCT, trigger for diagnosis, SCID type and genotype, race and ethnicity of the patient, non-HLA-matched sibling donor type, graft type, GVHD prophylaxis, and conditioning intensity. For 902 children with confirmed SCID, 5-year overall survival remained unchanged at 72%-73% for 28 years until 2010-18, when it increased to 87% (95% CI 82·1-90·6; n=268; p=0·0005). For children identified as having SCID by newborn screening since 2010, 5-year overall survival was 92·5% (95% CI 85·8-96·1), better than that of children identified by clinical illness or family history in the same interval (79·9% [69·5-87·0] and 85·4% [71·8-92·8], respectively [p=0·043]). Multivariable analysis demonstrated that the factors of active infection (hazard ratio [HR] 2·41, 95% CI 1·56-3·72; p<0·0001), age 3·5 months or older at HCT (2·12, 1·38-3·24; p=0·001), Black or African-American race (2·33, 1·56-3·46; p<0·0001), and certain SCID genotypes to be associated with lower overall survival during all time intervals. Moreover, after adjusting for several factors in this multivariable analysis, HCT after 2010 no longer conveyed a survival advantage over earlier time intervals studied (HR 0·73, 95% CI 0·43-1·26; p=0·097). This indicated that younger age and freedom from infections at HCT, both directly driven by newborn screening, were the main drivers for recent improvement in overall survival. Population-based newborn screening has facilitated the identification of infants with SCID early in life, in turn leading to prompt HCT while avoiding infections. Public health programmes worldwide can benefit from this definitive demonstration of the value of newborn screening for SCID. National Institute of Allergy and Infectious Diseases, Office of Rare Diseases Research, and National Center for Advancing Translational Sciences.

Newborn screening for severe combined immunodeficiency: lessons from a pilot study and prospects

The expansion of the neonatal screening program in Ukraine from October 2022 became an important achievement in the development of domestic medicine. Despite the severe challenges of the war and the burden of the COVID-19 pandemic, Ukraine was able to reach the level of the leading European countries, in which screening of newborns covers more than 20 disorders. Severe combined immunodeficiencies (SCID) are among the diseases included in the program of expanded mass screening of newborns. In this article, the authors focus on the challenges they faced during the implementation of the first pilot project in Ukraine on newborn screening for severe combined immunodeficiencies using TREC and KREC assay. The method allows to determine not only SCID, but also other conditions that occur with T- and/or B-lymphopenia, which can be considered both an advantage and a disadvantage of the method, because it requires to set the certain level of cutoff. The urgency of the investigation is critically important for SCID screening. Therefore, organizational issues and the coordinated functioning of the entire screening program are of decisive importance. The conducted analysis, considering our own experience and data of other studies, outlined the issues that need to be resolved in the further implementation of screening for SCID. Improvement of the screening algorithm (with clarifying examinations when taking the second sample, or genetic examination of the SCID panel already from the first sample); determining the path of a patient with a positive TREC result; solving the issue of measuring the lymphocyte subsets by flow cytometry at the regional centers; issues of BCG vaccination and prevention of cytomegalovirus infection; conducting trainings with doctors involved in the screening program; sharing the information among the medical community and the public will improve the newborn screening program for SCID, shorten the patient’s path to diagnosis, which in the end may have a positive impact on the quality of life and life expectancy of those with severe T- and/or B-lymphopenia.

Management of newborn screening for severe combined immunodeficiency at a quaternary referral centre—an updated algorithm

Severe combined immunodeficiency (SCID) is caused by critical genetic defects affecting the immune system. Early diagnosis and intervention are essential for preventing life-threatening infections, end-organ damage, and complications. Newborn screening for SCID is currently performed in many provinces and territories across Canada. The SickKids Newborn Screening Centre in Toronto, Ontario, is a quaternary referral centre that has evaluated SCID newborn screen-positive infants since the program’s introduction in 2013. Here, we provide updated algorithms for clinical investigation and follow-up of infants with an initial positive screen. Statement of novelty: We provide algorithms for the clinical follow-up of SCID newborn screen-positive infants at a quaternary referral centre.

Newborn screening has improved the survival of infants with severe combined immunodeficiency (SCID) – a Primary Immune Deficiency Treatment Consortium (PIDTC) study

BackgroundProspective/retrospective protocols of the PIDTC have collected detailed data from children undergoing allogeneic hematopoietic cell transplantation (HCT) for SCID at 33 North American centers since 1982. We previously reported that from 1982 to 2009, overall survival (OS) after HCT was unchanged. Newborn screening (NBS) for SCID, initiated in 2010, was hypothesized to improve SCID OS following HCT. MethodsChildren born and receiving HCT during 4 time intervals (1982–89; 1990–99; 2000–09; and 2010–18) were analyzed for categorial variables (chi-square test), continuous outcomes (Kruskal-Wallis test), and OS (Kaplan-Meier method). Results902 children with typical (n = 747) and atypical (n = 155) SCID were included. Unlike years 1982–2009 when 5-year OS after HCT was stagnant (72–73%), improvement was seen for the first time beginning in 2010, when 5-year OS increased to 87% (p < 0.001). To determine what contributed to this finding, multiple factors were evaluated to identify differences between children transplanted between 2010–18 compared to prior time intervals. Significant differences (all p < 0.001) were found in the trigger for diagnosis being NBS or family history as opposed to clinical illness, age at HCT, active infection at HCT, and transplant characteristics including conditioning intensity, stem cell source, and donor source. On multivariable analysis, which excluded matched sibling donors due to their consistently high rates of OS (≥92%) in all time intervals, active infection (HR 2.41, 95% CI 1.53–3.72; p < 0.001), age ≥3.5 months at HCT (HR 2.21, 95% CI 1.38–3.24; p = 0.001), certain genotypes (ADA, DCLRE1C/LIG4/NHEJ, and other rare genotypes) (HR 2.22–3.67, 95% CI 1.23–7.45; p < 0.001), and Black/African American race (HR 2.33, 95% CI 1.56–3.54; p < 0.001) were associated with lower survival rates. A subgroup multivariable analysis examining the effect of trigger for diagnosis in the era of NBS, adjusting for genotype and race, confirmed that improved OS with NBS was related to earlier age and fewer infections at time of HCT. ConclusionThis study confirmed for the first time the direct benefit of population-based SCID NBS in improving OS after HCT. Our findings support adoption of SCID NBS worldwide, but also point out that persistent racial disparities in survival despite universal availability of screening must be addressed.

Genomic-Based Newborn Screening for Inborn Errors of Immunity: Practical and Ethical Considerations

Inborn errors of immunity (IEI) are a group of over 450 genetically distinct conditions associated with significant morbidity and mortality, for which early diagnosis and treatment improve outcomes. Newborn screening for severe combined immunodeficiency (SCID) is currently underway in several countries, utilising a DNA-based technique to quantify T cell receptor excision circles (TREC) and kappa-deleting recombination excision circles (KREC). This strategy will only identify those infants with an IEI associated with T and/or B cell lymphopenia. Other severe forms of IEI will not be detected. Up-front, first-tier genomic-based newborn screening has been proposed as a potential approach by which to concurrently screen infants for hundreds of monogenic diseases at birth. Given the clinical, phenotypic and genetic heterogeneity of IEI, a next-generation sequencing-based newborn screening approach would be suitable. There are, however, several ethical, legal and social issues which must be evaluated in detail prior to adopting a genomic-based newborn screening approach, and these are discussed herein in the context of IEI.

Implementation of Newborn Screening for Conditions in the United States First Recommended during 2010-2018.

The Recommended Uniform Screening Panel (RUSP) is the list of conditions recommended by the US Secretary of Health and Human Services for inclusion in state newborn screening (NBS). During 2010-2022, seven conditions were added to the RUSP: severe combined immunodeficiency (SCID) (2010), critical congenital heart disease (CCHD) (2011), glycogen storage disease, type II (Pompe) (2015), mucopolysaccharidosis, type I (MPS I) (2016), X-linked adrenoleukodystrophy (X-ALD) (2016), spinal muscular atrophy (SMA) (2018), and mucopolysaccharidosis, type II (MPS II) (2022). The adoption of SCID and CCHD newborn screening by programs in all 50 states and three territories (Washington, D.C.; Guam; and Puerto Rico) took 8.6 and 6.8 years, respectively. As of December 2022, 37 programs screen for Pompe, 34 for MPS I, 32 for X-ALD, and 48 for SMA. The pace of implementation based on the average additional number of NBS programs per year was most rapid for SMA (11.3), followed by CCHD (7.8), SCID (6.2), MPS I (5.4), Pompe (4.9), and X-ALD (4.7).

Personalized hematopoietic stem cell transplantation for inborn errors of immunity.

Patients with inborn errors of immunity (IEI) have been transplanted for more than 50 years. Many long-term survivors have ongoing medical issues showing the need for further improvements in how hematopoietic stem cell transplantation (HSCT) is performed if patients in the future are to have a normal quality of life. Precise genetic diagnosis enables early treatment before recurrent infection, autoimmunity and organ impairment occur. Newborn screening for severe combined immunodeficiency (SCID) is established in many countries. For newly described disorders the decision to transplant is not straight-forward. Specific biologic therapies are effective for some diseases and can be used as a bridge to HSCT to improve outcome. Developments in reduced toxicity conditioning and methods of T-cell depletion for mismatched donors have made transplant an option for all eligible patients. Further refinements in conditioning plus precise graft composition and additional cellular therapy are emerging as techniques to personalize the approach to HSCT for each patient.

A high-throughput newborn screening approach for SCID, SMA, and SCD combining multiplex qPCR and tandem mass spectrometry.

Early diagnosis of severe combined immunodeficiency (SCID), spinal muscular atrophy (SMA), and sickle cell disease (SCD) improves health outcomes by providing a specific treatment before the onset of symptoms. A high-throughput nucleic acid-based method in newborn screening (NBS) has been shown to be fast and cost-effective in the early detection of these diseases. Screening for SCD has been included in Germany's NBS Program since Fall 2021 and typically requires high-throughput NBS laboratories to adopt analytical platforms that are demanding in terms of instrumentation and personnel. Thus, we developed a combined approach applying a multiplexed quantitative real-time PCR (qPCR) assay for simultaneous SCID, SMA, and 1st-tier SCD screening, followed by a tandem mass spectrometry (MS/MS) assay for 2nd-tier SCD screening. DNA is extracted from a 3.2-mm dried blood spot from which we simultaneously quantify T-cell receptor excision circles for SCID screening, identify the homozygous SMN1 exon 7 deletion for SMA screening, and determine the integrity of the DNA extraction through the quantification of a housekeeping gene. In our two-tier SCD screening strategy, our multiplex qPCR identifies samples carrying the HBB: c.20A>T allele that is coding for sickle cell hemoglobin (HbS). Subsequently, the 2nd tier MS/MS assay is used to distinguish heterozygous HbS/A carriers from samples of patients with homozygous or compound heterozygous SCD. Between July 2021 and March 2022, 96,015 samples were screened by applying the newly implemented assay. The screening revealed two positive SCID cases, while 14 newborns with SMA were detected. Concurrently, the qPCR assay registered HbS in 431 samples which were submitted to 2nd-tier SCD screening, resulting in 17 HbS/S, five HbS/C, and two HbS/β thalassemia patients. The results of our quadruplex qPCR assay demonstrate a cost-effective and fast approach for a combined screening of three diseases that benefit from nucleic-acid based methods in high-throughput NBS laboratories.

Updated Management Guidelines for Adenosine Deaminase Deficiency

Inherited defects in the adenosine deaminase (ADA) gene typically cause severe combined immunodeficiency. In addition to infections, ADA-deficient patients can present with neurodevelopmental, behavioral, hearing, skeletal, lung, heart, skin, kidney, urogenital, and liver abnormalities. Some patients also suffer from autoimmunity and malignancies. In recent years, there have been remarkable advances in the management of ADA deficiency. Most ADA-deficient patients can be identified by newborn screening for severe combined immunodeficiency, which facilitates early diagnosis and treatment of asymptomatic infants. Most patients benefit from enzyme replacement therapy (ERT). Allogeneic hematopoietic cell transplantation from an HLA-matched sibling donor or HLA-matched family member donor with no conditioning is currently the preferable treatment. When matched sibling donor or matched family member donor is not available, autologous ADA gene therapy with nonmyeloablative conditioning and ERT withdrawal, which is reported in recent studies to result in 100% overall survival and 90% to 95% engraftment, should be pursued. If gene therapy is not immediately available, ERT can be continued for a few years, although its excessive cost might be prohibitive. The recent improved outcome of hematopoietic cell transplantation using HLA-mismatched family-related donors or HLA-matched unrelated donors, after reduced-intensity conditioning, suggests that such procedures might also be considered rather than continuing ERT for prolonged periods. Long-term follow-up will further assist in determining the optimal treatment approach for ADA-deficient patients.

National experience with adenosine deaminase deficiency related SCID in Polish children.

Deficiency of adenosine deaminase (ADA) manifests as severe combined immunodeficiency (SCID), caused by accumulation of toxic purine degradation by-products. Untreated patients develop immune and non-immune symptoms with fatal clinical course. According to ESID and EBMT recommendations enzyme replacement therapy (ERT) should be implemented as soon as possible to stabilize the patient's general condition, normalize transaminases, treat pulmonary proteinosis, bone dysplasia, and protect from neurological damage. Hematopoietic stem cell transplantation (HSCT) from a matched related donor (MRD) is a treatment of choice. In absence of such donor, gene therapy (GT) should be considered. HSCT from a matched unrelated donor (MUD) and haploidentical hematopoietic stem cell transplantation (hHSCT) are associated with worse prognosis. We retrospectively evaluated the clinical course and results of biochemical, immunological and genetic tests of 7 patients diagnosed in Poland with ADA deficiency since 2010 to 2022. All patients demonstrated lymphopenia affecting of T, B and NK cells. Diagnosis was made on the basis of ADA activity in red blood cells and/or genetic testing. Patients manifested with various non-immunological symptoms including: lung proteinosis, skeletal dysplasia, liver dysfunction, atypical hemolytic-uremic syndrome, and psychomotor development disorders. Five patients underwent successful HSCT: 3 patients from matched unrelated donor, 2 from matched sibling donor, and 1 haploidentical from a parental donor. In 4 patients HSCT was preceded by enzyme therapy (lasting from 2 to 5 months). One patient with multiple organ failure died shortly after admission, before the diagnosis was confirmed. None of the patients had undergone gene therapy. It is important to diagnose ADA SCID as early as possible, before irreversible multi-organ failure occurs. In Poland HSCT are performed according to international immunological societies recommendations, while ERT and GT are less accessible. Implementation of Newborn Screening (NBS) for SCID in Poland could enable recognition of SCID, including ADA-SCID.

Advances and Challenges of the Decade: The Ever-Changing Clinical and Genetic Landscape of Immunodeficiency

In the past 10 years, we have witnessed major advances in clinical immunology. Newborn screening for severe combined immunodeficiency has become universal in the United States and screening programs are being extended to severe combined immunodeficiency and other inborn errors of immunity globally. Early genetic testing is becoming the norm for many of our patients and allows for informed selection of targeted therapies including biologics repurposed from other specialties. During the COVID-19 pandemic, our understanding of essential immune responses expanded and the discovery of immune gene defects continued. Immunoglobulin products, the backbone of protection for antibody deficiency syndromes, came into use to minimize side effects. New polyclonal and monoclonal antibody products emerged with increasing options to manage respiratory viral agents such as SARS-CoV-2 and respiratory syncytial virus. Against these advances, we still face major challenges. Atypical is becoming typical as phenotypes of distinct genetic disease overlap whereas the clinical spectrum of the same genetic defect widens. Therefore, clinical judgment needs to be paired with repeated deep immune phenotyping and upfront genetic testing, as technologies rapidly evolve, and clinical disease often progresses with age. Managing patients with organ damage resulting from immune dysregulation poses a special major clinical challenge and management often lacks standardization, from autoimmune cytopenias, granulomatous interstitial lung disease, enteropathy, and liver disease to endocrine, rheumatologic, and neurologic complications. Clinical, translational, and basic science networks will continue to advance the field; however, cross-talk and education with practicing allergists/immunologists are essential to keep up with the ever-changing clinical and genetic landscape of inborn errors of immunity.

Positive Newborn Screening for Severe Combined Immunodeficiency: What Should the Pediatrician Do?

Severe combined immunodeficiency (SCID) is a group of diseases characterized by low T-cell count and impaired T-cell function, resulting in severe cellular and humoral immune defects. If not diagnosed and treated promptly, infants affected by this condition can develop severe infections which will result in death. Delayed treatment can markedly reduce the survival outcome of infants with SCID. T-cell receptor excision circle (TREC) levels are measured on newborn screening to promptly identify infants with SCID. It is important for primary care providers and pediatricians to understand the approach to managing infants with positive TREC-based newborn screening as they may be the first contact for infants with SCID. Primary care providers should be familiar with providing anticipatory guidance to the family in regard to protective isolation, measures to minimize the risk of infection, and the coordination of care with the SCID coordinating center team of specialists. In this article, we use case-based scenarios to review the principles of TREC-based newborn screening, the genetics and subtypes of SCID, and management for an infant with a positive TREC-based newborn screen.

The diagnosis of severe combined immunodeficiency: Implementation of the PIDTC 2022 Definitions

Shearer etal in 2014 articulated well-defined criteria for the diagnosis and classification of severe combined immunodeficiency (SCID) as part of the Primary Immune Deficiency Treatment Consortium's (PIDTC's) prospective and retrospective studies of SCID. Because of the advent of newborn screening for SCID and expanded availability of genetic sequencing, revision of the PIDTC 2014 Criteria was needed. We developed and tested updated PIDTC 2022 SCID Definitions by analyzing 379 patients proposed for prospective enrollment into Protocol 6901, focusing on the ability to distinguish patients with various SCID subtypes. According to PIDTC 2022 Definitions, 18 of 353 patients eligible per 2014 Criteria were considered not to have SCID, whereas 11 of 26 patients ineligible per 2014 Criteria were determined to have SCID. Of note, very low numbers of autologous T cells (<0.05×109/L) characterized typical SCID under the 2022 Definitions. Pathogenic variant(s) in SCID-associated genes was identified in 93% of patients, with 7 genes (IL2RG, RAG1, ADA, IL7R, DCLRE1C, JAK3, and RAG2) accounting for 89% of typical SCID. Three genotypes (RAG1, ADA, and RMRP) accounted for 57% of cases of leaky/atypical SCID; there were 13 other rare genotypes. Patients with leaky/atypical SCID were more likely to be diagnosed at more than age 1 year than those with typical SCID lacking maternal T cells: 20% versus 1% (P< .001). Although repeat testing proved important, an initial CD3 T-cell count of less than 0.05×109/L differentiated cases of typical SCID lacking maternal cells from leaky/atypical SCID: 97% versus 7% (P< .001). The PIDTC 2022 Definitions describe SCID and its subtypes more precisely than before, facilitating analyses of SCID characteristics and outcomes.