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.

Management of children with febrile seizures: a Greek nationwide survey.

The purpose of this study was to investigate knowledge, principles, and practices concerning the management of children with febrile seizures among pediatricians in Greece. A cross-sectional study was performed across Greece. Pediatricians completed an anonymous and voluntary 11-item questionnaire about their knowledge, attitudes, and practices with respect to the management of febrile seizures; the survey also collected demographic data. It was first administered in paper form in October 2017. This was followed by an online survey performed between June and August of 2018 and publicized by medical boards across Greece. Descriptive statistics and comparisons between groups were conducted with the significance level set at p ≤ 0.05. We recorded 457 responses. Pediatricians admitted to modifying their advice to the parents of children with febrile seizures by suggesting more "aggressive" fever management at low temperatures or systematically (63%), referral to a specialist after any episode of febrile seizures (63%), or hospitalization in a subsequent episode (67%), even though 72% admitted these practices were of no efficacy. Almost one in three pediatricians (28%) believed aggressive management of fever could delay the onset of febrile seizures; increasing age was associated with this perception. A minority (28%) would make parents aware of febrile seizures before a first episode regardless of family history; 38% would do so in the event of family history. CONCLUSIONS: Several pediatricians in Greece use outdated and ineffective practices for the management of febrile seizures, despite the availability of updated evidence-based guidelines. Further training of practitioners is needed to bridge this gap. WHAT IS KNOWN: •Aggressive management of fever at low temperatures with antipyretics, referral to a neurologist, and hospitalization are not supported by evidence or recent guidelines on childhood febrile seizures. •Febrile seizures are especially disturbing to uninformed parents, who may be inclined to pursue aggressive but ineffective treatments as a result. WHAT IS NEW: •Pediatricians in Greece use non-evidence-based practices for the management of febrile seizures, even when they are aware that these practices are not effective. •Older age increases the likelihood that a pediatrician will pursue guideline non-compliant practices in Greece. At the same time, physicians with over 20 years of experience are more likely to inform parents in advance about febrile seizures.

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.

Real-life evaluation of a COVID-19 rapid antigen detection test in hospitalized children.

Rapid antigen detection (RAD) tests for the detection of SARS-CoV-2 are simpler, faster, and less expensive than the reverse-transcription polymerase chain reaction (RT-PCR) that is currently considered the gold standard for the diagnosis of coronavirus disease 2019 (COVID-19). The objective of this study was to determine the performance of the PANBIO COVID-19 Ag RAD (Abbott) test, a lateral flow immunoassay that detects the nucleocapsid protein, using as a reference RT-PCR method the Cobas®8800 System (Roche Diagnostics). This prospective study was conducted in a tertiary Children's Hospital and included individuals aged ≤16 years with COVID-19-related symptoms or epidemiological criteria for COVID-19. Two nasopharyngeal samples were collected to perform the PANBIO RAD test and RT-PCR. Of 744 children included, 51 (6.86%) had a positive RT-PCR result. The RAD test detected 42 of 51 PCR-positive children while there were no false-positive results. The overall sensitivity and specificity were 82.35% (95% CI, 71.9%-92.8%) and 100%, respectively. Sensitivity was >95% in symptomatic children. The assay performed poorly in asymptomatically infected children. In agreement with previous studies in adults, the PANBIO RAD test can be useful in screening for COVID-19 in children admitted with symptoms suggestive of the disease, especially in the first days of the illness.

Antibiotic prescribing and expenditures in outpatient paediatrics in Greece, 2010-13.

OBJECTIVES: The objectives of this study were to provide a nationally representative analysis of antibiotic prescribing in outpatient paediatrics and to assess overall and class-specific antibiotic costs in Greece. METHODS: Data on antibiotic prescriptions for patients aged ≤19 years old between July 2010 and June 2013 in Greece were extracted from the IMS Health Xponent database. Antibiotics were grouped into narrow- and broad-spectrum agents. The number of prescribed antibiotics and census denominators were used to calculate prescribing rates. The total costs associated with prescribed antibiotics were calculated. RESULTS: More than 7 million antibiotics were prescribed during the study period, with an annual rate of 1100 antibiotics/1000 persons. Prescribing rates were higher among children aged <10 years old. Acute respiratory tract infections (ARTIs) accounted for 80% of prescribed antibiotics, with acute otitis media (22.3%), acute tonsillitis (19.5%) and acute bronchitis/bronchiolitis (13.9%) being the most common clinical diagnoses. Cephalosporins (32.9%), penicillins (32.3%) and macrolides (32.1%) were the most commonly prescribed antibiotic classes. The majority (90.4%) of antibiotics were broad spectrum. Antibiotic expenditures totalled ∼€50 million. CONCLUSIONS: Broad-spectrum antibiotic prescribing is common in outpatient paediatric patients. These data provide important targets to inform the development of an outpatient antimicrobial stewardship programme targeting specific practices, providers and conditions.

Treatment with bortezomib-based regimens improves overall response and predicts for survival in patients with primary or secondary plasma cell leukemia: Analysis of the Greek myeloma study group.

Plasma cell leukemia (PCL) is a rare and aggressive plasma cell disorder, with poor outcome. Bortezomib-based regimens (BBR) are highly effective in myeloma, but there is limited information about their efficacy and safety in PCL. Thus, we retrospectively collected data from 42 consecutive PCL patients (25 with primary PCL-pPCL and 17 with secondary PCL-sPCL) to explore the role of BBR in this entity. BBR were administered in 29 of 42 patients, while 6 of 25 patients with pPCL underwent autologous transplantation. Objective response (≥partial response) was significantly higher in patients treated with BBR versus conventional therapies (69% vs. 30.8%, P = 0.04); 27.5% of patients treated with BBR achieved at least very good partial response (vgPR). The highest ORR was observed in pPCL patients treated with BBR (88.9%; ≥vgPR: 33.3%). In BBR-group, grade 3 of 4 hematological, neurological and renal toxicity and neutropenic infections were observed in 41.4%, 7%, 3.4%, and 31%, respectively. With a median follow-up of 51 months, median overall survival (OS) for patients treated with BBR versus conventional therapies was 13 versus 2 months (P < 0.007). Median OS of patients with pPCL and sPCL treated with BBR was 18 and 7 months, respectively (P < 0.001). In the multivariate analysis normal PLTs, treatment with BBR and high quality response were the only powerful predictors for survival. Our study carrying the longest reported median follow-up, demonstrated that treatment of PCL with BBR induces high response rates and prolongs survival over conventional therapies, regardless of additional autologous transplantation rescue or established high risk features, with manageable toxicity.

Markedly decreased antibody titers against hepatitis B in previously immunised children presenting with juvenile idiopathic arthritis.

OBJECTIVES: Hepatitis B is a vaccine preventable disease with intermediate endemicity in Greece. Patients with juvenile idiopathic arthritis (JIA) on immunomodulating therapy are prone to infection or reactivation of hepatitis B virus (HBV). The aim of this study is to define the immune status against HBV in children newly-diagnosed with JIA. METHODS: Case-control prospective study including 89 JIA patients and 89 controls matched for age and gender. Eighty-nine JIA patients were included in the study (22 males), with a mean age of 6.8 years. Sera were tested for hepatitis B surface antigen, hepatitis B core antibody, and anti-HBs. Patients with anti-HBs titers ≥10 IU/L were considered immune. Data were analysed with SPSS 18.0 version. RESULTS: In the JIA group 55% were HBV immune (anti-HBs level ≥10 IU/L) while in the control group 92% were immune against HBV (p<0.001). Antibody levels in the patient group were significantly lower compared to the control group. The mean concentration of anti-HBs levels in JIA patients was 18.3 IU/L versus 82.6 IU/L in the control group (p<0.001). CONCLUSIONS: Antibody titers against HBV in fully vaccinated JIA patients due to start treatment are significantly lower compared to matched healthy children in this study. Diagnosis of JIA and older age were associated with the absence of protective antibodies. Although there is no evidence to support the introduction of a booster HBV dose in healthy children who mount low antibody response following immunisation, further studies are required to address this question in patients with JIA.

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.

Comparing neonatal and paediatric antibiotic prescribing between hospitals: a new algorithm to help international benchmarking.

OBJECTIVES: The WHO anatomical therapeutic chemical (ATC)/defined daily dose (DDD) methodology is a standardized method of comparing antimicrobial use. The ATC/DDD is defined as the average maintenance daily dose of a drug used in a 70 kg adult, ignoring the considerable differences in body weight of neonates and children. The aim of this study was to develop a new standardized way of comparing rates of antimicrobial prescribing between European children's hospitals. METHODS: This pilot study at four European children's hospitals (in the UK, Greece and Italy) collected data including demographics, antibiotic use, dosing and indication in children and neonates over a 14 day period. RESULTS: A total of 1217 antibiotic prescriptions were issued with 47 different antibiotics used. Approximately half of all children and a third of all neonates received antibiotics, with wide variation between centres in the type and dose of antibiotic used. We propose a new pragmatic three-step algorithm. The first step includes a simple comparison of the proportion of hospitalized children on antibiotics by weight bands and the number of antimicrobials that account for 90% of total DDD drug usage (DU90%). The second step is a comparison of the dosing used (mg/kg/day). The third step is to compare overall drug exposure using DDD/100 bed days for standardized weight bands between centres. CONCLUSIONS: This novel method has the potential to be a useful tool to provide antibiotic use comparator data and requires validation in a large prospective point prevalence study.

The effect of age on whole blood interferon-gamma release assay response among children investigated for latent tuberculosis infection.

OBJECTIVE: To evaluate the effect of age upon QuantiFERON-TB Gold-In-Tube (QFT-IT) assay outcome among children examined for latent tuberculosis infection (LTBI). STUDY DESIGN: A cross-sectional study was conducted among 761 children (mean age ± SD: 7.84 ± 4.68 years) evaluated for LTBI. Participants were examined with both tuberculin skin test and QFT-IT (Cellestis, Australia) and categorized into 4 age groups. Multivariate logistic and linear regressions were used to evaluate the association between selected demographic and patient characteristics upon the qualitative and quantitative QFT-IT outcomes. Agreement between the tuberculin skin test and QFT-IT within groups was evaluated with the κ statistic. RESULTS: QFT-IT indeterminate results occurred more frequently among young children (8.1%; P < .0001) and children (2.7%; P = .025) than adolescents (0.7%). Among QFT-IT positive patients, infants had higher mean (± SD) interferon-gamma (IFNγ) concentration than adolescents. QFT-IT positive (vs negative) outcome was associated with origin from a high tuberculosis endemicity setting (AOR = 4.54; 95% CI, 3.22-6.25) and lack of previous Bacille Calmette Guerin immunization (AOR = 2.70; 95% CI, 1.89-3.85), but not patient age (AOR = 0.96; 95% CI, 0.92-0.99). However, among QFT-IT positive patients, the IFNγ concentration was inversely associated with patient age (P = .009) and positively with mitogen response (P = .0002). Agreement between tests was not significantly different between younger and older children in the different risk groups. CONCLUSIONS: Qualitative QFT-IT assay results are not affected by patient age. However, indeterminate results occur more frequently among younger children. Among patients with LTBI the quantitative QFT-IT result (ie, IFNγ) is inversely associated with patient age.

Favorable Outcome in Infants Hospitalized With COVID-19: Single Center Experience from Athens, Greece.

This study aims to describe the clinical characteristics and outcome of 92 infants (aged <12 months) with community-acquired coronavirus disease 2019 (COVID-19) between March, 2020 and June, 2021 at a single center in Athens. Infants with COVID-19 developed mild disease (89, 96.7%), and were infected mostly by their household contacts (74, 80.4%). Disease complications were rare, indicating that hospitalization is the result of low threshold for admission rather than disease severity.

A national study of antibiotic use in Greek pediatric hematology oncology and bone marrow transplant units.

Objective: We surveyed antimicrobials used in Greek pediatric hematology-oncology (PHO) and bone marrow transplant (BMT) units before and after an intervention involving education regarding the 2017 clinical practice guidelines (CPG) for the management of febrile neutropenia in children with cancer and hematopoietic stem-cell transplant recipients. Design: Antibiotic prescribing practices were prospectively recorded between June 2016 and November 2017. Intervention: In December 2017, baseline data feedback was provided, and CPG education was provided. Prescribing practices were followed for one more year. For antibiotic stewardship, days of therapy, and length of therapy were calculated. Setting: Five of the 6 PHO units in Greece and the single pediatric BMT unit participated. Participants: Admitted children in each unit who received the first 15 new antibiotic courses each month. Results: Administration of ≥4 antibiotics simultaneously and administration of antibiotics with overlapping activity for ≥2 days were significantly more common in PHO units in general hospitals compared to children's hospitals. Use of at least 1 antifungal was recorded in ∼47% of the patients before and after the intervention. De-escalation and/or discontinuation of antibiotics on day 6 of initial treatment increased significantly from 43% to 53.5% (P = .032). Although the number of patients requiring intensive care support for sepsis did not change, a significant drop was noted in all-cause mortality (P = .008). Conclusions: We recorded the antibiotic prescribing practices in Greek PHO and BMT units, we achieved improved prescribing with a simple intervention, and we identified areas in need of improvement.

Hand Hygiene Compliance Rates in 9 Pediatric Intensive Care Units Across Europe: Results from the Reducing Antimicrobial use and Nosocomial Infections in Kids Network.

A unified surveillance mechanism for hand hygiene and hospital-acquired infections for pediatric wards is lacking in Europe. We managed to setup such a mechanism in 9 pediatric intensive care units in 7 European countries, using World Health Organization's definitions and common methodology which allows for benchmarking among units and countries. Median hand hygiene compliance was found high 82.3% (interquartile range 71.6-94.5%), but gaps in practices were identified.

Reducing Duration of Antibiotic Use for Presumed Neonatal Early-Onset Sepsis in Greek NICUs. A "Low-Hanging Fruit" Approach.

Antibiotics are commonly prescribed in Neonatal Intensive Care Units (NICU), where stewardship interventions are challenging. Lowering antibiotic consumption is desperately needed in Greece, a country with high antibiotic resistance rates. We sought to assess the effectiveness of a low-cost and -resource intervention to reduce antibiotic use in Greek NICUs implementing a "low-hanging fruit" approach. A prospective quasi-experimental study was conducted in 15/17 public NICUs in Greece (9/2016-06/2019). The intervention selected was discontinuation of antibiotics within 5 days for neonates with gestational age ≥ 37 weeks, no documented signs or symptoms of sepsis, CRP ≤ 10 mg/L and negative cultures within 3 days of antibiotic initiation. Impact was evaluated by the percentage of discontinued regimens by day 5, length of therapy (LOT) and stay. Trends of antibiotic consumption were assessed with days of therapy (DOT) per 1000 patient-days. Overall, there was a 9% increase (p = 0.003) of antibiotic discontinuation in ≤5 days. In total, 7/13 (53.8%) units showed a ≥10% increase. Overall, 615 days on antibiotics per 1000 patients were saved. Interrupted time-series analysis established a declining trend in DOT/1000 patient-days relative to the pre-intervention trend (p = 0.002); a monthly decrease rate of 28.96 DOT/1000 patient-days (p = 0.001, 95%CI [-45.33, -12.60]). The intervention had no impact on antibiotic choice. Antibiotic use was successfully reduced in Greek NICUs using a "low-hanging fruit" approach. In resource-limited settings, similar targeted stewardship interventions can be applied.

Increasing skin infections and Staphylococcus aureus complications in children, England, 1997-2006.

During 1997-2006, general practitioner consultations for skin conditions for children <18 years of age in England increased 19%, from 128.5 to 152.9/1,000 child-years, and antistaphylococcal drug prescription rates increased 64%, from 17.8 to 29.1/1,000 child-years. During the same time period, hospital admissions for Staphylococcus aureus infections rose 49% from 53.4 to 79.3/100,000 child-years.