Humoral and cellular immunogenicity, effectiveness and safety of COVID-19 mRNA vaccination in patients with pediatric rheumatic diseases: A prospective cohort study.

OBJECTIVES: To evaluate immunogenicity, effectiveness and safety of COVID-19 vaccination in patients with pediatric autoimmune inflammatory rheumatic disease (pedAIIRD). METHODS: A prospective cohort study was performed at the pediatric rheumatology department of the Wilhelmina Children's Hospital in Utrecht, the Netherlands. Vaccination dates, COVID-19 cases and vaccine-related adverse events (AEs) were registered for all pedAIIRD patients during regular clinic visits from March 2021 - August 2022. SARS-CoV-2 IgG antibody levels and T-cell responses were measured from serum samples after vaccination, and clinical and drug therapy data were collected from electronic medical records. Rate of COVID-19 disease was compared between vaccinated and unvaccinated patients in a time-varying Cox regression analysis. RESULTS: A total of 157 patients were included in this study and 88 % had juvenile idiopathic arthritis (JIA). One hundred thirty-seven patients were fully vaccinated, of which 47 % used biological agents at the time of vaccination, and 20 patients were unvaccinated. Geometric mean concentrations (GMCs) of post-vaccine antibody levels against SARS-CoV-2 were above the threshold for positivity in patients who did and did not use biological agents at the time of vaccination, although biological users demonstrated significantly lower antibody levels (adjusted GMC ratio: 0.38, 95 % CI: 0.21 - 0.70). T-cell responses were adequate in all but two patients (9 %). The adjusted rate of reported COVID-19 was significantly lower for fully vaccinated patients compared to non-vaccinated patients (HR: 0.53, 95 % CI: 0.29 - 0.97). JIA disease activity scores were not significantly different after vaccination, and no serious AEs were reported. CONCLUSIONS: COVID-19 mRNA vaccines were immunogenic (both cellular and humoral), effective and safe in a large cohort of pedAIIRD patients despite their use of immunosuppressive medication.

Healthcare utilization is increased in children living in urban areas, with ethnicity-related disparities: A big data analysis study.

This study aimed to investigate differences in pediatric healthcare utilization in Israel over 10 years by examining differences across populations defined by living environment and ethnicity. Data was obtained from the Clalit Health Care data warehouse, covering over 250,000 children residing in Haifa and Western Galilee districts. The population groups were categorized based on ethnicity (Jewish vs Arab) and residential settings (urban vs rural). Healthcare utilization was consistently higher among Jewish than Arab children, irrespective of the specific dimension analyzed. Additionally, urban-dwelling children exhibited higher usage rates than those residing in rural areas in all investigated dimensions. However, Jewish children showed significantly about 18% lower hospitalization rates than Arab children across all years (P < 0.001). No significant differences in hospitalizations were observed between urban and rural children (RR 0.999, CI (0.987-1.011)). Notably, the study revealed reduced antibiotic consumption and hospitalizations over the years for all populations. Additionally, we found that Arab children and those living in rural areas had reduced access to healthcare, as evidenced by 10-40% fewer physician visits, laboratory tests, and imaging (P < 0.001).    Conclusion: This study highlights the substantial population-based disparities in healthcare utilization among children in Israel despite the equalizing effect of the national health insurance law. Rural and low socioeconomic populations seem to have reduced healthcare access, showing decreased healthcare utilization. Consequently, it is imperative to address these disparities and implement targeted interventions to enhance healthcare access for Arab children and rural communities. The decline in antibiotic usage and hospitalizations suggests positive trends in pediatric health care, necessitating ongoing efforts to ensure equitable access and quality of care for all populations. What is Known: • Healthcare systems worldwide vary in coverage and accessibility, including Israel, which stands out for its diverse population. • Existing research primarily focuses on healthcare utilization among adults, leaving a need for comprehensive data on children's healthcare patterns globally. What is New: • Investigating over 250,000 children, this study reveals higher healthcare utilization among Jewish and urban children across all dimensions. • Despite Israel's national health insurance law, the study underscores the significant population-based disparities in healthcare utilization.

The protective effect of COVID-19 vaccines on developing multisystem inflammatory syndrome in children (MIS-C): a systematic literature review and meta-analysis.

OBJECTIVE: To review whether the current COVID-19 vaccines can prevent the occurrence of multisystem inflammatory syndrome in children (MIS-C) and adolescents. METHODS: A systematic literature review and meta-analysis were performed. The data were abstracted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Primary outcome was the efficacy of COVID-19 vaccination in preventing MIS-C development. The search was performed in PubMed and Embase. RESULTS: The review yielded 13 studies, which were included for critical appraisal and data extraction. The available studies showed a reduced incidence of MIS-C after mRNA COVID-19 vaccination in children aged 12-18 years. Four studies were eligible for meta-analysis and the pooled odds ratio for MIS-C in vaccinated children compared to unvaccinated children was 0.04 (95% confidence interval: 0.03-0.06). Additionally, the risk of MIS-C as an adverse effect of vaccination was much lower compared to the risk of MIS-C post-infection. CONCLUSIONS: Our systematic review highlights the current available evidence on the efficacy of COVID-19 vaccination in preventing MIS-C. The published studies so far - mainly conducted during the Delta wave - indicate that (original strain) COVID-19 mRNA vaccines in children are safe and associated with significantly less development of MIS-C. These findings further reinforce the recommendation for COVID-19 vaccination in children, which should be promoted and largely supported.

Long-term immunoprotection after live attenuated measles-mumps-rubella booster vaccination in children with juvenile idiopathic arthritis.

INTRODUCTION: Vaccines, especially live attenuated vaccines, in children with JIA pose a great challenge due to both potential lower immunogenicity and safety as a result of immunosuppressive treatment. For many years, in the Netherlands, JIA patients receive a measles-mumps-rubella (MMR) booster vaccine at the age of nine years as part of the national immunization program. OBJECTIVES: To study long-term humoral immunoprotection in a large cohort of JIA patients who received the MMR booster vaccine while being treated with immunomodulatory therapies at the Wilhelmina Children's Hospital in Utrecht, the Netherlands. METHODS: MMR-specific IgG antibody concentrations in stored serum samples of vaccinated JIA patients were determined with chemiluminescent microparticle immunoassays (CMIA). Samples were analyzed five years after MMR booster vaccination and at last available follow-up visit using both crude and adjusted analyses. Additional clinical data were collected from electronic medical records. RESULTS: In total, 236 samples from 182 patients were analyzed, including 67 samples that were available five years post-vaccination, and an additional 169 samples available from last visits with a median duration after vaccination of 6.9 years (IQR: 2.8-8.8). Twenty-eight patients were using biologic disease-modifying antirheumatic drugs (bDMARDS) of whom 96% anti-TNF agents and 4% tocilizumab. Percentages of protective antibody levels against measles after five years were significantly lower for patients who used bDMARD therapy at vaccination compared to patients who did not: 60% versus 86% (P = 0.03). For mumps (80% versus 94%) and rubella (60% versus 83%) this difference did not reach statistical significance (P = 0.11 and P = 0.07, respectively). Antibody levels post-vaccination decreased over time, albeit not significantly different between bDMARD users and non-bDMARD users. CONCLUSION: The MMR booster vaccine demonstrated long-term immunogenicity in the majority of children with JIA from a large cohort, although lower percentages of protective measles antibody levels were observed in bDMARD users. Hence, it might be indicated to measure antibody levels at least five years after MMR booster vaccination in the latter group and advice an extra booster accordingly.

Safety of Measles-Mumps-Rubella booster vaccination in patients with juvenile idiopathic arthritis: A long-term follow-up study.

OBJECTIVES: To study short and long-term disease activity and vaccine-related adverse events in a cohort of JIA patients who received the live attenuated measles-mumps-rubella (MMR) booster vaccine while being treated with immunosuppressive and immunomodulatory therapies. METHODS: A retrospective study was performed in the UMC Utrecht, clinical and therapeutic data were collected from electronic medical records for two visits before and two visits after the MMR booster vaccine of JIA patients. Drug therapy was collected and adverse events related to the vaccine were requested from the patients during clinical visits or by short phone interviews. Associations between MMR booster vaccination and the active joint count, physician global assessment of disease activity, patient-reported visual analogue scale (VAS) for well-being and clinical Juvenile Arthritis Disease Activity Score (cJADAS) were analyzed using multivariable linear mixed effects analyses. RESULTS: A total of 186 JIA patients were included in the study. At the time of vaccination, 51% of the patients used csDMARD and 28% used bDMARD therapy. Overall, adjusted disease activity scores after MMR booster vaccination were not significantly different compared to pre-vaccination. Mild adverse events related to the MMR booster were reported for 7% of the patients. No serious adverse events were reported. CONCLUSION: MMR booster vaccination was safe and did not worsen disease activity during long-term follow-up in a large cohort of JIA patients being treated with both csDMARDs and biological DMARDs.

Retropharyngeal abscess-like as an atypical presentation of Kawasaki disease: a case report and literature review.

BACKGROUND: Kawasaki disease (KD) is a systemic inflammatory condition primarily affecting young children. Although 90% of KD patients present with variable head and neck manifestations, especially cervical lymphadenopathy, peritonsillar, retropharyngeal and parapharyngeal involvement are uncommonly reported as initial manifestations of KD. CASE REPORT: Eight-year-old girl with prolonged fever, clinical and a radiological picture suggestive of retropharyngeal abscess, unresponsive to three changes in the antibiotic regimen and surgical drainage. The disease progressed with the development of additional signs and symptoms as non-purulent conjunctivitis (with uveitis), mucosal involvement (strawberry tongue and cracked lips), edema of her hands and feet, and arthritis. A diagnosis of Kawasaki disease was reached with complete remission after Intravenous Immunoglobulin (IVIG) treatment. In addition, we present a literature review of similar cases reported in the last thirty years. CONCLUSION: Kawasaki disease requires a high index of suspicion and awareness of unusual presentations. It should be kept in mind as one of the differential diagnosis of patients with febrile inflammation of the retropharyngeal and parapharyngeal spaces who do not respond to antibiotic treatment in the relevant clinical context.

Pneumonia in the presentation of Kawasaki disease: The syndrome or a sequence of two diseases?

Two cases of Kawasaki disease (KD) presented as persistent lung consolidation associated with Group A Streptococcus and Influenza A co-infection, which resolved following intravenous immunoglobulin. Thus, pediatricians should consider the diagnosis of KD in the presence of pneumonia that is nonresponsive to antibiotic therapy with prolonged fever and inflammatory reactions.

Periorbital Edema as the Initial Manifestation of Pediatric Systemic Lupus Erythematosus.

Periorbital edema as a sole initial manifestation, without any evidence of other significant cutaneous or systemic involvement, is rare in systemic lupus erythematosus (SLE). We report a 16 year-old female who presented with bilateral periorbital edema as the sole initial manifestation of SLE. As the disease progressed, a kidney biopsy was performed demonstrating lupus nephritis stage II. This report emphasizes the importance of the index of suspicion of SLE as one of the differential diagnosis of patients with periorbital edema in the relevant clinical context.

Case Series of Myocarditis Following mRNA COVID Vaccine Compared to Pediatric Multisystem Inflammatory Syndrome: Multicenter Retrospective Study.

INTRODUCTION: Since the development of COVID-19 vaccines, more than 4.8 billion people have been immunized worldwide. Soon after vaccinations were initiated, reports on cases of myocarditis following the second vaccine dose emerged. This study aimed to report our experience with adolescent and young adults who developed post-COVID-19 vaccine myocarditis and to compare these patients to a cohort of patients who acquired pediatric inflammatory multisystem syndrome (PIMS/PIMS-TS) post-COVID-19 infection. METHODS: We collected reported cases of patients who developed myocarditis following COVID-19 vaccination (Pfizer mRNA BNT162b2) from all pediatric rheumatology centers in Israel and compared them to a cohort of patients with PIMS. RESULTS: Nine patients with post-vaccination myocarditis were identified and compared to 78 patients diagnosed with PIMS. All patients with post-vaccination myocarditis were males who developed symptoms following their second dose of the vaccine. Patients with post-vaccination myocarditis had a shorter duration of stay in the hospital (mean 4.4 ± 1.9 vs. 8.7 ± 4.7 days) and less myocardial dysfunction (11.1% vs. 61.5%), and all had excellent outcomes as compared to the chronic changes among 9.2% of the patients with PIMS. CONCLUSION: The clinical course of vaccine-associated myocarditis appears favorable, with resolution of the symptoms in all the patients in our cohort.

Rheumatic fever in a developed country - is it still relevant? A retrospective, 25 years follow-up.

BACKGROUND: Our aims were to clinically and epidemiologically characterize rheumatic fever (RF) in the current era in Israel. Although there has been a steady decline in the incidence of RF in the western world, evidence of disease resurgence in developed countries continues to be published. The paucity of recent epidemiological data prompted our study. METHODS: Medical files were retrospectively reviewed for all children with RF in our tertiary pediatric university-affiliated hospital from 1993 to 2017. Main outcome measures were patients and disease related characteristics, incidence trends, risk factors, disease course, relapse rates and secondary prophylaxis. RESULTS: The cohort included 307 children. Sixty-four percent presented with arthritis, interestingly including hips and small joints of hands and feet at presentation, 52% presented with carditis. Severe carditis developed in 31 patients (19.5%), of whom 21 (13.2% of all carditis patients) acquired heart failure, 5 required intensive care monitoring, with one recent death. The percentage of patients with acute carditis of the overall RF patients remained relatively stable. Thirty-two patients (10% of patients with RF) relapsed, including 11 with a cardiac relapse (3.6% of all cardiac patients). The recurrence rate of RF continued to rise up to 9 years from the initial episode. One of 147 patients (< 0.7%) with a non-cardiac initial presentation had carditis at relapse. CONCLUSION: RF and rheumatic heart disease remain an important cause of morbidity and mortality including developed countries, with relapse rate continuing after 9 years of prophylaxis. Presentation of small joints as well as hips, although uncommon, should not exclude the diagnosis.

Assistance of Medical Clowns Improves the Physical Examinations of Children Aged 2-6 Years.

BACKGROUND: A good physical exam is necessary to help pediatricians make the correct diagnosis and can save unnecessary imaging or invasive procedures. Distraction by medical clowns may create the optimal conditions for a proper physical examination. METHODS: Children aged 2-6 years who required physical examination in the pediatric emergency department were recruited and randomly assigned to one of two groups: physical exam by a pediatrician in the presence of caregivers vs. physical exam with the assistance of a medical clown. Outcome measures consisted of the level of child's discomfort, anxiety, and the quality of the physical examination. RESULTS: Ninety three children participated. Mean age was 3.3 ± 3.6 years (range 2-6). The duration of the physical exam was similar between the clown and control groups (4.6 ± 1.4 minutes vs. 4.5 ± 1.1 minutes (P = 0.64). The duration of discomfort was shorter in the clown group (0.2 ± 0.6 minutes) than the control group(1.6 ± 2.0 minutes, P = 0.001). In the medical clown group, 94% of pediatricians reported that the medical clown improved their ability to perform a complete physical examination. A trend of less hospitalization in the medical clown group was also noticed (11.3% in the medical clown group vs. 18.3% in the control group, P = 0.1); however, further study is required to verify this observation. CONCLUSIONS: Integration of a medical clown in physical examination improves the overall experience of the child and the caregivers and helps the pediatrician to perform a complete physical examination.

Fear of clowns in hospitalized children: prospective experience.

Medical clowns (MC) have become an integral part of the pediatric staff of hospital wards. While several studies have demonstrated the huge benefits of MC, there are almost no data regarding fear of clowns, a known phenomenon that means an irrational fear of clowns. In the current study, we sought to examine the prevalence of fear of clowns in pediatrics wards, and to characterize the affected children. The clinical work of three certified MCs was prospectively assessed. Every child with fear of clowns was noted, data were retrieved from the medical records, and the parents/child completed a specific questionnaire with a research assistant. Fear of clowns was defined as crying, anxiety response or effort to avoid contact with the MCs in small children, while in older children, it was determined if the child either reported fear of MCs or made actions to avoid clowns' intervention. A total of 1160 children participated in the study. All were hospitalized in the department of pediatrics or the pediatric emergency medicine department at Carmel Medical Center, and were exposed to a MC intervention session. Of the 1160 children, 14 children experienced fear of clowns (1.2%). The average age of children who experienced fear of clowns was 3.5 years (range 1-15). Interestingly, most of the children demonstrating fear of clowns were girls (12 out of 14, 85.7%). We found no association between fear of clowns and specific diagnosis, fever, clinical appearance, religion, or ethnicity. CONCLUSION: The prevalence of fear of clowns in the general pediatric hospitalized population was 1.2%, with a significant predominance of girls (85.7%). Children who experienced significant fear of clowns also experienced significant fear of encountering or thinking about a MC visit. Fear of clowns can affect children at any age (range 1-15), any ethnicity, religion, or degree of illness. Further large scale studies are required to better understand this unique phenomenon of fear of clowns. What is Known: • Fear of clowns is a phenomenon known for more than several decades and related to the increased use of clowns as negative characters in horror movies and TV shows. • The increased use of medical clowns in hospital wards and corridors increases the significance of defining and characterizing this phenomenon in hospital wards. What is New: • The study is novel by giving new data related to the extent of fear of clowns in pediatrics wards and giving demographic characteristic of children experiencing fear of clowns.