Raising AWaRe-ness of Antimicrobial Stewardship Challenges in Pediatric Emergency Care: Results from the PERFORM Study Assessing Consistency and Appropriateness of Antibiotic Prescribing Across Europe.

BACKGROUND: Optimization of antimicrobial stewardship is key to tackling antimicrobial resistance, which is exacerbated by overprescription of antibiotics in pediatric emergency departments (EDs). We described patterns of empiric antibiotic use in European EDs and characterized appropriateness and consistency of prescribing. METHODS: Between August 2016 and December 2019, febrile children attending EDs in 9 European countries with suspected infection were recruited into the PERFORM (Personalised Risk Assessment in Febrile Illness to Optimise Real-Life Management) study. Empiric systemic antibiotic use was determined in view of assigned final "bacterial" or "viral" phenotype. Antibiotics were classified according to the World Health Organization (WHO) AWaRe classification. RESULTS: Of 2130 febrile episodes (excluding children with nonbacterial/nonviral phenotypes), 1549 (72.7%) were assigned a bacterial and 581 (27.3%) a viral phenotype. A total of 1318 of 1549 episodes (85.1%) with a bacterial and 269 of 581 (46.3%) with a viral phenotype received empiric systemic antibiotics (in the first 2 days of admission). Of those, the majority (87.8% in the bacterial and 87.0% in the viral group) received parenteral antibiotics. The top 3 antibiotics prescribed were third-generation cephalosporins, penicillins, and penicillin/ß-lactamase inhibitor combinations. Of those treated with empiric systemic antibiotics in the viral group, 216 of 269 (80.3%) received ≥1 antibiotic in the "Watch" category. CONCLUSIONS: Differentiating bacterial from viral etiology in febrile illness on initial ED presentation remains challenging, resulting in a substantial overprescription of antibiotics. A significant proportion of patients with a viral phenotype received systemic antibiotics, predominantly classified as WHO Watch. Rapid and accurate point-of-care tests in the ED differentiating between bacterial and viral etiology could significantly improve antimicrobial stewardship.

SARS-CoV-2 seroprevalence among children in Greece during Omicron variant period.

The Omicron variant is associated with increased transmissibility, but evidence about the impact of Omicron in seropositivity of children is limited. This study aims to evaluate SARS-CoV-2 seroprevalence in children during the different variants' subperiods. A prospective multicenter seroprevalence study was conducted in 7 University public hospitals in Greece from November 2021 to August 2022 (3 subperiods: November 2021-February 2022, March 2022-May 2022, June 2022-August 2022). Children from different age groups, admitted to the hospital or examined in outpatient clinics for reasons other than COVID-19 were enrolled. Neutralizing antibodies (Nabs), anti-Spike (anti-S) and anti-nucleocapsid (anti-N) SARS-CoV-2 IgG in serum were evaluated. A total of 2127 children (males:57,2%; median age:4,8years) were enrolled. Anti-N IgG seropositivity increased from 17,8% in the first sub-period to 40,7% in the second sub-period and then decreased in the third sub-period (36,7%). Anti-S IgG seropositivity appeared to have an increasing trend over the study period, starting from 34,8% and reaching 80,7%. Children aged 1-4 years old have significantly higher anti-N IgG titers compared to children aged 0-1 years old (p < 0,001). Infants have significantly lower anti-S IgG titers compared to all other age groups (p < 0,001). Immunocompromised children and infants have the lowest seropositivity for NAbs.Conclusions During the Omicron period, seropositivity significantly increased, as a result of higher transmissibility. Neonates and infants have lower antibody titers compared to other age groups, while young children aged 1-4 years old present higher antibody titers, suggesting that this age group may mount a higher antibody response. Continuous surveillance seroprevalence studies are needed in children, in order to identify the true extent of SARS-CoV-2 and guide the planning of adequate public health measures.

WHAT IS KNOWN: • Seroprevalence surveys among children may be extremely useful, in order to properly monitor the immunity, either natural or acquired, through the quantification of IgG antibodies and to plan further immunization policies. • There are variations in the seroprevalence of COVID-19 between the different periods, according to the vaccination rates, the type of circulating variant and the transmissibility of the virus. • The Omicron variant is associated with increased transmissibility, but evidence about the impact of Omicron in seropositivity of children is limited. WHAT IS NEW: • In this large multicenter seroepidemiological study, SARS-CoV-2 seroprevalence rate in children is higher during the Omicron period in comparison to the previous pandemic waves, due to the high transmissibility of the virus and the increased rates of reinfection. • Neonates and infants have lower antibody titers compared to other age groups, while young children aged 1­4 years old present higher antibody titers, indicating that the children of this age group mount a higher antibody response. • This study provides essential information about immunity and the level of protection in the pediatric population, as neutralizing antibodies were evaluated, in addition to the anti-N and anti-S IgG antibodies.

Multisystem inflammatory syndrome in children (MIS-C): A nationwide collaborative study in the Greek population.

Multisystem inflammatory syndrome in children (MIS-C) is a rare but severe hyperinflammatory condition that may occur following SARS-CoV-2 infection. This retrospective, descriptive study of children hospitalized with multisystem inflammatory syndrome in children (MIS-C) in 12 tertiary care centers from 3/11/2020 to 12/31/2021. Demographics, clinical and laboratory characteristics, treatment and outcomes are described. Among 145 patients (95 males, median age 8.2 years) included, 123 met the WHO criteria for MIS-C, while 112 (77%) had serological evidence of SARS-CoV-2 infection. Fever was present in 99%, gastrointestinal symptoms in 77%, mucocutaneous involvement in 68% and respiratory symptoms in 28%. Fifty-five patients (38%) developed myocarditis, 29 (20%) pericarditis and 19 (13%) coronary aneurysms. Among the above cases 11/55 (20%), 1/29 (3.4%) and 5/19 (26.3%), respectively, cardiac complications had not fully resolved at discharge. Underlying comorbidities were reported in 18%. Median CRP value was 155 mg/l, ferritin 535 ng/ml, PCT 1.6 ng/ml and WBC 14.2 × 109/mm3. Most patients had elevated troponin (41.3%) and/or NT-pro-BNP (49.6%). Intravenous immunoglobulin plus corticosteroids were used in 117/145 (80.6%), monotherapy with IVIG alone in 13/145 (8.9%) and with corticosteroids alone in 2/145 (1.3%). Anti-IL1 treatment was added in 15 patients (10.3%). Thirty-three patients (23%) were admitted to the PICU, 14% developed shock and 1 required ECMO. Mortality rate was 0.68%. The incidence of MIS-C was estimated at 0.69/1000 SARS-CoV-2 infections. Patients who presented with shock had higher levels of NT-pro-BNP compared to those who did not (p < 0.001). Acute kidney injury and/or myocarditis were associated with higher risk of developing shock. CONCLUSION: MIS-C is a novel, infrequent but serious disease entity. Cardiac manifestations included myocarditis and pericarditis, which resolved in most patients before discharge. Timely initiation of immunomodulatory therapy was shown to be effective. NT-pro-BNP levels may provide a better prediction and monitoring of the disease course. Further research is required to elucidate the pathogenesis, risk factors and optimal management, and long-term outcomes of this clinical entity. WHAT IS KNOWN: • MIS-C is an infrequent but serious disease entity. • Patients with MIS-C present with multi-organ dysfunction, primarily involving the gastrointestinal and cardiovascular systems. WHAT IS NEW: • NT-pro-BNP levels may provide a better prediction and monitoring of the disease course. • Acute kidney injury and/or myocarditis were associated with higher risk of developing shock.

Immunogenicity 6 months post COVID-19 mRNA vaccination among adolescents with juvenile idiopathic arthritis on treatment with TNF inhibitors.

OBJECTIVES: Mass vaccination is the most effective strategy for controlling the COVID-19 pandemic. This study aimed to evaluate the 6-month immunogenicity after BNT162b2-COVID-19 vaccination in adolescents with JIA on TNFi treatment. METHODS: This single-centre study included adolescents with JIA treated with TNFi for at least 18 months. Patients received two doses of COVID-19 vaccine (Pfizer-BioNTech) from 15 April to 15 May 2021. Quantitative measurement of IgG antibodies to SARS-CoV-2-spike-protein-1 was performed at 1, 3 and 6 months post-vaccination. RESULTS: Overall, 21 adolescents with JIA in clinical remission at the time of vaccinations were enrolled. None of them discontinued TNFi/MTX treatment at the time of vaccine administration or during the follow-up period. All patients developed a sustained humoral response against SARS-CoV-2 at 1 and 3 months after vaccination (P < 0.05). The antibody levels decreased significantly at 6 months post-vaccination (P < 0.01). The type of JIA did not reveal any differences in the humoral response at 3 (P = 0.894) or 6 months post-vaccination (P = 0.72). No difference was detected upon comparison of the immunogenicity between the different treatment arms (adalimumab vs etanercept) at 3 (P = 0.387) and 6 months (P = 0.526), or TNFi monotherapy vs combined therapy (TNFi plus methotrexate) at 3 (P = 0.623) and 6 months (P = 0.885). CONCLUSIONS: Although mRNA vaccines develop satisfactory immunogenicity at 1 month and 3 months post-vaccination in adolescents with JIA on TNFi, SARS-CoV-2 antibody titres decrease significantly overtime, remaining at lower levels at 6 months. Further collaborative studies are required to determine long-term immunogenicity, real duration of immune protection and the need for a booster vaccine dose.

Potential benefit from the implementation of the Kaiser Permanente neonatal early-onset sepsis calculator on clinical management of neonates with presumed sepsis.

To assess the potential benefit from the implementation of the Kaiser Permanente early-onset sepsis calculator (EOS-C), in terms of antibiotic use and requested laboratory tests, in a network of neonatal intensive care units (NICUs) in Greece, and to determine the incidence of early-onset sepsis (EOS) in Greek NICUs, a prospective surveillance study was conducted in 7 NICUs between April 2018 and June 2019. Data were collected for all newborns ≥ 34 weeks' gestation receiving empiric antibiotic therapy within the first 3 days of life. The number of live births and positive blood or cerebrospinal fluid cultures within the first 3 days of life were used for calculation of EOS incidence. Evaluation of possible impact of implementing the calculator was done by comparing the clinicians' recorded management to the calculator's suggested course of action. The unit-specific incidence of culture-proven EOS ranged between 0 and 2.99/1000 live births. The weighted incidence rate for all 7 units was 1.8/1000 live births. Management of EOS guided by the calculator could lead to a reduction of empiric antibiotic initiation up to 100% for the group of "well-appearing" neonates and 86% for "equivocal," lowering exposure to antibiotics by 4.2 and 3.8 days per neonate, respectively. Laboratory tests for blood cultures drawn could be reduced by up to 100% and 68%, respectively. Sensitivity of the EOS-C in identifying neonates with positive blood cultures was high.Conclusion: Management strategies based on the Kaiser Permanente neonatal sepsis calculator may significantly reduce antibiotic exposure, invasive diagnostic procedures, and hospitalizations in late preterm and term neonates. What is Known: • Neonates are frequently exposed to antibiotics for presumed EOS. • The Kaiser Permanente sepsis calculator can reduce antibiotic exposure in neonates.. What is New: • EOS calculator can be an effective antibiotic stewardship tool in a high prescribing country and can reduce invasive diagnostic procedures and mother-baby separation. • Incidence of EOS in Greece is higher compared to other European countries.

Child Car Safety: A Parental Survey at a Tertiary Care Emergency Treatment Center in Greece.

OBJECTIVES: This study aimed to assess parental behavior in terms of child restraint systems (CRS) use under emergency conditions while driving to the hospital's outpatient settings as well as their routine child car safety (CCS) practices. METHODS: A cross-sectional survey of parents/caregivers transporting children 13 years or younger was conducted at the Emergency Treatment Center of a pediatric tertiary care center in Athens, Greece. Participants completed a questionnaire inquiring about the possession of CRS, and type and use of appropriate CRS while driving to the Emergency Treatment Center and under routine conditions. In addition, presence and type of parental education with regard to CCS and the use of seat belts among drivers were assessed. RESULTS: Of 444 participants, 51.4% children were carried restrained, although 48.6% were fastened in an improper seat for their age, in contrast with 23.7% who travel unrestrained on a daily basis. Forward-facing restraint seats were most popular, with 53.9% total use even in children younger than 2 years or older than 4 years, whereas booster seats (9.4%) and rear-facing restraint seats (18.2%) were inappropriately disfavored. Children younger than 4 years, male drivers, and drivers who had received information on CCS had higher odds of using CRS. The proportion of those had never been provided any CCS education was 38.5%. CONCLUSIONS: Child restraint systems use was inappropriately low under routine conditions and declined even further under emergency circumstances. Most children younger than 2 years and older than 4 years traveled inappropriately restrained in a forward-facing restraint seat. Parents should be more intensively educated on child car safety seat and the proper CRS use.

A National Survey Across Primary Care Pediatricians Regarding Immunization Views and Practices in Children With Rheumatic Diseases.

METHODS: Cross-sectional survey conducted with an anonymous questionnaire of 34 items distributed to pediatricians via an online platform. Four hundred questionnaires were sent, and 256 were returned and analyzed using STATA 13. Data collection included demographics, questions on knowledge, perceptions, and opinions, as well as advice given to families. RESULTS: The majority of doctors felt that vaccination in children with RDs is essential. Responders were using a variety of guidelines to reach a clinical decision. Fifty percent were hesitant to adhere to the national vaccination scheme without expert input. Reasons were as follows: not convinced from current literature that the vaccine is safe (32%), afraid to cause disease flare (43%), and unable to deal with parental concerns/refusal (54%). Twelve percent of responders felt that the RD may have been triggered by a vaccine. The majority (82%) of doctors were pro annual influenza vaccination. Seventy percent of doctors were keener to administer booster doses rather than primary ones. CONCLUSIONS: Variation in opinion and clinical practice exists. Overall, although general pediatricians are informed regarding efficacy and adverse effects of immunizations in patients with RDs, there are steps to be made from principle to practice. Vaccinating these children is of vital importance, and primary care pediatricians should be updated regarding existing guidelines referring to this field.

Immunogenicity and side-effects of the inactivated hepatitis A vaccine in periodic fever, aphthous stomatitis, pharyngitis, and adenitis patients.

The aim of this study was to compare the immunogenicity and side-effects of hepatitis A virus (HAV) vaccination between periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) patients and healthy controls who have not been previously exposed to HAV. A prospective observational study was carried out of 28 PFAPA patients and 76 controls who received two doses of the vaccine. Immunogenicity was expressed as seroconversion and seroprotection rates; mean HAV-immunoglobulin G concentration was measured at 0, 1, 7 and 18 months. Side-effects were defined as incidence of adverse events and the effect of vaccination on PFAPA symptoms. All participants were seronegative and seroconverted at 1 month. One month after primary vaccination, 92.9% of PFAPA patients and 77.6% of the controls attained seroprotection, while the rates increased to 100% and 96.1%, respectively, 1 month after the second dose. Seroprotection rates remained adequate 1 year after completion of vaccination. In conclusion, two doses of the inactivated HAV vaccine are well-tolerated and effective in children with PFAPA.

Immunogenicity and safety of the inactivated hepatitis A vaccine in children with juvenile idiopathic arthritis on methotrexate treatment: a matched case-control study.

OBJECTIVES: To describe the immunogenicity and side effects of immunisation against hepatitis A virus (HAV) in JIA patients on methotrexate treatment, who have not been previously exposed to HAV. METHODS: Case-control study performed in JIA patients and healthy controls matched on age and gender. The subjects received two doses of inactivated anti-HAV vaccine (720 mIU/ml) intramuscularly at 0 and 6 months. Seroconversion, seroprotection rates and anti-HAV-IgG titres were measured at 1, 7 and 18 months. Children were monitored for adverse events. RESULTS: 83 JIA patients and 76 controls were enrolled in the study. At one month, seroprotection rates were lower in children with, as compared to those without JIA (48.2% vs. 65%; p=0.05). At 7 and 18 months, rates of seroprotection rose significantly and were similar in both groups. The titre of anti-HAV-IgG was lower in children with JIA than healthy children at all time points (p<0.001). Vaccines were well tolerated. CONCLUSIONS: Two doses of inactivated HAV vaccine were well tolerated and immunogenic in most immunosuppressed children with JIA; however, a single dose of HAV vaccine was insufficient to induce seroprotection in half of the patients. Further studies are required to analyse the long-term immunity against HAV in this population and optimal HAV immunisation regimen.

Characteristics of Bordetella pertussis infection among infantsand children admitted to paediatric intensive care units in Greece: A multicentre, 11-year study.

AIM: To describe children with pertussis who required intensive care. METHODS: This is a retrospective analysis of pertussis admissions to all (six) national intensive care units in Greece from 2003 to 2013. RESULTS: A total of 31 children were included, 28 of whom were younger than 12 months old. Cough was the most prominent symptom, being present in 27 of 31 (87%) patients, and on admission, only 7 (22.6%) satisfied the case definition. Mechanical ventilation was initiated in 13 (42%) patients. Six patients died because of respiratory failure (two) or multi-organ system failure (four). The patients who died had significantly higher white blood cell counts (WBC) (77 800-31 600, P = 0.031) and neutrophils (29 016-12 795, P = 0021) than those who survived and lower minimum values of serum sodium (125-133, P = 0002). They also had a longer duration of hospitalisation prior to their paediatric intensive care unit admission (6-1 days, P = 0022). Three patients were diagnosed with pulmonary hypertension, and only one of them survived. Age, gender and immunisation status did not differ between survivors and non-survivors. Two patients received exchange blood transfusion, and survival benefit was not apparent. CONCLUSION: Young infants are at risk of severe pertussis, resulting in serious complications or death. Elevated WBC and low serum sodium are associated with higher mortality. Despite advances in life support and treatment of organ failure in childhood critical illness, pertussis still has substantial mortality.

SARS-CoV-2 Antibody Kinetics in Unvaccinated Hospitalized Children With COVID-19.

BACKGROUND: Antibody levels decline a few months post-acute COVID-19, but humoral memory persists in adults. Age and disease severity may affect antibody responses. This study aims to evaluate the presence and durability of antibody responses in children with COVID-19. METHODS: A prospective, single-center study, involving unvaccinated children 0-16 years of age who were hospitalized with COVID-19 between October 2020 and December 2021, was conducted. Serological testing for anti-Spike severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) IgG and neutralizing antibodies was performed at diagnosis and at 1-, 3-, 6- and 12-months post-infection. RESULTS: A total of 65 immunocompetent children were enrolled [mean age (±SD): 6.7 (±6.4) years; males: 56.9%]. At 3 months, 40/44 (91%) children were seropositive; seropositivity persisted in 22/26 (85%) children at 6 months and in 10/12 (83%) children at 12 months. There was no evidence that age was modifying the prediction of variance of SARS-CoV-2 IgG levels. In contrast, SARS-CoV-2 IgG levels varied with time and disease severity. The association with time was non-linear, so that with increasing time there was a significant reduction in SARS-CoV-2 IgG levels [coef, 0.044 (95% confidence interval {CI}: 0.061-0.028), P < 0.001]. For each increment of time, the higher disease severity group was associated with 0.9 lower SARS-CoV-2 IgG levels. Everyone varied from the average effect of time with an SD of 0.01, suggesting that individuals may have different trajectories across time. CONCLUSION: Disease severity, but not age, influences antibody titers among children hospitalized with COVID-19. SARS-CoV-2 infection induces durable seroconversion in these children with detectable IgG levels at 1 year after infection.

Biofilm-Forming Bacteria Implicated in Complex Otitis Media in Children in the Post-Heptavalent Pneumococcal Conjugate Vaccine (PCV7) Era.

Background: Chronic media with effusion (COME) and recurrent acute otitis media (RAOM) are closely related clinical entities that affect childhood. The aims of the study were to investigate the microbiological profile of otitis-prone children in the post-PCV7 era and, to examine the biofilm-forming ability in association with clinical history and outcome during a two-year post-operative follow-up. Methods: In this prospective study, pathogens from patients with COME and RAOM were isolated and studied in vitro for their biofilm-forming ability. The minimum inhibitory concentrations (MIC) of both the planktonic and the sessile forms were compared. The outcome of the therapeutic method used in each case and patient history were correlated with the pathogens and their ability to form biofilms. Results: Haemophilus influenzae was the leading pathogen (35% in COME and 40% in RAOM), and Streptococcus pneumoniae ranked second (12% in COME and 24% in RAOM). Polymicrobial infections were identified in 5% of COME and 19% of RAOM cases. Of the isolated otopathogens, 94% were positive for biofilm formation. Conclusions: This is the first Greek research studying biofilm formation in complex otitis media-prone children population in the post-PCV7 era. High rates of polymicrobial infections, along with treatment failure in biofilms, may explain the lack of antimicrobial efficacy in otitis-prone children.

Decreasing Incidence of the Multisystem Inflammatory Syndrome in Children Over 3 Pandemic Waves.

In this nationwide retrospective study, a substantial decline in the incidence of multisystem inflammatory syndrome in children over 3 successive pandemic waves characterized by different severe acute respiratory syndrome coronavirus 2 variants was documented-from 3.4 of 1000 to 1.1 of 1000 and finally to 0.25 of 1000 confirmed severe acute respiratory syndrome coronavirus 2 positive cases (P < 0.0001), respectively, whereas clinical findings and severity did not significantly vary.

External validation of a multivariable prediction model for identification of pneumonia and other serious bacterial infections in febrile immunocompromised children.

OBJECTIVE: To externally validate and update the Feverkids tool clinical prediction model for differentiating bacterial pneumonia and other serious bacterial infections (SBIs) from non-SBI causes of fever in immunocompromised children. DESIGN: International, multicentre, prospective observational study embedded in PErsonalised Risk assessment in Febrile illness to Optimise Real-life Management across the European Union (PERFORM). SETTING: Fifteen teaching hospitals in nine European countries. PARTICIPANTS: Febrile immunocompromised children aged 0-18 years. METHODS: The Feverkids clinical prediction model predicted the probability of bacterial pneumonia, other SBI or no SBI. Model discrimination, calibration and diagnostic performance at different risk thresholds were assessed. The model was then re-fitted and updated. RESULTS: Of 558 episodes, 21 had bacterial pneumonia, 104 other SBI and 433 no SBI. Discrimination was 0.83 (95% CI 0.71 to 0.90) for bacterial pneumonia, with moderate calibration and 0.67 (0.61 to 0.72) for other SBIs, with poor calibration. After model re-fitting, discrimination improved to 0.88 (0.79 to 0.96) and 0.71 (0.65 to 0.76) and calibration improved. Predicted risk <1% ruled out bacterial pneumonia with sensitivity 0.95 (0.86 to 1.00) and negative likelihood ratio (LR) 0.09 (0.00 to 0.32). Predicted risk >10% ruled in bacterial pneumonia with specificity 0.91 (0.88 to 0.94) and positive LR 6.51 (3.71 to 10.3). Predicted risk <10% ruled out other SBIs with sensitivity 0.92 (0.87 to 0.97) and negative LR 0.32 (0.13 to 0.57). Predicted risk >30% ruled in other SBIs with specificity 0.89 (0.86 to 0.92) and positive LR 2.86 (1.91 to 4.25). CONCLUSION: Discrimination and calibration were good for bacterial pneumonia but poorer for other SBIs. The rule-out thresholds have the potential to reduce unnecessary investigations and antibiotics in this high-risk group.