Case Report: A Novel Synonymous ARPC1B Gene Mutation Causes a Syndrome of Combined Immunodeficiency, Asthma, and Allergy With Significant Intrafamilial Clinical Heterogeneity

Recently, a novel syndrome of combined immune deficiency, infections, allergy, and inflammation has been attributed to mutations in the gene encoding actin-related protein 2/3 complex subunit 1B (ARPC1B), which is a key molecule driving the dynamics of the cytoskeleton. Homozygous mutations in the ARPC1B gene have been found to result in the disruption of the protein structure and cause an autosomal recessive syndrome of combined immune deficiency, impaired T-cell migration and proliferation, increased levels of immunoglobulin E (IgE) and immunoglobulin A (IgA), and thrombocytopenia. To date, only a few individuals have been diagnosed with the ARPC1B deficiency syndrome worldwide. In this case series, we report the wide spectrum of phenotype in 3 siblings of a consanguineous family from Afghanistan with a novel homozygous synonymous pathogenic variant c.783G>A, p. (Ala261Ala) of the ARPC1B gene that causes a similar syndrome but no thrombocytopenia. Targeted RNA studies demonstrated that the variant affects the splicing process of mRNA, resulting in a marked reduction of the levels of primary (normal) RNA transcript of the ARPC1B gene in the affected patients and likely premature termination from the abnormally spliced mRNA. The next generation sequencing (NGS) studies facilitated the diagnosis of this rare combined immunodeficiency and led to the decision to treat the affected patients with hematopoietic cell transplant (HCT) from an human leukocyte antigen (HLA)-matched healthy sibling.

Clinical, Immunological, and Molecular Features of Severe Combined Immune Deficiency: A Multi-Institutional Experience From India

BackgroundSevere Combined Immune Deficiency (SCID) is an inherited defect in lymphocyte development and function that results in life-threatening opportunistic infections in early infancy. Data on SCID from developing countries are scarce.ObjectiveTo describe clinical and laboratory features of SCID diagnosed at immunology centers across India.MethodsA detailed case proforma in an Excel format was prepared by one of the authors (PV) and was sent to centers in India that care for patients with primary immunodeficiency diseases. We collated clinical, laboratory, and molecular details of patients with clinical profile suggestive of SCID and their outcomes. Twelve (12) centers provided necessary details which were then compiled and analyzed. Diagnosis of SCID/combined immune deficiency (CID) was based on 2018 European Society for Immunodeficiencies working definition for SCID.ResultsWe obtained data on 277 children; 254 were categorized as SCID and 23 as CID. Male-female ratio was 196:81. Median (inter-quartile range) age of onset of clinical symptoms and diagnosis was 2.5 months (1, 5) and 5 months (3.5, 8), respectively. Molecular diagnosis was obtained in 162 patients - IL2RG (36), RAG1 (26), ADA (19), RAG2 (17), JAK3 (15), DCLRE1C (13), IL7RA (9), PNP (3), RFXAP (3), CIITA (2), RFXANK (2), NHEJ1 (2), CD3E (2), CD3D (2), RFX5 (2), ZAP70 (2), STK4 (1), CORO1A (1), STIM1 (1), PRKDC (1), AK2 (1), DOCK2 (1), and SP100 (1). Only 23 children (8.3%) received hematopoietic stem cell transplantation (HSCT). Of these, 11 are doing well post-HSCT. Mortality was recorded in 210 children (75.8%).ConclusionWe document an exponential rise in number of cases diagnosed to have SCID over the last 10 years, probably as a result of increasing awareness and improvement in diagnostic facilities at various centers in India. We suspect that these numbers are just the tip of the iceberg. Majority of patients with SCID in India are probably not being recognized and diagnosed at present. Newborn screening for SCID is the need of the hour. Easy access to pediatric HSCT services would ensure that these patients are offered HSCT at an early age.

Preventing Transmission of Vaccine-Associated Viral Infections from a Patient With Severe Combined Immune Deficiency

Background: The transmissibility of vaccine-strain viruses from immunocompromised patients, such as those with severe combined immune deficiency (SCID) is unknown. The infection control management of a patient diagnosed with SCID and infected with vaccine-strain varicella zoster virus (VZV) and measles virus is described below. A previously healthy, full-term boy was vaccinated at 14 months with measles mumps rubella varicella (MMR) vaccine. He had received prior vaccinations, including rotavirus, without adverse effects. During the 6 weeks after vaccination, the patient developed signs and symptoms clinically consistent with chicken pox and measles. An immune work-up revealed SCID. Methods: The Alberta Health Services (AHS) SCID protocol was followed to manage the patient upon admission at 17 months of age. Multiple meetings with various stakeholders were held to ensure appropriate precautions were followed to minimize the risk of pathogen transmission. Results: The patient was placed on airborne and contact precautions in a negative-pressure room. The pressure differential of the room to the corridor was continually monitored and displayed at the entry to the room. Staff known to be immune to VZV or measles were not required to wear an N95 respirator. All intrahospital movement of the patient was coordinated with the respective care teams and departments, including infection prevention and control, facilities maintenance and engineering, respiratory therapy, and diagnostic imaging. A mask was placed on the patient when movement outside the room was required. VZV testing was positive for the Oka/vaccine strain on all samples tested (ie, nasopharyngeal, skin, blood, and cerebrospinal fluid). Nasopharyngeal swabs and blood were PCR positive for measles genotype A/vaccine strain virus. Both viruses were persistently positive in spite of treatment with acyclovir, valganciclovir, varicella zoster immune globulin, and intravenous immune globulin. Conclusions: There is currently no documented transmission of measles vaccine-strain virus, and transmission of VZV vaccine-strain virus is rare. According to the AHS SCID protocol, the use of airborne and contact precautions for a patient identified with measles and/or VZV supersedes the use of a positive-pressure room for patients identified with SCID. Newborn screening for SCID was implemented in Alberta in June 2019. As a result, more SCID patients will be diagnosed earlier in their course, and therefore prior to most routine vaccinations. However, newborn screening will not pick up some types of combined immune deficiencies. Some children may still be at risk of vaccine-associated illnesses due to undiagnosed underlying immune deficiencies.Funding: NoneDisclosures: None

12 Cost-Benefit Analysis of Newborn Screening for Severe Combined Immune Deficiency: literature review and results transferability

Background The purpose of screening for Severe Combined Immune Deficiency (SCID) is to enable timely diagnosis and treatment for this condition. Untreated SCID is uniformly fatal by 2 years of age. Hematopoietic stem cell transplantation is an effective treatment for SCID, and the success rate depends on the age at which it is performed. Earlier treatment improves survival, long term quality of life and decreases costs of treating patients, specifically by shortening hospitalization days. Screening, however, carries short-term implementation costs, that could potentially be a barrier to adding SCID to the newborn screening (NBS) panels. Objectives This literature review aimed to evaluate the cost-effectiveness of NBS for SCID and perform basic economic analysis review on available published sources. We also assessed the published results and clinical inputs for transferability between different centers. Design/Methods We conducted a systematic search of medical electronic databases: Google Scholar, Ovid, Medline, PubMed, CINAHL, EMBASE, the Cochrane Library, Science Citation Index and Evidence-Based Medicine and hand searched related references. We used the Preferred Reporting Items for Systematic review and Meta-analyses (PRISMA-2009) statement to report the findings. We extracted the details of individual study characteristics from each publication, assessed study quality, evaluated the effect sizes and assessed the influence of study design on the estimated effect size. The presence of small effect sizes was investigated using Funnel plots and Egger’s tests. Search terms included: newborn, SCID, newborn screening, cost-effectiveness, cost-benefit, cost-effectiveness analysis, cost-utility analysis, medical costs, the value of a statistical life, quality-adjusted life-years (QALYs) We included cross-sectional, case-control, and cohort studies that have been published in peer-reviewed journals, data from regional/national surveys. Results 298 records identified through database searching, 192 records removed. A total of 106 articles were found to be eligible for screening, 72 sources were excluded after abstracts review. Forty-four full -text articles were assessed for eligibility, and 14 were excluded (lack of relevance, misleading abstract). Thirty articles were included in the final literature review. We were looking for Level I evidence studies as a high-quality randomized trial or prospective study, sensible costs and alternatives, values obtained from many studies with multiway sensitivity analyses, a systematic review of Level I RCTs and Level I studies. A comparative economic analysis was performed on reviewed sources to determine the average cost-benefit of NBS for SCID among different centers. We used standard conversion to calculate total health costs and charges in US dollars. An average cost of screening for SCID per sample varies between 3.0 -6.0 US$, and at present, there are no known missed cases in SCID NBS programs. The average cost of treatment and QALY were the most common variables used in all reviewed sources and presented in Table 1. Charges for hospital care were more than 5 times higher for late-diagnosed cases of SCID compare to the early diagnosed cases (within the first 2 months of life). These results found to be none-specific to the particular countries, and have high potential transferability among different centers. Conclusion Our literature review analysis supports the cost-effectiveness of NBS for SCID. The opportunity of early treatment is a strong economic rationale for the addition of SCID screening to NBS programs.