Reducing Mortality and Morbidity in Children with Severe Combined Immunodeficiency in Switzerland: the Role of Newborn Screening.

Newborn screening (NBS) for severe combined immunodeficiency (SCID) has been introduced in various countries with the aim of reducing morbidity and mortality. However, studies analyzing outcomes before and after the implementation of NBS programs remain limited. This study sought to compare the outcomes of SCID patients identified through Switzerland's national SCID NBS program, introduced in January 2019, with those of a historical cohort diagnosed between 2007 and 2019. The study included seven patients (32%) identified through NBS, and 15 (68%) born before NBS implementation and diagnosed based on clinical signs. Children in the NBS group were younger at diagnosis (median age 9 days vs 9 months, P = .002) and at hematopoietic stem cell transplantation (HSCT, median age 5 months vs 11 months, P = .003) compared to the clinical group. The NBS group had a lower incidence of infections before HSCT (29% vs 93%, P = .004). Although not statistically significant, the overall survival rate on last follow-up was higher in the NBS group (86% vs 67%, P = .62). Importantly, patients with active infections undergoing HSCT had a significantly lower overall survival probability compared to those without (P = .01). In conclusion, the introduction of NBS in Switzerland has led to earlier and often asymptomatic diagnosis of affected children, enabling timely intervention, infection prevention, and prompt treatment. These factors have contributed to higher survival rates in the NBS group. These findings underscore the critical importance of NBS for SCID, offering potential life-saving benefits through early detection and intervention.

Prospective Newborn Screening for SCID in Germany: A First Analysis by the Pediatric Immunology Working Group (API).

BACKGR OUND: T-cell receptor excision circle (TREC)-based newborn screening (NBS) for severe combined immunodeficiencies (SCID) was introduced in Germany in August 2019. METHODS: Children with abnormal TREC-NBS were referred to a newly established network of Combined Immunodeficiency (CID) Clinics and Centers. The Working Group for Pediatric Immunology (API) and German Society for Newborn Screening (DGNS) performed 6-monthly surveys to assess the TREC-NBS process after 2.5 years. RESULTS: Among 1.9 million screened newborns, 88 patients with congenital T-cell lymphocytopenia were identified (25 SCID, 17 leaky SCID/Omenn syndrome (OS)/idiopathic T-cell lymphocytopenia, and 46 syndromic disorders). A genetic diagnosis was established in 88%. Twenty-six patients underwent hematopoietic stem cell transplantation (HSCT), 23/26 within 4 months of life. Of these, 25/26 (96%) were alive at last follow-up. Two patients presented with in utero onset OS and died after birth. Five patients with syndromic disorders underwent thymus transplantation. Eight syndromic patients deceased, all from non-immunological complications. TREC-NBS missed one patient, who later presented clinically, and one tracking failure occurred after an inconclusive screening result. CONCLUSION: The German TREC-NBS represents the largest European SCID screening at this point. The incidence of SCID/leaky SCID/OS in Germany is approximately 1:54,000, very similar to previous observations from North American and European regions and countries where TREC-NBS was implemented. The newly founded API-CID network facilitates tracking and treatment of identified patients. Short-term HSCT outcome was excellent, but NBS and transplant registries will remain essential to evaluate the long-term outcome and to compare results across the rising numbers of TREC-NBS programs across Europe.

Clinical and Genetic Characteristics of BCG Disease in Chinese Children: a Retrospective Study.

PURPOSE: Summarize the characteristics of a large cohort of BCG disease and compare differences in clinical characteristics and outcomes among different genotypes and between primary immunodeficiency disease (PID) and patients without identified genetic etiology. METHODS: We collected information on patients with BCG disease in our center from January 2015 to December 2020 and divided them into four groups: chronic granulomatous disease (CGD), Mendelian susceptibility to mycobacterial disease (MSMD), severe combined immunodeficiency disease (SCID), and gene negative group. RESULTS: A total of 134 patients were reviewed, and most of them had PID. A total of 111 (82.8%) patients had 18 different types of pathogenic gene mutations, most of whom (91.0%) were classified with CGD, MSMD, and SCID. CYBB was the most common gene mutation (52/111). BCG disease behaves differently in individuals with different PIDs. Significant differences in sex (P < 0.001), age at diagnosis (P = 0.013), frequency of recurrent fever (P = 0.007), and vaccination-homolateral axillary lymph node enlargement (P = 0.039) and infection severity (P = 0.006) were noted among the four groups. The CGD group had the highest rate of males and the oldest age at diagnosis. The MSMD group had the highest probability of disseminated infection (48.3%). The course of anti-tuberculosis treatment and the survival time between patients with PID and without identified genetic etiology were similar. CONCLUSION: Greater than 80% of BCG patients have PID; accordingly, gene sequencing should be performed in patients with BCG disease for early diagnosis. BCG disease behaves differently in patients with different types of PID. Patients without identified genetic etiology had similar outcomes to PID patients, which hints that they may have pathogenic gene mutations that need to be discovered.

Neonatal Lymphopenia Screening Is Important for Early Diagnosis of Severe Combined Immunodeficiency.

OBJECTIVE: T-cell receptor excision circles are expensive for neonatal severe combined immunodeficiency screening in developing countries. We aimed to detect immunodeficiencies presenting with lymphopenia to enable screening in the general population and to improve awareness regarding lymphopenia among clinicians. STUDY DESIGN: This study was conducted prospectively. In all newborns included, complete blood count from umbilical cord blood samples was recorded. Absolute lymphopenia was defined as absolute lymphocyte count <3,000/mm3 in umbilical cord blood sample. Complete blood count was repeated at month 1 in cases found to have lymphopenia. RESULTS: Overall, 2,000 newborns were included in the study. Absolute lymphopenia was detected in 42 newborns (2.1%), while lymphocyte count was >3,000/mm3 in 1,958 newborns (97.9%). Two infants with persisted lymphopenia at the end of the first month; therefore, further evaluations such as lymphocyte subsets for severe combined immunodeficiency (SCID) were done. In the first infant, the lymphocyte subgroups were detected as compatible with T (-), B (-), natural killer cells (NK) (+) SCID phenotype RAG defect. Sanger sequencing revealed that NM_000448 c.2209C > T (p.R737C) homozygous mutation of RAG1 gene. In the other infant, the lymphocyte subgroups were found as considered with T (-), B (+) NK (-) SCID phenotype JAK3 defect. Both patients underwent hematopoietic stem cell transplantation from human leukocyte antigen-matched family member. CONCLUSION: Absolute lymphopenia by complete blood count is a more simpler, relatively noninvasive and inexpensive screening methodfor detection of SCID in newborns compared with T-cell receptor excision circles technique. KEY POINTS: · Our study was conducted with a much smaller number of study groups compared with the previous ones.. · However, SCID was found at a higher rate compared with other studies.. · Our study for this disease that is common in our country where consanguineous marriages are common.

[Newborn screening for severe combined immunodeficiencies (SCID) in Germany]. / Neugeborenenscreening auf schwere kombinierte Immundefekte (SCID) in Deutschland.

Patients with a severe combined immunodeficiency (SCID) harbor genetic mutations disrupting T cell immunity and hence suffer severe, life-threatening infections or manifestations of immune dysregulation within the first months of their life. The only cure is to correct their immune system, usually by means of hematopoietic stem cell transplantation (HSCT). Pilot studies and national programs in the United States and in European countries have shown that patients can be identified at an early asymptomatic stage through newborn screening. This allows treatment before the occurrence of severe complications, which improves the outcome of curative strategies like HSCT.After assessment by the Federal Joint Committee (G-BA), the SCID screening was implemented into newborn screening in Germany in 2019. The first results of the screening (dry blood spot cards from around 2 million newborns between August 2019 and February 2022) were recently published. As expected, in addition to classic SCID diseases (incidence 1:54,000), infants with syndromic disorders and T cell lymphopenia were also identified. All patients with classic SCID were scheduled for curative treatment. Of the 25 patients with classic SCID, 21 were already transplanted at the time of data analysis. Only one of 21 transplanted patients died due to pre-existing infections. A comparison of the recent screening data with historical data suggests that SCID newborn screening has been successfully implemented in Germany. Patients with SCID are routinely identified very early and scheduled for curative therapy.

SCID and Other Inborn Errors of Immunity with Low TRECs - the Brazilian Experience.

Severe combined immunodeficiency, SCID, is a pediatric emergency that represents the most critical group of inborn errors of immunity (IEI). Affected infants present with early onset life-threatening infections due to absent or non-functional T cells. Without early diagnosis and curative treatment, most die in early infancy. As most affected infants appear healthy at birth, newborn screening (NBS) is essential to identify and treat patients before the onset of symptoms. Here, we report 47 Brazilian patients investigated between 2009 and 2020 for SCID due to either a positive family history and/or clinical impression and low TRECs. Based on clinical presentation, laboratory finding, and genetic information, 24 patients were diagnosed as typical SCID, 14 as leaky SCID, and 6 as Omenn syndrome; 2 patients had non-SCID IEI, and 1 remained undefined. Disease onset median age was 2 months, but at the time of diagnosis and treatment, median ages were 6.5 and 11.5 months, respectively, revealing considerable delay which affected negatively treatment success. While overall survival was 51.1%, only 66.7% (30/45) lived long enough to undergo hematopoietic stem-cell transplantation, which was successful in 70% of cases. Forty-three of 47 (91.5%) patients underwent genetic testing, with a 65.1% success rate. Even though our patients did not come from the NBS programs, the diagnosis of SCID improved in Brazil during the pilot programs, likely due to improved medical education. However, we estimate that at least 80% of SCID cases are still missed. NBS-SCID started to be universally implemented in the city of São Paulo in May 2021, and it is our hope that other cities will follow, leading to early diagnosis and higher survival of SCID patients in Brazil.

Severe Combined Immunodeficiency (SCID) Screening in Arizona: Lessons Learned from the First 2 Years.

PURPOSE: The incidence of severe combined immunodeficiency (SCID) in the USA was reported as 1 in 58,000 live births. In Arizona, it was anticipated that newborn screening would identify two to four cases of SCID per year. This estimate did not consider ethnic nuances in Arizona, with higher percentages of Native American and Hispanic populations compared to national percentages. The true incidence of SCID and non-SCID T cell lymphopenia has not previously been reported in Arizona. METHODS: A retrospective chart review was performed on all abnormal SCID newborn screening (NBS) tests in Arizona from January 1, 2018, to December 31, 2019, using data from the Arizona Department of Health Services and the Phoenix Children's Hospital's electronic medical record [IRB# 20-025]. RESULTS: Seven infants were diagnosed with SCID, yielding an incidence of 1 in 22,819 live births. Four of these infants had Artemis-type SCID. Thirteen infants were identified with an abnormal initial NBS which ultimately did not lead to a diagnosis of SCID. Four of these infants were diagnosed with congenital syndromes associated with T cell lymphopenia. Infants of Hispanic ethnicity were over-represented in this cohort. CONCLUSION: Over 2 years, NBS in Arizona confirmed an incidence more than 2.5 times that reported nationally. This increased incidence is likely reflective of Arizona's unique population profile, with a higher percentage of Native American population. The findings in our non-SCID cohort are in alignment with previously published data, except for an increased percentage of infants of Hispanic/Latino ethnicity, possibly reflecting Arizona's increased percentage of Hispanic/Latino population compared to the general US population.

Hematopoietic Cell Transplantation for Inborn Errors of Immunity Other than Severe Combined Immunodeficiency in Japan: Retrospective Analysis for 1985-2016.

PURPOSE: Hematopoietic cell transplantation (HCT) is a curative therapy for most patients with inborn errors of immunity (IEI). We conducted a nationwide study on HCT for patients with IEI other than severe combined immunodeficiency (non-SCID) in Japan. METHODS: Data from the Japanese national database (Transplant Registry Unified Management Program, TRUMP) for 566 patients with non-SCID IEI, who underwent their first HCT between 1985 and 2016, were retrospectively analyzed. RESULTS: The 10-year overall survival (OS) and event-free survival (EFS) were 74% and 64%, respectively. The 10-year OS for HCT from unrelated bone marrow (URBM), accounting for 39% of HCTs, was comparable to that for HCT from matched sibling donor (MSD), 79% and 81%, respectively. HCT from unrelated cord blood (URCB), accounting for 28% of HCTs, was also common, with a 10-year OS of 69% but less robust engraftment. The intensity of conditioning was not associated with OS or neutrophil recovery; however, myeloablative conditioning was more frequently associated with infection-related death. Patients who received myeloablative irradiation showed poor OS. Multivariate analyses revealed that HCT in 1985-1995 (hazard ratio [HR], 2.0; P = 0.03), URCB (HR, 2.0; P = 0.01), and related donor other than MSD (ORD) (HR, 2.9; P < 0.001) were associated with poor OS, and URCB (HR, 3.6; P < 0.001) and ORD (HR, 2.7; P = 0.02) showed a higher incidence of retransplantation. CONCLUSIONS: We present the 1985-2016 status of HCT for non-SCID IEI in Japan with sufficient statistical power, highlighting the potential of URBM as an alternative donor and the feasibility of reduced intensity conditioning.

Clinical and Immunological Features of 96 Moroccan Children with SCID Phenotype: Two Decades' Experience.

Severe combined immunodeficiency (SCID) is a heterogeneous group of primary immunodeficiency diseases (PIDs) characterized by a lack of autologous T lymphocytes. This severe PID is rare, but has a higher prevalence in populations with high rates of consanguinity. The epidemiological, clinical, and immunological features of SCIDs in Moroccan patients have never been reported. The aim of this study was to provide a clinical and immunological description of SCID in Morocco and to assess changes in the care of SCID patients over time. This cross-sectional retrospective study included 96 Moroccan patients referred to the national PID reference center at Casablanca Children's Hospital for SCID over two decades, from 1998 to 2019. The case definition for this study was age < 2 years, with a clinical phenotype suggestive of SCID, and lymphopenia, with very low numbers of autologous T cells, according to the IUIS Inborn Errors of Immunity classification. Our sample included 50 male patients, and 66% of the patients were born to consanguineous parents. The median age at onset and diagnosis were 3.3 and 6.5 months, respectively. The clinical manifestations commonly observed in these patients were recurrent respiratory tract infection (82%), chronic diarrhea (69%), oral candidiasis (61%), and failure to thrive (65%). The distribution of SCID phenotypes was as follows: T-B-NK+ in 44.5%, T-B-NK- in 32%, T-B+NK- in 18.5%, and T-B+NK+ in 5%. An Omenn syndrome phenotype was observed in 15 patients. SCID was fatal in 84% in the patients in our cohort, due to the difficulties involved in obtaining urgent access to hematopoietic stem cell transplantation, which, nevertheless, saved 16% of the patients. The autosomal recessive forms of the clinical and immunological phenotypes of SCID, including the T-B-NK+ phenotype in particular, were more frequent than those in Western countries. A marked improvement in the early detection of SCID cases over the last decade was noted. Despite recent progress in SCID diagnosis, additional efforts are required, for genetic confirmation and particularly for HSCT.

Newborn Screening for Severe Combined Immunodeficiency: 10-Year Experience at a Single Referral Center (2009-2018).

In 2008, newborn screening (NBS) for severe combined immunodeficiency (SCID) began as a pilot study in Wisconsin and has recently been added to every state's newborn screen panel. The incidence of SCID is estimated at 1 per 58,000 births which may suggest infrequent NBS SCID screen positive results in states with low annual birth rates. In this study, we report our center's experience with NBS positive SCID screen referrals over a 10-year period. A total of 68 full-term newborns were referred to our center for confirmatory testing. Of these referrals, 50% were false positives, 12% were SCID diagnoses, 20% syndromic T cell lymphopenia (TCL) disorders, and 18% non-SCID, non-syndromic TCL. Through collaboration with our newborn screening lab, second-tier targeted gene sequencing was performed for newborns with SCID screen positive results from communities with known founder pathogenic variants and provided rapid genetic confirmation of SCID and non-SCID TCL disorders. Despite extensive genetic testing, two of the eight (25%) identified newborns with SCID diagnoses lacked a definable genetic defect. Additionally, our referrals included ten newborns who were otherwise healthy newborns with idiopathic TCL and varied CD3+ T cell number longitudinal trajectories. Collectively, referrals to our single site over a 10-year period describe a broad spectrum of medically actionable and idiopathic TCL disorders which highlight the importance of clinical immunology expertise in all states, demonstrate efficiencies and challenges for second-tier genetic testing, and further emphasize the need to development standardized evaluation algorithms for non-SCID TCL.

Infections in Infants with SCID: Isolation, Infection Screening, and Prophylaxis in PIDTC Centers.

PURPOSE: The Primary Immune Deficiency Treatment Consortium (PIDTC) enrolled children with severe combined immunodeficiency (SCID) in a prospective natural history study of hematopoietic stem cell transplant (HSCT) outcomes over the last decade. Despite newborn screening (NBS) for SCID, infections occurred prior to HSCT. This study's objectives were to define the types and timing of infection prior to HSCT in patients diagnosed via NBS or by family history (FH) and to understand the breadth of strategies employed at PIDTC centers for infection prevention. METHODS: We analyzed retrospective data on infections and pre-transplant management in patients with SCID diagnosed by NBS and/or FH and treated with HSCT between 2010 and 2014. PIDTC centers were surveyed in 2018 to understand their practices and protocols for pre-HSCT management. RESULTS: Infections were more common in patients diagnosed via NBS (55%) versus those diagnosed via FH (19%) (p = 0.012). Outpatient versus inpatient management did not impact infections (47% vs 35%, respectively; p = 0.423). There was no consensus among PIDTC survey respondents as to the best setting (inpatient vs outpatient) for pre-HSCT management. While isolation practices varied, immunoglobulin replacement and antimicrobial prophylaxis were more uniformly implemented. CONCLUSION: Infants with SCID diagnosed due to FH had lower rates of infection and proceeded to HSCT more quickly than did those diagnosed via NBS. Pre-HSCT management practices were highly variable between centers, although uses of prophylaxis and immunoglobulin support were more consistent. This study demonstrates a critical need for development of evidence-based guidelines for the pre-HSCT management of infants with SCID following an abnormal NBS. TRIAL REGISTRATION: NCT01186913.

TREC Screening for WHIM Syndrome.

PURPOSE: T cell receptor excision circle (TREC) quantification is a recent addition to newborn screening (NBS) programs and is intended to identify infants with severe combined immunodeficiencies (SCID). However, other primary immunodeficiency diseases (PID) have also been identified as the result of TREC screening. We recently reported a newborn with a low TREC level on day 1 of life who was diagnosed with WHIM (warts, hypogammaglobulinemia, infections, myelokathexis) syndrome, a non-SCID primary immunodeficiency caused by mutations in the chemokine receptor CXCR4. METHODS: We have now retrospectively reviewed the birth and clinical histories of all known WHIM infants born after the implementation of NBS for SCID. RESULTS: We identified six infants with confirmed WHIM syndrome who also had TREC quantification on NBS. Three of the six WHIM infants had low TREC levels on NBS. All six patients were lymphopenic but only one infant had a T cell count below 1,500 cells/µL. The most common clinical manifestation was viral bronchiolitis requiring hospitalization. One infant died of complications related to Tetralogy of Fallot, a known WHIM phenotype. CONCLUSION: The results suggest that WHIM syndrome should be considered in the differential diagnosis of newborns with low NBS TREC levels. TRIAL REGISTRATION: Not applicable.

Parents' Perspectives and Societal Acceptance of Implementation of Newborn Screening for SCID in the Netherlands.

PURPOSE: While neonatal bloodspot screening (NBS) for severe combined immunodeficiency (SCID) has been introduced more than a decade ago, implementation in NBS programs remains challenging in many countries. Even if high-quality test methods and follow-up care are available, public uptake and parental acceptance are not guaranteed. The aim of this study was to describe the parental perspective on NBS for SCID in the context of an implementation pilot. Psychosocial aspects have never been studied before for NBS for SCID and are important for societal acceptance, a major criterion when introducing new disorders in NBS programs. METHODS: To evaluate the perspective of parents, interviews were conducted with parents of newborns with abnormal SCID screening results (N = 17). In addition, questionnaires about NBS for SCID were sent to 2000 parents of healthy newborns who either participated or declined participation in the SONNET-study that screened 140,593 newborns for SCID. RESULTS: Support for NBS for SCID was expressed by the majority of parents in questionnaires from both a public health perspective and a personal perspective. Parents emphasized the emotional impact of an abnormal screening result in interviews. (Long-term) stress and anxiety can be experienced during and after referral indicating the importance of uniform follow-up protocols and adequate information provision. CONCLUSION: The perspective of parents has led to several recommendations for NBS programs that are considering screening for SCID or other disorders. A close partnership of NBS programs' stakeholders, immunologists, geneticists, and pediatricians-immunologists in different countries is required for moving towards universal SCID screening for all infants.

Primary immunodeficiency testing in a Massachusetts tertiary care NICU: persistent challenges in the extremely premature population.

BACKGROUND: Prematurity presents a diagnostic challenge in interpreting primary immunodeficiency (PID) testing. METHODS: We retrospectively reviewed the charts of all infants in our level IV referral neonatal intensive care unit (NICU) in Massachusetts, with immunologic testing performed from 2006 to 2018. RESULTS: The overall rate of PID testing was enriched in our population, with 1% of admitted patients having extended immunologic testing. The addition of TREC (T cell receptor excision circle) newborn screening in Massachusetts in 2009 increased the proportion of infants tested for PID in our NICU by 3-fold (1.21% post-newborn screening (NBS) vs. 0.46% pre-NBS). A majority of the term and late preterm (≥34 weeks) infants (31 of 41, 76%), as well as very premature (29-33 weeks) infants (12 of 17, 71%), who had immune testing, had a genetic diagnosis associated with secondary immunodeficiency or a PID. Most infants who were born extremely premature (EP, <29 weeks) (25 of 29, 86%) had no identifiable cause of immunodeficiency besides prematurity, despite a mean postmenstrual age of 40.1 weeks at the time of testing. CONCLUSIONS: Persistent immune derangements were present within a subgroup of the EP population through term postmenstrual age. EP infants with significant infectious history and abnormal immune testing at term-corrected age should be considered for genetic testing. IMPACT: The role of immunologic testing in the premature population is unclear, we therefore reviewed the records of all infants in our NICU who had immunologic testing, to rule out immunodeficiency, done from 2006 to 2018. The addition of newborn screening for SCID in 2009 doubled the number of infants who had immune investigations. The extremely premature cohort included many infants with persistent immune derangements through term-corrected gestational age, suggesting a persistent effect of prematurity on immune development and potential function. We propose that former premature infants with clinical evidence of immunodeficiency and sustained immune abnormalities by term-corrected age undergo genetic testing for immunodeficiency.

Morbidity in an adenosine deaminase-deficient patient during 27 years of enzyme replacement therapy.

INTRODUCTION: Adenosine deaminase (ADA) deficiency causes severe immunodeficiency that is lethal in infancy. Enzyme replacement therapy (ERT) can improve the metabolic, immune and non-immune abnormalities in patients prior to transplantation, however, its benefits over extended periods are not well characterized. We describe a 28-year-old female who received ERT for 27 years. She suffered from EBV negative B cell lymphoma of the hip at 14 years of age and Guillian-Barre Syndrome 2 years later. At 22 years of age, she experienced a gastrointestinal infection with Mycobacterium genavense. At 26 years of age, lymphoma reoccurred with multiple liver lesions followed by Mycobacterium genavense infection with dissemination to the brain. Throughout this period, ADA activity in the plasma was within the therapeutic range. Repeated evaluations demonstrated very low lymphocyte counts and impaired T cell function. CONCLUSIONS: ERT might be insufficient to maintain normal immunity over extended periods in some ADA-deficient patients.

Incidence of SCID in Germany from 2014 to 2015 an ESPED* Survey on Behalf of the API*** Erhebungseinheit für Seltene Pädiatrische Erkrankungen in Deutschland (German Paediatric Surveillance Unit) ** Arbeitsgemeinschaft Pädiatrische Immunologie.

PURPOSE: Severe combined immunodeficiencies (SCID) are a heterogeneous group of fatal genetic disorders, in which the immune response is severely impaired. SCID can be cured if diagnosed early. We aim to determine the incidence of clinically defined SCID cases, acquire data of reported cases and evaluate their possible prediction by newborn screening, before introduction of a general screening program in Germany. METHODS: The German Surveillance Unit for rare Paediatric Diseases (ESPED) prospectively queried the number of incident SCID cases in all German paediatric hospitals in 2014 and 2015. Inclusion criteria were (1) opportunistic or severe infections or clinical features associated with SCID (failure to thrive, lacking thymus or lymphatic tissue, dysregulation of the immune system, graft versus host reaction caused by maternal T cells), (2) dysfunctional T cell immunity or proof of maternal T cells and (3) exclusion of a secondary immunodeficiency such as human immunodeficiency virus (HIV) infection. In a capture-recapture analysis, cases were matched with cases reported to the European Society for Immunodeficiencies (ESID). RESULTS: Fifty-eight patients were initially reported to ESPED, 24 reports could be confirmed as SCID, 21 patients were less than 1 year old at time of diagnosis. One SCID case was reported to ESID only. The estimated incidence of SCID in Germany is 1.6/100,000 (1:62,500) per year in children less than 1 year of age. Most patients reported were symptomatic and mortality in regard to reported outcome was high (29% (6/22)). The majority of incident SCID cases were considered to be probably detectable by newborn screening. CONCLUSIONS: SCID is a rare disease with significant mortality. Newborn screening may give the opportunity to improve the prognosis in a significant number of children with SCID.

Retrospective Analysis of a New York Newborn Screen Severe Combined Immunodeficiency Referral Center.

In 2010, the New York State (NYS) Newborn Screen (NBS) Program added the T cell receptor excision circle (TREC) assay to screen for severe combined immunodeficiency disorder (SCID). The objective of this study was to perform a retrospective chart review of 199 infants referred to a single institution for abnormal TREC on NYS NBS between 2010 and 2017. Statistical analysis included analysis of variance, logistic regression models, chi-square, and linear mixed models. One hundred ninety-nine infants were found to have a TREC value of fewer than 200 copies/µL on NYS NBS. Infants were stratified as primary immunodeficiency (PID) (n = 54), immunocompetent (n = 133), lost to follow-up (n = 8), or deceased (n = 4). PID included SCID (n = 3), DiGeorge (n = 6), idiopathic lymphopenia (IL) (n = 44), and other syndromes associated with lymphopenia (n = 3). The 3 SCID cases were identified and brought to treatment, although all experienced significant infections. The study population was found to be predominately non-Hispanic, African American, and male. There was a difference in the average TREC values among those with immunocompetence (83 copies/µL), IL (81 copies/µL), and PID (40 copies/µL) (p < 0.05). On follow-up of 40 patients with IL, patients typically did not have severe infections during first few years of life. This study demonstrates that TREC value can be used to stratify infants for further confirmatory testing to exclude PID. Risk factors, such as stressful prenatal/postnatal conditions, prematurity, race, and sex may affect TREC value but cannot explain all causes of lymphopenia. This study may assist providers in risk stratifying the likelihood of PID with an abnormal TREC and determining the extent of the initial work up that is necessary at the time of a newborn's presentation.

Adenosine Deaminase (ADA)-Deficient Severe Combined Immune Deficiency (SCID) in the US Immunodeficiency Network (USIDNet) Registry.

Clinical data from ADA-SCID patients registered in the U.S. Immunodeficiency Network (USIDNet) Repository were analyzed. Sixty-four ADA-SCID patients born between 1981 and 2017 had clinical data entered by their local (or home) enrolling institution. Median age at diagnosis was 1 month for those with a positive family history and 3 months for those without a prior family history, with some diagnosed at birth and one as late as 9 years of age. Overall survival was 79.7%, which increased to 94.1% since 2010. These patients had multiple infections and pulmonary, gastrointestinal, and neurological complications. The majority received enzyme replacement therapy (ERT) at some time, including 88% of those born since 2010. Twenty-six patients underwent allogeneic hematopoietic stem cell transplant (HSCT). HSCT successfully supported survival (17/26, 65%) using a variety of cell sources (bone marrow, mobilized peripheral blood, and cord blood) from sibling, family and unrelated donors. Nineteen patients underwent autologous HSCT with gene therapy (GT) using retroviral and lentiviral vectors and all are surviving. The prognosis for patients with ADA-SCID has continued to improve but these patients do have multiple early and potentially long-term conditions that require medical monitoring and management.

[Severe combined immunodeficiency, report of chilean patients diagnosed during the 1999-2020 period]. / Inmunodeficiencia Combinada Severa, reporte de pacientes chilenos diagnosticados durante el período 1999-2020.

INTRODUCTION: Severe combined immunodeficiency (SCID) is the most severe form of primary immunodeficiency. To date, there is little local information about this disease. OBJECTIVE: To describe the epidemiology, complications, prognosis, and use of the BCG vaccine in Chilean patients with SCID. PATIENTS AND METHOD: Retrospective review of the clinical records of patients diagnosed with SCID by clinical immunologists between 1999 and 2020 throughout Chile. SCID was diagnosed according to the cri teria proposed by Shearer: T lymphocytes (CD3+) < 300 cells/µL and proliferation 10% of the limit of normality in response to phytohemagglutinin or presence of T lymphocytes of maternal origin. Data collected from the clinical records were: sex, age at diagnosis, consanguinity, region of origin, lymphocyte subpopulations, genetic diagnosis, infectious and non-infectious complications, BCG vaccination and its complications, age at referral to the bone marrow transplant (BMT) center, and cause of non-BMT-related mortality. RESULTS: Between 1999 and 2020, 25 patients were diagnosed with SCID. 78% of them were male, mean age at first manifestation of the disease was 2.3 months (0-7), while the mean age at diagnosis was 3.4 months (0-7). 16% of patients had a family history of SCID. 40% of cases were diagnosed within the Metropolitan Region. The most frequent immuno- phenotype was T-B-NK+ SCID (48%). Genetic studies were done in 69.5% of cases, mutations in the RAG2 gene were the most common etiology of SCID (39%). 88% of SCID patients received the Bacillus Calmette-Guerin (BCG) vaccine before diagnosis, including 2 cases with a known family history of SCID. 36% of those who received the vaccine had BCG-related complications. The mean age at referral to a bone marrow transplant center was 7.4 months (5-16). 11/25 patients died before being transferred to a transplant center. DISCUSSION: There is a clinically significant delay between the first manifestations and the diagnosis of SCID in Chilean patients, as well as an important time gap between the diagnosis of SCID and referral to a center for BMT. Most SCID cases in Chile receive the BCG vaccine, despite a known family history of the disease, and frequently develop vaccine-related complications.

Clinical Features and HSCT Outcome for SCID in Turkey.

Severe combined immunodeficiency (SCID) is the most serious PID, characterized by T cell lymphopenia and lack of antigen-specific T cell and B cell immune responses, inevitably leading to death within the first year of life if hematopoietic stem cell transplantation (HSCT) is not performed. PURPOSE AND METHODS: Since SCID is a common type of PID with an estimated incidence of 1/10.000 in Turkey, a retrospective analysis of HSCT characteristics, survival, immune recovery, and the major clinical features of SCID prior to HSCT is the aim of this multi-transplant center-based analysis. RESULTS: A total of 234 SCID patients transplanted between the years 1994 and 2014 were included in the study. Median age at diagnosis was 5 months, at transplantation, 7 months, B- phenotype and RAGs were the most common defects among others. Immune phenotype did not seem to have an effect on survival rate (p > 0.05), Immunoglobulin (Ig) requirement following HSCT did not differ between B+ and B- phenotypes (p > 0.05). Overall survival rate was 65.7% over a period of 20 years. It increased from 54% (1994-2004) to 69% (p = 0.052) during the last 10 years (2005-2014). Ten-year survival after HSCT has improved over time although the difference was not significant. Infection at the time of transplantation (p = 0.006), mismatched related donor (MMRD) (haploidentical parents), and matched unrelated donor (MUD) donor transplants p < 0.001 were the most important factors, significantly affecting the outcome. CONCLUSIONS: This is the first multicenter study with the largest data obtained from transplanted SCID patients in Turkey. Early diagnosis with newborn screening (NBS) together with emerging referrals, treatment by transplantation centers, and specialized teams are mandatory in countries with high parental consanguinity such as Turkey.