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.

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.

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.

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 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.

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.

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.

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.

The Sesame-Peanut Conundrum in Israel: Reevaluation of Food Allergy Prevalence in Young Children.

BACKGROUND: Food allergies (FAs) are on the rise worldwide. A previous cross-sectional study from 2002 in Israel estimated the prevalence of IgE-mediated FA among young children at 0.85%. Although sesame was found to be a common allergen, peanuts were found to be a rare allergen. OBJECTIVE: To determine the prevalence and distributions of IgE-mediated FAs among young children in Israel compared with previous data. METHODS: A total of 1932 young children (56% males, 44% females) with a mean age of 22.4 months (range, 18-30 months) were sequentially recruited from 15 government family health care centers in north Israel. Parents completed a questionnaire with 2 screening questions for suspected FA. Subjects with suspected FA underwent further evaluation including telephone interview, skin prick tests, and oral food challenge as needed. RESULTS: After analyzing the questionnaires, 146 subjects were suspected to have FA. Seventy-nine subjects were excluded by telephone interview and 13 were excluded on the basis of negative oral food challenge. We identified 54 of 1932 (2.8%) young children with 75 IgE-mediated FAs. Thirty-nine of 54 (72.2%) had allergy to 1 food and 9 (16.6%) to 2 foods. The most common food allergens were cow's milk (1%), eggs (0.88%), sesame (0.93%), tree nuts (0.57%), peanuts (0.2%), and fish (0.2%). CONCLUSIONS: The prevalence of IgE-mediated FA among young children in Israel has increased dramatically from 0.85% to 2.8%. The relative prevalence of the most common food allergens is similar to that identified in 2002, with a high prevalence of sesame FA and low prevalence of peanut FA.

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.

Kawasaki disease with a concomitant primary Epstein - Barr virus infection.

BACKGROUND: Kwasaki disease (KD) is the leading cause of acquired heart disease in children in most developed countries. The cause of KD remains unknown. The presumed theory is that KD occurs due to one or more infectious agents who evoke an abnormal immunological response in susceptible individuals. Epstein - Barr virus (EBV) infection has been considered as a suspected causative agent because of the potential effect on the immune system. CASE PRESENTATION: A previously healthy 19 month old boy presented with a 6 day history of fever accompanied by a diffuse macular erythematous rash that appeared 1 day after. The physical examination on admission revealed bilateral non-suppurative conjunctivitis, dry fissured and injected lips without "strawberry" tongue, diffuse macular rash on the trunk, face and limbs, swelling of the hands and feet, and right cervical lymphadenopathy (2 cm in diameter). Following fulfillment of all the clinical criteria, the diagnosis of KD was made and treatment with IVIG 2 g/Kg was administered along with oral aspirin (80 mg/ kg/day). However, despite the treatment, he remained febrile for an additional 2 days with persistent clinical manifestations. Therefore, he received a second 2 g/kg IVIG course with a favorable response. On the 14th day of illness the patient became febrile again and was readmitted. Blood examinations revealed remarkable leukocytosis up to 35.7 X 109/L with 87.3% lymphocytes and the blood smear revealed atypical lymphocytes and monocytes. The liver enzymes were elevated. The serology for infectious mononucleosis from his first admission revealed: IgM CMV (+), IgG CMV (-); IgM VCA EBV (+) IgG VCA EBV (-), IgG EBNA (-). To confirm infectious mononucleosis following the administration of 2 doses of IVIG, serum EBV PCR was performed and was positive (1.6X 103 cp/ml). CONCLUSIONS: We describe here a case of KD with a concomitant primary EBV infection. To the best of our knowledge, this is the first case in western country that describes KD with acute EBV infection as confirmed by PCR. The case we described stands as a contribution in favor of the possible role of EBV in the development of KD.

Characterization of Congenital Toxoplasmosis in Israel: A 17-year Nationwide Study Experience.

BACKGROUND: Congenital toxoplasmosis (CT) can cause significant neurologic manifestations and other untoward sequelae. Neither the current epidemiology nor the disease severity of CT in Israel is known. METHODS: Records of CT were collected from the National Toxoplasmosis Reference Laboratory and from 15 medical centers across Israel between 2001 and 2017. Eligible case-patients were fetuses or infants <12 months of age at the time of diagnosis. RESULTS: Of the 43 CT cases identified, 24 (55%) were in Jews and the remaining 19 cases were in patients of Arab (non-Bedouin) origin. The overall annual estimated rate of symptomatic CT was calculated as 0.55 per 100,000 live births. One or more severe clinical manifestations were reported in 12 (46%) of the 28 live-born infants and included cerebral calcifications (7 cases), chorioretinitis (4 cases), hydrocephalus (2 cases) and 1 case of death. Sensitivities of blood polymerase chain reaction (PCR), cerebrospinal fluid PCR and IgM antibody tests were 50% each. However, analyzing PCR samples from both sites, together with IgM testing, increased the sensitivity to 93%. CONCLUSIONS: The relative rate of severe manifestations was higher than in previous European reports. It is possible that the greater disease severity observed in Israel is in part due to the lack of systematic antenatal treatment and screening. Arab (non-Bedouin) infants are at higher risk for contracting CT. Performing serologic and PCR tests simultaneously is essential to improve CT diagnosis. This study demonstrates a need for an educational program to target high-risk populations.

Minor Clinical Impact of COVID-19 Pandemic on Patients With Primary Immunodeficiency in Israel.

In the last few months the world has witnessed a global pandemic due to severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection causing coronavirus disease 2019 (COVID-19). Obviously, this pandemic affected individuals differently, with a significant impact on populations considered to be at high-risk. One such population, was assumed to be patients with primary genetic defect involving components or pathways of the immune system. While human immunity against COVID-19 is not fully understood, it is, so far, well documented, that both adaptive and innate cells have a critical role in protection against SARS-CoV-2. Here, we aimed to summarize the clinical and laboratory data on primary immunodeficiency (PID) patients in Israel, who were tested positive for SARS-CoV-2, in order to estimate the impact of COVID-19 on such patients. Data was collected from mid-February to end-September. During this time Israel experienced two "waves" of COVID-19 diseases; the first, from mid-February to mid-May and the second from mid-June and still ongoing at the end of data collection. A total of 20 PID patients, aged 4 months to 60 years, were tested positive for SARS-CoV-2, all but one, were detected during the second wave. Fourteen of the patients were on routine monthly IVIG replacement therapy at the time of virus detection. None of the patients displayed severe illness and none required hospitalization; moreover, 7/20 patients were completely asymptomatic. Possible explanations for the minimal clinical impact of COVID-19 pandemic observed in our PID patients include high level of awareness, extra-precautions, and even self-isolation. It is also possible that only specific immune pathways (e.g. type I interferon signaling), may increase the risk for a more severe course of disease and these are not affected in many of the PID patients. In some cases, lack of an immune response actually may be a protective measure against the development of COVID-19 sequelae.