Evolution of Gene Therapy for Inborn Errors of Immunity.

This Viewpoint reviews the history and current state of gene therapy for inborn errors of immunity.

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

PURPOSE OF REVIEW: 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. RECENT FINDINGS: 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. SUMMARY: 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.

Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.

Patients with inherited CARMIL2 or CD28 deficiency have defective T cell CD28 signaling, but their immunological and clinical phenotypes remain largely unknown. We show that only one of three CARMIL2 isoforms is produced and functional across leukocyte subsets. Tested mutant CARMIL2 alleles from 89 patients and 52 families impair canonical NF-κB but not AP-1 and NFAT activation in T cells stimulated via CD28. Like CD28-deficient patients, CARMIL2-deficient patients display recalcitrant warts and low blood counts of CD4+ and CD8+ memory T cells and CD4+ TREGs. Unlike CD28-deficient patients, they have low counts of NK cells and memory B cells, and their antibody responses are weak. CARMIL2 deficiency is fully penetrant by the age of 10 yr and is characterized by numerous infections, EBV+ smooth muscle tumors, and mucocutaneous inflammation, including inflammatory bowel disease. Patients with somatic reversions of a mutant allele in CD4+ T cells have milder phenotypes. Our study suggests that CARMIL2 governs immunological pathways beyond CD28.

Novel DNMT3B Mutation in a Patient with Immunodeficiency, Centromeric Instability, and Facial Anomalies (ICF) Syndrome and a Bronchopulmonary Collateral Artery.

BACKGROUND: Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is a rare autosomal recessive disorder. ICF1 is caused by bi-allelic mutations in the gene encoding deoxyribonucleic acid methyltransferase-3B (DNMT3B). Herein, we report a novel homozygous DNMT3B mutation in a patient with ICF1. CASE PRESENTATION: An eight-month-old Iranian Caucasian infant of consanguineous 1st-degree cousins presented to our clinic for evaluation of neutropenia. Physical examination was unremarkable except for low-set ears and a systolic cardiac murmur. He had a history of recurrent respiratory infections and oral thrush. Moreover, a collateral artery between the bronchial and pulmonary arteries was observed on the angiogram, mimicking a patent ductus arteriosus on the echocardiogram. Growth percentiles were normal; however, he had a neurodevelopmental delay. Family history was significant for a sibling who deceased at nine months of age after recurrent respiratory infections. Laboratory evaluation revealed a normal white blood cell count with neutropenia and normal bone marrow studies. He had hypogammaglobinemia with normal flow cytometric studies and was treated with prophylactic trimethoprim-sulfamethoxazole and itraconazole. After that, he was re-admitted three times due to recurrent episodes of pneumonia and an episode of pseudomonas aeruginosa meningitis. Currently, he is five years old and doing well on monthly intravenous immunoglobulin. Due to recurrent infections, hypogammaglobulinemia, and neutropenia, as well as a family history of consanguinity and a sibling who deceased during infancy, a primary immune deficiency was suspected. Genetic studies utilizing whole-exome sequencing demonstrated a homozygous missense mutation in DNMT3B (LRG_56t1:c.2008C>T; p.Arg670Trp) in the patient studied. The mutation has not been previously reported. CONCLUSION: We describe a novel homozygous DNMT3B mutation in an Iranian boy with ICF1. It is associated with recurrent infections, hypogammaglobinemia, neutropenia, mild facial anomalies, and a bronchopulmonary collateral artery.

Quantifying the Population-Level Effect of the COVID-19 Mass Vaccination Campaign in Israel: A Modeling Study.

Background: Estimating real-world vaccine effectiveness is challenging as a variety of population factors can impact vaccine effectiveness. We aimed to assess the population-level reduction in cumulative severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cases, hospitalizations, and mortality due to the BNT162b2 mRNA coronavirus disease 2019 (COVID-19) vaccination campaign in Israel during January-February 2021. Methods: A susceptible-infected-recovered/removed (SIR) model and a Dynamic Survival Analysis (DSA) statistical approach were used. Daily counts of individuals who tested positive and of vaccine doses administered, obtained from the Israeli Ministry of Health, were used to calibrate the model. The model was parameterized using values derived from a previous phase of the pandemic during which similar lockdown and other preventive measures were implemented in order to take into account the effect of these prevention measures on COVID-19 spread. Results: Our model predicted for the total population a reduction of 648 585 SARS-CoV-2 cases (75% confidence interval [CI], 25 877-1 396 963) during the first 2 months of the vaccination campaign. The number of averted hospitalizations for moderate to severe conditions was 16 101 (75% CI, 2010-33 035), and reduction of death was estimated at 5123 (75% CI, 388-10 815) fatalities. Among children aged 0-19 years, we estimated a reduction of 163 436 (75% CI, 0-433 233) SARS-CoV-2 cases, which we consider to be an indirect effect of the vaccine. Conclusions: Our results suggest that the rapid vaccination campaign prevented hundreds of thousands of new cases as well as thousands of hospitalizations and fatalities and has probably averted a major health care crisis.

Novel Variants of DOCK8 Deficiency in a Case Series of Iranian Patients.

BACKGROUND: Dedicator of Cytokinesis 8 (DOCK8) deficiency, the most frequent cause of autosomal recessive hyper immunoglobulin (Ig)E syndrome, is a rare combined immunodeficiency. OBJECTIVE: In this study, we report seven patients, with consanguineous parents, with five novel variants within the DOCK8 gene. METHODS: For genetic analysis, we performed Whole Exome Sequencing (WES) or targeted sequencing by means of Next-generation sequencing (NGS) for some of the patients. For others, Sanger sequencing, Fluorescence-activated cell sorting (FACS), or polymerase chain reaction (PCR) were used. RESULTS: We report five novel variants within the DOCK8 gene: three deletions (deletion of exons 4-12, 24-30, and 22-27), one frameshift (LRG_196:g.189315dup;p.(Leu1052Profs*7)), and a splice region variant (LRG_196t1:c.741+5G>T). Patients presented with skin lesions, food allergy, candidiasis, otitis, recurrent respiratory infections, short stature, aortic aneurism, gynecomastia, and coarse facial features. Patients had leukocytosis, eosinophilia, lymphopenia, and monocytosis, elevated IgE, IgG, IgA, reduced IgM and IgA levels. Patients had a low percentage of CD3+ and CD4+ cells and a high percentage of CD19+, CD27+CD19+, and recent thymic emigrants T cells. The percentage of natural killer cells was increased in one of the patients while it was decreased in another patient. One patient died due to disseminated intravascular coagulation after hematopoietic stem cell transplantation. CONCLUSION: We reported novel variants within the DOCK8 gene and highlighted the risk of aneurysms in these patients, which have been rarely reported in these patients.

Coronavirus Disease Spread during Summer Vacation, Israel, 2020.

The relative increase in coronavirus disease incidence during summer 2020 in Israel was most prominent in young children. This finding contrasts with the lower increase in incidence observed in children than in adults during the school attendance period. School closure without lockdown conditions might not be independently effective at reducing spread.

Comparison of the medical burden of COVID-19 with seasonal influenza and measles outbreaks.

AIM: To examine and compare the medical burden of measles, influenza and COVID-19 outbreaks in the city of Bnei Brak, Israel. METHODS: The study was conducted during 2018-2021. The numbers of hospitalisations for these infections and their complications were recorded. Hospitalisation rates were determined by using the number of children residing in Bnei Brak and hospitalised with these infections during the study period as the numerators. The denominators were the estimated paediatric cases of measles, influenza and COVID-19 in Bnei Brak and were calculated under both pragmatic and conservative assumptions. RESULTS: A total of 247, 65 and 32 children were hospitalised with influenza, COVID-19 and measles respectively. Complication rates were higher following measles than after influenza and SARS-CoV-2 infections. Hospitalisation rates were 10% for measles, 0.6%-1.2% for influenza and 0.15% - 0.25% for COVID-19 infections. Relative risks (RR) with 95% confidence intervals (CI) for hospitalisation following measles compared with COVID-19 ranged from 42 (26.3-67.3) to 70.1 (43.8-112.1), while the relative risks for influenza hospitalisation ranged from 2.5 (1.83-3.41) to 8.2 (6.0-11.2), compared with COVID-19 infection. CONCLUSION: Hospitalisation rates and direct medical burdens of measles and influenza were significantly higher than those of COVID-19 infection in children.

Intrafamilial Spread and Altered Symptomatology of SARS-CoV-2, During Predominant Circulation of Lineage B.1.1.7 Variant in Israel.

The dynamics of intrafamilial spread of SARS-CoV-2 during January-February 2021 when variant B.1.1.7 predominated were compared with data from April to May 2020, when other circulating variants prevailed. Much higher intrafamilial transmission rates among all age groups, in particular in young children, and lower rates of sensory impairment were demonstrated during January-February 2021.

Exploring genetic defects in adults who were clinically diagnosed as severe combined immune deficiency during infancy.

Genetic diagnostic tools including whole-exome sequencing (WES) have advanced our understanding in human diseases and become common practice in diagnosing patients with suspected primary immune deficiencies. Establishing a genetic diagnosis is of paramount importance for tailoring adequate therapeutic regimens, including identifying the need for hematopoietic stem cell transplantation (HSCT) and genetic-based therapies. Here, we genetically studied two adult patients who were clinically diagnosed during infancy with severe combined immune deficiency (SCID). Two unrelated patients, both of consanguineous kindred, underwent WES in adulthood, 2 decades after their initial clinical manifestations. Upon clinical presentation, immunological workup was performed, which led to a diagnosis of SCID. The patients presented during infancy with failure to thrive, generalized erythematous rash, and recurrent gastrointestinal and respiratory tract infections, including episodes of Pneumocystis pneumonia infection and Candida albicans fungemia. Hypogammaglobulinemia and T-cell lymphopenia were detected. Both patients were treated with a 10/10 HLA matched sibling donor unconditioned HSCT. Retrospective genetic workup revealed homozygous bi-allelic mutations in IL7RA in one patient and in RAG2 in the other. Our study exemplifies the impact of retrospectively establishing a genetic diagnosis. Pinpointing the genetic cause raises several issues including optimized surveillance and treatment, understanding disease mechanisms and outcomes, future family planning, and social and psychological considerations.

Reopening Schools and the Dynamics of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infections in Israel: A Nationwide Study.

BACKGROUND: Benefits of school reopening must be weighed against the morbidity and mortality risks and the impact of enhancing spread of coronavirus disease 2019 (COVID-19). We investigated the effects of school reopening and easing of social-distancing restrictions on dynamics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in Israel between March and July 2020. METHODS: We examined the nationwide age-wise weekly incidence, prevalence, SARS-CoV-2 polymerase chain reaction tests, their positivity, COVID-19 hospitalizations, and associated mortality. Temporal differences in these parameters following school reopening, school ending, and following easing of restrictions such as permission of large-scale gatherings were examined. RESULTS: Incidence of SARS-CoV-2 infections gradually increased following school reopening in all age groups, with a significantly higher increase in adults than children. Higher rate ratios (RRs) of sample positivity rates 21-27 days following school reopening relative to positivity rates prior to openings were found for the age groups 40-59 (RR, 4.72; 95% CI, 3.26-6.83) and 20-39 (RR, 3.37 [2.51-4.53]) years, but not for children aged 0-9 (RR, 1.46 [.85-2.51]) and 10-19 (RR, .93 [.65-1.34]) years. No increase was observed in COVID-19-associated hospitalizations and deaths following school reopening. In contrast, permission of large-scale gatherings was accompanied by increases in incidence and positivity rates of samples for all age groups, and increased hospitalizations and mortality. CONCLUSIONS: This analysis does not support a major role of school reopening in the resurgence of COVID-19 in Israel. Easing restrictions on large-scale gatherings was the major influence on this resurgence.

Type 1 Plasminogen Deficiency With Pulmonary Involvement: Novel Treatment and Novel Mutation.

Type 1 plasminogen deficiency is a rare genetic disorder. Type 1 plasminogen deficiency is characterized by fibrin-rich pseudomembrane formation on mucosal surfaces, particularly the conjunctiva. Tracheobronchial tree involvement is a less common reported manifestation of type 1 plasminogen deficiency. Pseudomembranes in the tracheobronchial tree may result in respiratory compromise and ultimately fail if not recognized and treated. Currently, there is no specific replacement therapy approved for the treatment of congenital plasminogen deficiency. In the present paper, we report that type 1 plasminogen deficiency with novel frameshift mutation and pulmonary involvement was treated initially with systemic fresh frozen plasma followed by pulmonary lavage with fresh frozen plasma and tissue plasminogen activator.

Inherited SLP76 deficiency in humans causes severe combined immunodeficiency, neutrophil and platelet defects.

The T cell receptor (TCR) signaling pathway is an ensemble of numerous proteins that are crucial for an adequate immune response. Disruption of any protein involved in this pathway leads to severe immunodeficiency and unfavorable clinical outcomes. Here, we describe an infant with severe immunodeficiency who was found to have novel biallelic mutations in SLP76. SLP76 is a key protein involved in TCR signaling and in other hematopoietic pathways. Previous studies of this protein were performed using Jurkat-derived human leukemic T cell lines and SLP76-deficient mice. Our current study links this gene, for the first time, to a human immunodeficiency characterized by early-onset life-threatening infections, combined T and B cell immunodeficiency, severe neutrophil defects, and impaired platelet aggregation. Hereby, we characterized aspects of the patient's immune phenotype, modeled them with an SLP76-deficient Jurkat-derived T cell line, and rescued some consequences using ectopic expression of wild-type SLP76. Understanding human diseases due to SLP76 deficiency is helpful in explaining the mixed T cell and neutrophil defects, providing a guide for exploring human SLP76 biology.

Age-Dependent Sensory Impairment in COVID-19 Infection and its Correlation with ACE2 Expression.

Among individuals who tested positive for coronavirus disease 2019, smell and taste sensations were significantly less impaired among children than among adults, in a stepwise manner. Sensory impairment was correlated with recent data of angiotensin-converting enzyme 2 expression in the corresponding age groups. This is the first report to compare sensory impairment in children and adults testing positive for coronavirus disease 2019.

[CURRENT KNOWLEDGE ON COVID-19 IN CHILDREN - CAUTIOUS OPTIMISM].

INTRODUCTION: The recent outbreak of COVID-19 which began in Wuhan, China in December 2019 and rapidly spread worldwide evolving into a pandemic, poses a global health emergency. As of mid-April over 2 million people have been infected with over 145 thousand casualties. The disease is more severe in the older population, whereas in children lower infection rates and milder symptoms are more common. Severe symptoms in the pediatric population, although uncommon, have been reported mainly in infants younger than 1 year of age. Perinatal transmission is infrequent and associated with a relatively mild illness in the newborn.

Author Correction: Human FCHO1 deficiency reveals role for clathrin-mediated endocytosis in development and function of T cells.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.