NFκB pathway dysregulation due to reduced RelB expression leads to severe autoimmune disorders and declining immunity.

BACKGROUND: Genetic aberrations in the NFκB pathway lead to primary immunodeficiencies with various degrees of severity. We previously demonstrated that complete ablation of the RelB transcription factor, a key component of the alternative pathway, results in an early manifested combined immunodeficiency requiring stem cell transplantation. OBJECTIVE: To study the molecular basis of a progressive severe autoimmunity and immunodeficiency in three patients. METHODS: Whole exome sequencing was performed to identify the genetic defect. Molecular and cellular techniques were utilized to assess the variant impact on NFκB signaling, canonical and alternative pathway crosstalk, as well as the resultant effects on immune function. RESULTS: Patients presented with multiple autoimmune progressive severe manifestations encompassing the liver, gut, lung, and skin, becoming debilitating in the second decade of life. This was accompanied by a deterioration of the immune system, demonstrating an age-related decline in naïve T cells and responses to mitogens, accompanied by a gradual loss of all circulating CD19+ cells. Whole exome sequencing identified a novel homozygous c. C1091T (P364L) transition in RELB. The P364L RelB protein was unstable, with extremely low expression, but retained some function and could be transiently and partially upregulated following Toll-like receptor stimulation. Stimulation of P364L patient fibroblasts resulted in a marked rise in a cluster of pro-inflammatory hyper-expressed transcripts consistent with the removal of RelB inhibitory effect on RelA function. This is likely the main driver of autoimmune manifestations in these patients. CONCLUSION: Incomplete loss of RelB provided a unique opportunity to gain insights into NFκB's pathway interactions as well as the pathogenesis of autoimmunity. The P364L RelB mutation leads to gradual decline in immune function with progression of severe debilitating autoimmunity.

Higher Rates of Hospitalizations among Pediatric Refugees than Local Population Attending the Emergency Department and Longer In-patient Stay.

BACKGROUND: The global refugee crises have raised concerns among medical communities worldwide; nonetheless, access to healthcare has rarely been studied even though refugees are a medically high-risk group. OBJECTIVES: To compare pediatric department admission rates from the pediatric emergency department (PED) of refugees and Israelis. METHODS: We compared data from refugee and Israeli children admitted to the pediatric department at Wolfson Medical Center in Israel between 2013-2017. RESULTS: A total of 104,244 patients (aged 0-18 years) came to the PED. Admission rate to the pediatric department for refugees was 695/2541 (27%) compared to 11,858/101,703 (11.7%) Israeli patients (P < 0.001). Hospital stay for patients 0-2-years of age was 3.22 ± 4.80 days for refugees vs. 2.78 ± 3.17 for Israelis (P < 0.03). Re-admission rate within 7 days was 1.3% for refugees and 2.6% for Israelis (P < 0.05). Dermatological diseases (e.g., impetigo and cellulitis) were more frequent in refugees (23.30% vs. 13.15%, P < 0.01); however, acute gastroenteritis and respiratory diagnoses were more common in Israelis (18.52% vs. 11.72%, P < 0.05 and 14.84% vs. 6.26%, P < 0.01, respectively). Neurological diseases (e.g., febrile convulsions) were also more frequent in Israelis (7.7% vs. 3%, P < 0.05). Very significantly, 23% of refugees had no healthcare coverage, while only 0.2% of the Israelis had none (P < 0.001). CONCLUSIONS: We found significant morbidity in refugees compared to the local Israeli pediatric population, highlighting the need for different approaches for each population.

Pediatrician, watch out for corona-phobia.

The current outbreak of COVID-19 raging globally is taking a heavy toll on the adult population, with a rapidly growing number of newly infected and critically ill patients. However, to date, mortality rate among children is low as they mostly suffer from a mild disease. Yet, other more routinely encountered childhood diseases do not stand still and continue to be the main share of pediatricians' everyday challenges. Here we describe a case series of routinely seen pediatric diseases with delayed diagnosis due to different aspects of what we call "Corona-phobia". These cases were easily collected within a 1-week period which implies that this is a more widespread phenomenon.In conclusion, this raises the possibility that measures taken to mitigate this pandemic may be more damaging to children overall than the virus itself. We believe that pediatricians as well as policy makers should take this important aspect into consideration. What is Known: • COVID-19 manifests as a mild disease in most children; however, children are an important reservoir and may become spreaders of the disease. • Social distancing and isolation are important tools in mitigating COVID-19 transmission. What is New: • This case series describes 7 cases with delayed diagnosis of every-day pediatric diseases that were not caused by COVID-19 but were highly influenced by different aspects of "Corona-phobia". • Our objective is to highlight the possibility that measures taken to mitigate this pandemic may lead to a substantial delay in the diagnosis of other non-COVID-19 related diseases.

Home-video EEG monitoring in a pediatric setting.

Introduction: Pediatric video-EEG monitoring is a standard procedure in epilepsy clinics, typically conducted in in-hospital settings.However, hospitalizationis sometimesunnecessary and imposes a burden on children and their families. In response to the rise of telehealth, home video-EEG monitoring has emerged, utilizing portable EEG equipment and video-cameras. Objective: The aim of this study was to assess the feasibility of home video-EEGin a pediatric population. Methods: We conducteda prospective pilot study of twentyhome video-EEG tests in children. We evaluated the quality of EEG and video recordings using a 5-point scale.Demographic, clinical and quality data were comparedto a similar group undergoing in-hospital video-EEG monitoring. Results: Twenty children aged 2.1-17.2 years (mean 9.57 ± 1.01), 12 females (60 %), underwent home video-EEG. A higher proportion of children with intellectual disability/autism were observed in the home-EEG group compared to the in-hospital group: 12 patients (60 %) vs. 5 (25 %) (p < 0.05*, Fisher exact test). In the ambulatory group patients with developmental and epileptic encephalopathy were overrepresented (7 i.e., 35 % vs. 0), while those withself-limited childhood epilepsy were more prevalent in the in-hospital group (5 i.e., 25 % vs 0) (p < 0.05*, Chi square). In the ambulatory group the reasons for referral were seizure localization/classification in 11 patients (55 %), paroxysmal event classification in 5 (25 %) and quantification of sleep epileptic activity in 4(20 %),similar to the in-hospital group (40 %, 40 % and 20 % respectively, p > 0.05, Chi square). The quality of the EEG recording was higher compared to in-hospital tests: median 5 [IQR 3.25-5] vs 4[IQR 3-4] (p < 0.05*, Mann-Whitney U test), while the quality of video recording was lower compared to in-hospital recordings: median 3[IQR 2.25-4] vs 5[IQR4-5] (p < 0.01**, Mann-Whitney U test). Conclusions: Home video-EEG monitoring is apromising option forlong-termpediatric EEG monitoring, particularlyfor children with special needs.

Defining combined immunodeficiency.

BACKGROUND: Although the extreme condition of typical profound T-cell dysfunction (TD), severe combined immunodeficiency (SCID), has been carefully defined, we are currently in the process of better defining less typical T-cell deficiencies, which tend to present with autologous circulating T-cell combined immunodeficiency (CID). Because autologous cells might interfere with the outcome of bone marrow transplantation, protocols usually include conditioning regimens. Therefore it is important to define the numbers of autologous cells usually detected in patients with CID versus those with SCID. OBJECTIVES: We sought to determine the number of circulating T cells in patients with SCID as opposed to those with CID, to study their function, and to evaluate their possible detection during newborn screening using T-cell receptor excision circle (TREC) analysis. METHODS: Numbers of circulating CD3(+) T cells (as determined by means of flow cytometry), in vitro responses to PHA, and TREC levels, all measured at presentation, were compiled from the research charts of the entire cohort of patients followed prospectively for T-cell immunodeficiency at the Hospital for Sick Children. Clinical data were ascertained retrospectively from the patient's hospital charts. RESULTS: One hundred three patients had CD3(+) determinations, and 80 of them had a genetic diagnosis. All patients considered to have typical SCID had CD3(+) T-cell counts of fewer than 500 cells/µL. Some variability was observed among different genotypes. In vitro responses to PHA were recorded in 88 patients, of whom 68 had a genetic diagnosis. All patients with low CD3(+) T-cell numbers (<500 cells/µL) also had markedly decreased responses to PHA (typical SCIDs). However, responses ranged widely in the groups of patients with TD who had more than 500 CD3(+) autologous circulating T cells per microliter. Although patients with Omenn syndrome and ζ chain-associated protein, 70 kDa (ZAP70), and purine nucleoside phosphorylase (PNP) deficiencies had low responses, patients with the p.R222C mutation in the IL-2 receptor γ(IL2RG) gene as well as IL-10 receptor and CD40 ligand deficiencies had normal or near-normal mitogen responses. Finally, 51 patients had TREC levels measured. All patients with typical SCID, Omenn syndrome, and ZAP70 deficiency had low TREC levels. In contrast, patients with mutations in forkhead box protein 3 (FOXP3), CD40 ligand (CD40L), and IL-10 receptor α(IL10RA), as well as patients with the p.R222C mutation in the IL2RG gene, had normal TREC levels. CONCLUSION: Patients with typical SCID can be defined as having fewer than 500 circulating CD3(+) T cells. Most patients with autologous T cells still have profound TD, as defined by reduced in vitro function and thymus output. Some patients with conditions including TD have normal TREC levels and will therefore not be detected in a TREC-based newborn screening program.

Sesame seed food allergy.

The number of reports regarding sesame seed food allergy (SFA) has increased significantly worldwide over the past two decades, either due to a genuine increase in SFA or merely an increase in its awareness. Its prevalence is difficult to estimate due to the lack of well designed prospective population-based studies. Based on the available data, we estimate that SFA affects 0.1-0.2 % of the population, in areas where the food is available. Albeit this prevalence appears to be relatively low, it is approximately one-half of that of persistent cow's milk allergy. While only one fatality has been reported, the significant number of SFA patients presenting as anaphylaxis indicates the potential risk. Many reports based the diagnosis of SFA on sensitization criteria alone, particularly amongst atopic dermatitis patients. Elimination of sesame from the diet of these children utilizing such criteria is not justified, and may even increase the risk for developing SFA.

The impact of the COVID-19 pandemic on respiratory morbidity during infancy: A birth-cohort study.

OBJECTIVE: To evaluate the incidence of wheezing and overall respiratory morbidity in healthy infants born during the first peak of the coronavirus disease-2019 (COVID-19) pandemic, compared with infants born during the preceding year. METHODS: This was a single-center retrospective birth cohort study to compare a cohort of children born between February and March 2020 (COVID-19 group) to a control group of children born between February and March 2019 (pre-COVID-19 group). At 1 year of age, we collected respiratory data using parental and telephone questionnaires. PRIMARY OUTCOME: wheezing incidence and/or bronchodilator use. SECONDARY OUTCOMES: recurrent wheezing, emergency-room visits, hospital admissions, pneumonia diagnosis, and admissions due to lower-respiratory-tract-infections (LRTI). We included the following covariate risk factors in the logistic regression models; atopy, daycare attendance, breastmilk feeding, parental smoking, C-section, siblings, and gestational age. RESULTS: We enrolled 588 infants, 294 in each group (48% males). Demographic, perinatal, and atopic characteristics were similar between the groups. Compared to the pre-COVID-19 group, infants born during the COVID-19 period were significantly less likely to report wheezing and/or bronchodilator use (adjusted-odds ratio [OR], 0.4; 95% confidence interval [CI] 0.28-0.59), systemic steroid use, (adjusted-OR, 0.47; 95% CI 0.24-0.91), emergency-room visits (adjusted-OR, 0.36; 95% CI 0.17-0.72), LRTI admissions (adjusted-OR, 0.2; 95% CI 0.05-0.74), or pneumonia diagnosis (adjusted-OR, 0.22; 95% CI 0.09-0.53). CONCLUSIONS: This study investigated wheezing and respiratory morbidity over the first year of the COVID-19 pandemic in infants born during the first peak of COVID-19. The study demonstrated a significant decrease in most aspects of respiratory morbidity. A longitudinal follow-up study to explore the subsequent impact of these findings is warranted.

Bronchoscopy in the management of children from developing countries undergoing congenital heart surgery.

OBJECTIVES: To study the clinical characteristics and impact of bronchoscopy in children from developing countries, referred for cardiac surgery, through the "Save a Child's Heart" (SACH) organization. METHODS: We performed a retrospective hospital-chart review of SACH children (0-18 years old) referred between 2006 and 2021 who underwent fiberoptic bronchoscopy. We examined demographics, congenital-heart-disease (CHD) types, bronchoscopy's indications and findings, subsequent recommendations, number of ventilation, and intensive-care-unit days. The primary outcome was percent changes in management and diagnosis, following the bronchoscopy. We included a control group matched-for-age and CHD type, who did not undergo bronchoscopy. RESULTS: We performed 82 bronchoscopies in 68 children: 18 (26.5%) preoperatively; 46 (67.6%) postoperatively; and four (5.9%) both. The most prevalent CHDs were Tetralogy-of-Fallot (27.9%) and ventricular-septal-defect (19.1%). The main indications were persistent atelectasis (41%) and mechanical ventilation/weaning difficulties (27.9%). Bronchoscopic evaluations revealed at least one abnormality in 51/68 (75%) children. The most common findings were external airway compression (23.5%), bronchomalacia (19.1%), and mucus secretions (14.7%). Changes in management were made in 35 (51.4%) cases, with a major change made in 14/35 (40%) children. Compared to the control group, the children undergoing bronchoscopy were both ventilated longer (median 6 vs. 1.5 days, p < 0.0001) and stayed longer in the intensive care unit (median 1.5 vs. 18.5 days, p < 0.0001). CONCLUSION: A bronchoscopy is an important tool in the diagnosis and management of the unique group of children from developing countries with CHD referred for cardiac surgery. The results of our study, reveal a more complicated clinical course in children requiring bronchoscopy compared to controls.

The Burden of COVID-19 in Children and Its Prevention by Vaccination: A Joint Statement of the Israeli Pediatric Association and the Israeli Society for Pediatric Infectious Diseases.

As of October 2021, SARS-CoV-2 infections were reported among 512,613 children and adolescents in Israel (~33% of all COVID-19 cases). The 5-11-year age group accounted for about 43% (223,850) of affected children and adolescents. In light of the availability of the Pfizer-BioNTech BNT162b2 vaccine against COVID-19 for children aged 5-11 years, we aimed to write a position paper for pediatricians, policymakers and families regarding the clinical aspects of COVID-19 and the vaccination of children against COVID-19. The first objective of this review was to describe the diverse facets of the burden of COVID-19 in children, including the direct effects of hospitalization during the acute phase of the disease, multisystem inflammatory syndrome in children, long COVID and the indirect effects of social isolation and interruption in education. In addition, we aimed to provide an update regarding the efficacy and safety of childhood mRNA COVID-19 vaccination and to instill confidence in pediatricians regarding the benefits of vaccinating children against COVID-19. We reviewed up-to-date Israeli and international epidemiological data and literature regarding COVID-19 morbidity and its sequelae in children, vaccine efficacy in reducing COVID-19-related morbidity and SARS-CoV-2 transmission and vaccine safety data. We conducted a risk-benefit analysis regarding the vaccination of children and adolescents. We concluded that vaccines are safe and effective and are recommended for all children aged 5 to 11 years to protect them from COVID-19 and its complications and to reduce community transmissions. Based on these data, after weighing the benefits of vaccination versus the harm, the Israeli Ministry of Health decided to recommend vaccination for children aged 5-11 years.

Unintentional Acute Poisoning Related Emergency Department Visits in Children in a Single-Center: A Nine-Year Prospective Survey.

Pediatric morbidity due to unintentional poison exposure is a significant burden on public health. We prospectively characterize patterns of unintentional poison exposure in a single pediatric emergency department, using a detailed computerized questionnaire for all unintentional injuries admitted during 2009 to 2017. Out of 71,765 visits due to unintentional injuries, 252 children were admitted due to unintentional poison exposure. Most (198/252, 79%) were between 1 and 3 years of age. The majority of events (209/252, 82.9%) occurred at the patient's home and 81% (205/255) were classified as exploratory ingestion. In 41/252 (14%) cases, exposure to more than one substance was reported. Most events 231/293 (79%) involved medications and 21% were due to domestic products. Four medications account for 45% of the events (Paracetamol, Salbutamol, Antihypertensive, and Antidepressants). Opioids were responsible for only 1.7%. By, collaboration between government, public health, educational institutions and commercial companies, can the burden of pediatric unintentional poison exposure be reduced.

Lessons Learned From Five Years of Newborn Screening for Severe Combined Immunodeficiency in Israel.

BACKGROUND: Implementation of newborn screening (NBS) programs for severe combined immunodeficiency (SCID) have advanced the diagnosis and management of affected infants and undoubtedly improved their outcomes. Reporting long-term follow-up of such programs is of great importance. OBJECTIVE: We report a 5-year summary of the NBS program for SCID in Israel. METHODS: Immunologic and genetic assessments, clinical analyses, and outcome data from all infants who screened positive were evaluated and summarized. RESULTS: A total of 937,953 Guthrie cards were screened for SCID. A second Guthrie card was requested on 1,169 occasions (0.12%), which resulted in 142 referrals (0.015%) for further validation tests. Flow cytometry immune-phenotyping, T cell receptor excision circle measurement in peripheral blood, and expression of TCRVß repertoire for the validation of positive cases revealed a specificity and sensitivity of 93.7% and 75.9%, respectively, in detecting true cases of SCID. Altogether, 32 SCID and 110 non-SCID newborns were diagnosed, making the incidence of SCID in Israel as high as 1:29,000 births. The most common genetic defects in this group were associated with mutations in DNA cross-link repair protein 1C and IL-7 receptor α (IL-7Rα) genes. No infant with SCID was missed during the study time. Twenty-two SCID patients underwent hematopoietic stem cell transplantation, which resulted in a 91% survival rate. CONCLUSIONS: Newborn screening for SCID should ultimately be applied globally, specifically to areas with high rates of consanguineous marriages. Accumulating data from follow-up studies on NBS for SCID will improve diagnosis and treatment and enrich our understanding of immune development in health and disease.

Novel mutations in RAG1/2 and ADA genes in Israeli patients presenting with T-B-SCID or Omenn syndrome.

The relative frequency of the different forms of SCID may vary in different countries. The most frequent form in Israel is the autosomal-recessive T-B- SCID or Omenn syndrome while X-linked SCID is rare. We report our immunological and genetic analyses in multicentre study of patients presenting with either T-B- SCID or Omenn syndrome. Among 16 patients, we identified 7 novel mutations in 6 patients. In the RAG1 gene we detected two novel mutations: L454Q and 469 fs-4bpdel. In the RAG 2 gene: 3 novel mutations: D65Y, G157V, and E480X. One T-B- SCID patient was found to be a compound heterozygote for new mutations in the ADA gene: W264X and R235W. Prenatal diagnosis was performed in 8 families while others refused due to religious reasons. Identification of the new mutations expands our knowledge regarding the unique features of SCID phenotype in Israel and may help the families seeking for genetic counseling.

Screening criteria for diagnosis of infantile feeding disorders as a cause of poor feeding or food refusal.

OBJECTIVES: Infantile feeding disorders (IFDs) are a common cause of food refusal, failure to thrive, and vomiting, but they may be difficult to diagnose. We have previously identified certain patterns of pathological feeding and behaviors as high-risk characteristics for IFDs and subsequently developed the diagnostic Wolfson criteria. Here, we evaluate these high-risk behaviors and prospectively compare the Wolfson criteria with 2 existing classifications of IFD, the Chatoor and that in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). PATIENTS AND METHODS: Infants and young children referred for food refusal were invited to participate by completing a feeding pattern questionnaire. Following physicians' interview and examination, patients were scored by all 3 criteria and enrolled in a structured treatment program for IFD. Infants whose food refusal was associated with an organic cause served as a comparison group. The ability of the criteria to detect IFD and to predict response to therapy was compared with an intention-to-treat analysis. RESULTS: Eighty-five infants with new-onset IFD and 55 controls were included. The Wolfson criteria, Chatoor, and DSM-IV accurately diagnosed 100%, 77%, and 56% of the patients with IFD, respectively. Anticipatory gagging occurred in 47% of the children with IFD compared to 2% controls (P < 0.001). The response to therapy was similar among the 3 criteria (73-76%), suggesting that the Wolfson criteria did not incorrectly diagnose organic disease as IFD. The 20 infants who were diagnosed as having IFD by Wolfson but not by Chatoor responded equally well (80%) to an IFD treatment program. CONCLUSIONS: Diagnostic criteria of IFD that are based on food refusal, pathological feeding, and anticipatory gagging have a higher detection rate than the present criteria and are simpler to implement.

The pendulum between food protein-induced enterocolitis syndrome and IgE-mediated milk allergy.

UNLABELLED: The transition from milk protein-induced enterocolitis syndrome to IgE-mediated milk allergy is uncommon. Herein, we describe three infants that suffered from recurrent vomiting and restlessness in response to cow's milk formula with negative skin prick to milk and therefore diagnosed as milk protein-induced enterocolitis syndrome. After recovering and reintroducing cow's milk formula, they developed disseminated urticaria and positive skin prick test to cow milk compatible with IgE-mediated milk allergy. CONCLUSION: An infant that recovers from cow milk food-induced enterocolitis syndrome might develop afterward IgE-mediated cow milk allergy.

Recent use of formaldehyde-'free' hair straightening product and severe acute kidney injury.

Formaldehyde is present in hair straightening products even when labeled as formaldehyde-free. Inhaled absorption of formaldehyde causes renal tubular cytotoxicity. We report a teenager who developed severe acute kidney injury requiring renal replacement therapy shortly after exposure to a formaldehyde-'free' hair straightening product. Kidney biopsy showed acute tubular necrosis and images compatible with microcalcifications. Kidney function improved while on continuous venous-venous hemodialysis.

Safety and Tolerability of Mebendazole in Infants Under 1 Year of Age.

This paper presents the largest cohort to date of infants under 1 year of age treated with mebendazole. We evaluated the occurrence of mebendazole-associated clinical and laboratory toxicity as safety data in this age group are currently lacking.