Is there a "European Paediatrics"?

The journey from birth to adulthood is paved with threats to health and wellbeing, rendering this age group with its invaluable future potential particularly vulnerable. Therefore, children and adolescents deserve medical attention of the highest professional level based on solid, well founded training guidelines, the availability of a well-coordinated platform for the continuous acquisition of knowledge, exchange of ideas, and collaboration on research and clinical projects, and comprehensive continuing education. For the European region these crucial specifications are met to varying degrees by three major paediatric organisations: the European Academy of Paediatrics (EAP) with the European Board of Paediatrics (EBP) as the paediatric section of the European Union of Medical Specialists (UEMS PS), the European Paediatric Association (EPA/UNEPSA) and the European Confederation of Primary Care Paediatricians (ECPCP). A major goal of this paper is to call for the closest possible collaboration between these organizations in advocating for the health and rights of European children and adolescents and in effectively fostering the paediatric profession with a strong, unified voice.

Availability and use of rapid diagnostic tests for the management of acute childhood infections in Europe: A cross-sectional survey of paediatricians.

BACKGROUND: Point-of-care-tests (POCTs) have been advocated to optimise care in patients with infections but their actual use varies. This study aimed to estimate the variability in the adoption of current POCTs by paediatricians across Europe, and to explore the determinants of variability. METHODS AND FINDINGS: A cross-sectional survey was conducted of hospital and primary care paediatricians, recruited through professional networks. Questions focused on the availability and use of currently available POCTs. Data were analysed descriptively and using Median Odds Ratio (MOR) to measure variation between countries. Multilevel regression modelling using changes in the area under the receiver operating characteristic curve of models were used to assess the contribution of individual or workplace versus country level factors, to the observed variation. The commonest POCT was urine dipsticks (UD) which were available to >80% of primary care and hospital paediatricians in 68% (13/19) and 79% (23/29) countries, respectively. Availability of all POCTs varied between countries. In primary care, the country (MOR) varied from 1.61 (95%CI: 1.04-2.58) for lactate to 7.28 (95%CI: 3.04-24.35) for UD. In hospitals, the country MOR varied from 1.37 (95%CI:1.04-1.80) for lactate to 11.93 (95%CI:3.35-72.23) for UD. Most paediatricians in primary care (69%, 795/1154) and hospital (81%, 962/1188) would use a diagnostic test in the case scenario of an infant with undifferentiated fever. Multilevel regression modelling showed that the country of work was more important in predicting both the availability and use of POCTs than individual or workplace characteristics. CONCLUSION: There is substantial variability in the adoption of POCTs for the management of acute infections in children across Europe. To inform future implementation of both existing and innovative tests, further research is needed to understand what drives the variation between countries, the needs of frontline clinicians, and the role of diagnostic tests in the management of acute childhood infections.

COVID-19 Era Effect on Pandemic and Post-pandemic Pediatric Telemedicine Use: A Survey of the European Academy of Pediatrics Research in Ambulatory Settings Network.

Background: During the COVID-19 pandemic, telemedicine use has increased within community pediatrics. This trend runs counter to reluctance to adaptation of the new mode of healthcare that existed prior to the pandemic. Little is known about what we can expect after the pandemic: if physicians will opt for telemedicine modalities and if tele-pediatrics will continue to be a significant mode of community pediatric care. Objective: The goal of this study was to survey primary pediatric care providers as to their experiences and clinical decision making with telemedicine modalities prior to and during the COVID-19 pandemic, as well as their projected use after the pandemic ends. Material and methods: Using the EAPRASnet database we surveyed pediatricians throughout Europe, using a web-based questionnaire. The survey was performed during the COVID-19 pandemic (June-July 2020), assessed telemedicine use for several modalities, prior to and during the pandemic as well as predicted use after the pandemic will have resolved. Participants were also surveyed regarding clinical decision making in two hypothetical clinical scenarios managed by telemedicine. Results: A total of 710 physicians participated, 76% were pediatricians. The percentage of respondents who reported daily use for at least 50% of all encounters via telemedicine modalities increased during the pandemic: phone calls (4% prior to the pandemic to 52% during the pandemic), emails (2-9%), text messages (1-6%), social media (3-11%), cell-phone pictures/video (1-9%), and video conferencing (1-7%) (p < 0.005). The predicted post-pandemic use of these modalities partially declined to 19, 4, 3, 6, 9, and 4%, respectively (p < 0.005), yet demonstrating a prospectively sustained use of pictures/videos after the pandemic. Reported high likelihood of remotely treating suspected pneumonia and acute otitis media with antibiotics decreased from 8 to 16% during the pandemic to an assumed 2 and 4% after the pandemic, respectively (p < 0.005). Conclusions: This study demonstrates an increased utilization of telemedicine by pediatric providers during the COVID-19 pandemic, as well as a partially sustained effect that will promote telemedicine use as part of a hybrid care provision after the pandemic will have resolved.

SARS-CoV-2 Vaccination in Children and Adolescents-A Joint Statement of the European Academy of Paediatrics and the European Confederation for Primary Care Paediatricians.

Stopping the COVID-19 pandemic and its socio-economic consequences is only possible with a multifaceted strategy, including mass vaccination. Studies have been conducted mainly in adults, and data on the pediatric population is relatively limited. However, it appears that vaccination in children and adolescents is highly effective and safe. Despite the apparent benefits of vaccinating this age group, there are some medical and ethical concerns. Based on the above considerations, the European Academy of Paediatrics (EAP) and the European Confederation of Primary Care Pediatricians (ECPCP) assessed the current situation and presented recommendations for international and national authorities, pediatricians, and pediatric societies regarding vaccination against SARS-CoV-2 in children and adolescents.

Rotavirus vaccination for all children or subgroups only? Comment of the European Academy of Paediatrics (EAP) and the European Society for Paediatric Infectious Diseases (ESPID) recommendation group for rotavirus vaccination.

Rotavirus gastroenteritis affects all children. Studies indicate that by the age of 5 years, almost all children have developed rotavirus antibodies. It has been estimated that in Europe, approximately 6550 children each year die as a result of rotavirus infection. Most of this mortality does not affect children from identifiable risk groups, but previously healthy infants. There is no accountable evidence on increased severity of rotavirus infection in specific risk groups, including children previously born preterm or immunocompromised children. Universal immunization in areas that have successfully achieved large coverage has greatly improved the health of children, reducing infection rates, hospitalization, and costs. Vaccination of infants with presumed high risk may be beneficial for the vaccinated individuals, and such a strategy may also be cost-effective in certain settings. Identifying all high-risk infants within the first few weeks of life is rather difficult especially in countries without primary care pediatricians and goes along with additional costs.Conclusion: Rotavirus vaccines should be recommended as a universal approach for all children and not be restricted to subgroups with assumed increased risk. Targeted vaccination could be considered as an option in countries with limited financial resources.

Vaccine confidence among parents: Large scale study in eighteen European countries.

BACKGROUND: Despite the fact that vaccines save 2-3 million lives worldwide every year, a percentage of children are not getting appropriately vaccinated, thus leading to disease outbreaks. One of the major reasons of low vaccine uptake in Europe is vaccine hesitancy, contributing to the recent measles outbreaks. Monitoring of vaccine hesitancy is valuable in early identification of vaccine concerns. METHODS: We performed an eighteen country European survey on parents' attitudes and behaviors regarding their children's immunization. Parents having at least one child 1-4 years old were mostly recruited by primary care paediatricians to reply to a web-based questionnaire. The questionnaire was developed by the European Academy of Paediatrics Research in Ambulatory Setting Network steering committee, based on similar surveys. An individual level hesitancy score was constructed using the answers to 21 questions, and correlations of the score with socio-demographic characteristics and types of providers were explored. To assess inter country differences, a country level self -reported confidence was defined. RESULTS: Fifty six percent and 24% of 5736 respondents defined themselves as "not at all hesitant", and "somewhat hesitant", respectively. Parents who consulted general practitioners were more hesitant than parents who consulted pediatricians (p < 0.05). Consultation with homeopathists was associated with the highest reported hesitancy (p < 0.05). Vaccine confidence was highest in Portugal and Cyprus, and lowest in Bulgaria and Poland. CONCLUSION: The majority of parents in Europe believe in the importance of childhood vaccination. However, significant lack of confidence was found in certain European countries, highlighting the need for continuous monitoring, awareness and response plans. The possible influence of different types of healthcare providers on parental decisions demonstrated for the first time in our survey, calls for further research. Monitoring and continuous medical education efforts aimed mostly at those professionals who might not be likely to recommend vaccination are suggested.

Mandatory vaccination: a joint statement of the Ethics and Vaccination working groups of the European Academy of Paediatrics.

Vaccinating children is amongst the most cost-effective interventions for reducing children's morbidity and mortality. Parents who choose not to vaccinate their children despite having been informed about the evidence on safety and efficacy of vaccines may seriously jeopardise the health of both their own children and others. Contemporary ethical thinking about the limits of parental decision-making over their children's healthcare treatment often considers the zone of parental discretion. However, with vaccination this is slightly less direct as the benefits are not only accumulated by an individual child but also by children as a population. Forcing parents is of course not the only solution to counteracting the fear of vaccines. Health authorities should certainly fund research and deploy resources on combatting vaccine disinformation.Conclusion: It would be preferable to achieve high rates of vaccination coverage by educating both parents and physicians without adopting any legislation for mandatory vaccination. However, in countries where vaccination uptake is low and/or outbreaks of vaccine-preventable diseases occur, the implementation of mandatory vaccination will most probably save children's lives. EAP calls for action to make all scheduled childhood vaccinations a matter of fact for all European children.

Enterovirus infections in pediatric hematologic/oncologic patients.

BACKGROUND: Enteroviruses (EV) are a large group of Picornaviruses associated with respiratory, gastrointestinal, and neurologic symptoms in the immunocompetent host. Little is known about the epidemiologic and clinical impact in pediatric hematologic/oncologic patients. PROCEDURE: From 2001 through 2017, different clinical specimens were collected from pediatric hematologic/oncologic patients and were tested for enteroviral RNA. RESULTS: Of 13 004 specimens collected from 761 patients, 38 (0.3%) obtained from 14 patients (1.8%) tested positive for EV RNA. Viral shedding was observed without viremia and vice versa. None of 80 cerebrospinal fluid specimens obtained from 60 patients with neurologic symptoms were positive for EV RNA. None of 14 patients positive for EV RNA showed EV-specific symptoms. In 11/14 patients, EV RNA was found to be negative in the follow-up specimen. The remaining patient with a severe primary immune deficiency showed repeated positive EV RNA results for >5 years. CONCLUSIONS: In this pediatric hematologic/oncologic cohort, EV infection occurred rarely and without related symptoms. Specimens concurrently obtained from one patient are commonly not in accordance with each other. In the vast majority of patients, EV RNA appears to turn negative in the follow-up specimen. EV infections seem to have a low impact in this patient cohort.

Low penetration of caspofungin into cerebrospinal fluid following intravenous administration of standard doses.

The kinetics of caspofungin (CAS) in cerebrospinal fluid (CSF) following intravenous (i.v.) administration has been studied exclusively in animal models. Human data are missing so far. In this study, 13 CSF samples were obtained at different time points following i.v. infusion of CAS in ten paediatric haemato-/oncological patients (age range 1.0-14.2 years, median 8.6 years) without signs of central nervous system (CNS) infection (n = 10 samples) or with infectious meningitis (n = 3 samples). Serum samples were obtained concurrently. Liquid chromatography-tandem mass spectrometry was used for CAS quantification. Whilst CAS serum levels were in the expected range, varying between 0.6 and 20.3 µg/mL (median 7.0 µg/mL), 11 of 13 CSF levels were below the limit of detection of 0.084 µg/mL at 3.0-48.0 h (median 23.3 h) following i.v. infusion. Only two (of three) levels in patients with bacterial meningitis were above the limit of detection (0.3 µg/mL and 0.09 µg/mL, respectively). These results indicate the low capacity of CAS to penetrate into the CNS even in inflamed meninges. Monotherapy with standard doses of CAS appears not to be suitable for treatment of fungal CNS infections.

Human papillomavirus vaccination crisis in Japan.

The European Academy of Paediatrics (EAP) is gravely concerned about the human papillomavirus (HPV) vaccination crisis in Japan and particularly about the negative position taken by governmental authorities. Given that the HPV vaccine is both safe and effective, there is no recognizable reason to date to withhold this lifesaving and cost effective public health measure from a population. Therefore, the EAP strongly encourages the Japanese health authorities to actively support HPV vaccination for the future health of their children and adolescents.

Amphotericin B transfer to CSF following intravenous administration of liposomal amphotericin B.

OBJECTIVES: Although amphotericin B (AmB) and its lipid formulations are used for the treatment of fungal infections of the CNS, the kinetics of AmB in the CSF after intravenous administration of liposomal amphotericin B (LAmB) are not well characterized. PATIENTS AND METHODS: From 14 paediatric haemato-oncological patients (aged 0.4-19.5 years, median 7.6 years), we obtained 30 CSF samples by means of routine punctures (performed for intrathecal treatment of the underlying diseases) at different timepoints after the prophylactic intravenous infusion of LAmB (AmBisome, 3 mg/kg/day). Concurrent serum samples were obtained to calculate the transfer rates. An HPLC method was used for AmB detection. RESULTS: CSF levels of AmB 1-100 h after the intravenous infusion of LAmB were between 10 and 120 ng/mL, except in one case with a level of 529 ng/mL. Concurrent serum levels were about 1000-fold higher, ranging between 3 and 75 µg/mL. CSF levels did not show a clear time-dependent concentration profile, but remained at a steady-state for longer than 48 h after infusion. The transfer rate ranged from 0.02% to 0.92% (median 0.13%) and correlated significantly (r=0.801, P<0.001) with increasing time after infusion. CONCLUSIONS: After the intravenous administration of LAmB, AmB CSF levels were low, confirming published animal data. CSF levels remained at a steady-state level for longer than 48 h. As indicated by published post mortem data, higher levels in brain tissue, which would be necessary for the successful treatment of CNS infections, might be possible.

Age- and gender-related differences in teicoplanin levels in paediatric patients.

OBJECTIVES: Teicoplanin is a glycopeptide antibiotic active against Gram-positive bacteria, including methicillin-resistant staphylococci. While teicoplanin trough levels (TTLs) >10 mg/L are commonly considered appropriate, levels >20 mg/L are aimed for in the treatment of severe infections. Due to toxicity, it is recommended to avoid levels >60 mg/L. PATIENTS AND METHODS: In our institution, the initial dosing schedule of teicoplanin (10-15 mg/kg every 12 h for three loading doses and every 24 h thereafter) is adapted according to TTLs analysed by a fluorescence polarization immunoassay on treatment days 2 to 4. Teicoplanin peak levels (TPLs) are analysed in selected cases 30 min after the end of infusion. In a retrospective analysis we evaluated 1357 TTLs and 333 TPLs from 410 treatment episodes from 2005 to 2011. RESULTS: Initial TTLs were <10 mg/L in 14.1% and <20 mg/L in 72.6% of episodes. Toddlers had significantly lower TTLs, with a 2-fold and 2.5-fold increased risk of having levels <10 mg/L (24.6%) and <20 mg/L (82.6%), respectively. For the entire cohort, follow-up TTLs were less likely to be <10 mg/L and more likely to be >20 mg/L when compared with initial TTLs (P < 0.001, each). Adolescent girls had significantly higher initial TPLs (P = 0.001) and significantly higher follow-up TTLs (P = 0.016) than adolescent boys. In parallel, adolescent girls had initial TPLs >60 mg/L significantly more frequently (P = 0.012) and follow-up TTLs <10 mg/L significantly less frequently (P = 0.005). CONCLUSIONS: More tailored dosing regimens with higher loading doses, especially for toddlers, should be considered. While further pharmacokinetic data in paediatric patients are pending, therapeutic drug monitoring is mandatory.

Effective management of pulmonary aspergillosis invading the thoracic spine in a child with high risk ALL requiring allogeneic bone marrow transplantation.

Due to unacceptably high mortality, invasive fungal infections (IFI) have long been considered a contraindication against allogeneic stem cell transplantation. Despite severe immunosuppression an 11-year-old girl requiring allogeneic bone marrow transplant (BMT) for relapsed acute lymphoblastic leukemia was cured of a concurrent invasive pulmonary aspergillosis. Treatment comprised combinations of liposomal amphotericin B, caspofungin and voriconazole with donor granulocyte transfusions. This therapeutic regimen, including the choice of reduced intensity conditioning (RIC), allowed the patient to receive an allogeneic BMT. In hematological remission the child later developed fatal chronic graft-versus-host disease. Combined antifungal treatment and granulocyte support allow for effective management of IFI even in allogeneic stem cell transplant recipients. However, short-term benefits of RIC may be outweighed by late complications.

Intracerebral cavernous hemangioma after cranial irradiation in childhood. Incidence and risk factors.

BACKGROUND AND PURPOSE: Radiotherapy is an integral part of various therapeutic regimens in pediatric and adult oncology. Endocrine dysfunction, neurologic and psychiatric deficits, secondary malignancies and radiation-induced necrosis are well-known possible late effects of cranial irradiation. However, only sporadic cases of radiation-induced cavernous hemangiomas (RICH) have been reported so far. PATIENTS AND METHODS: Pediatric patients who underwent cranial radiation therapy for malignant diseases between January 1980 and December 2003 were retrospectively analyzed. After the end of therapy they entered a detailed follow-up program. RESULTS: Of 171 patients, eight (three patients with medulloblastoma, three patients with acute lymphoblastic leukemia, and one patient each with ependymoma and craniopharyngioma) developed intracerebral cavernoma 2.9-18.4 years after irradiation representing a cumulative incidence (according to the Kaplan-Meier method) of 2.24%, 3.86%, 4.95%, and 6.74% within 5, 10, 15, and 20 years following radiation therapy, respectively. In patients treated in the first 10 years of life, RICH occurred with shorter latency and significantly more often (p = 0.044) resulting in an even higher cumulative incidence. CONCLUSION: These findings and previously published cases show that cavernous hemangiomas may occur after irradiation of the brain several years after the end of therapy irrespective of the radiation dose and type of malignancy. Particularly children < 10 years of age at the time of irradiation are at higher risk. Since patients with RICH frequently do not show symptoms but hemorrhage is a possible severe complication, imaging of the central nervous system should be performed routinely for longer follow- ups, particularly in patients who were treated as young children.

Non-infectious causes of elevated procalcitonin and C-reactive protein serum levels in pediatric patients with hematologic and oncologic disorders.

BACKGROUND: Procalcitonin (PCT) is considered a sensitive and specific diagnostic and prognostic marker of systemic bacterial infection, but its value is questionable in certain clinical conditions, particularly in hemato-oncological patients. MATERIALS AND METHODS: We analyzed PCT and C-reactive protein (CRP) levels in 56 patients of a pediatric hematology-oncology unit during 110 consecutive non-infectious febrile episodes related to administration of T-cell antibodies (group A; n = 22), alemtuzumab (monoclonal CD52 antibody, CAMPATH-1H/group B; n = 8), interleukin-2 (IL-2/group C; n = 41), prophylactic donor granulocyte transfusions (group D; n = 9), or to acute graft-versus-host disease (aGvHD/group E; n = 10) and compared the results with 20 episodes of Gram-negative sepsis (group F). MAIN RESULTS: In the majority of the non-infectious episodes PCT and CRP increased to serum levels statistically indistinguishable from Gram-negative sepsis. Median peak levels of PCT (normal < 0.5 ng/ml)/CRP (normal < 8 mg/l) for groups A-F were 4.34/59.0 (A), 10.14/93.5 (B), 1.11/175.0 (C), 1.43/164 (D), 0.96/34.0 (E), and 8.14 ng/ml /126.0 mg/l (F). Highest single levels were observed in groups A and F. CONCLUSIONS: PCT and CRP are of limited value as diagnostic markers of sepsis during T-cell-directed immunomodulatory treatment, granulocyte support, or acute GvHD.

Polymorphisms in the chemokine (C-X-C motif) ligand 10 are associated with invasive aspergillosis after allogeneic stem-cell transplantation and influence CXCL10 expression in monocyte-derived dendritic cells.

Patients after allogeneic stem-cell transplantation (alloSCT) have an increased risk for invasive aspergillosis (IA). Here, recipients of an allograft with IA (n=81) or without IA (n=58) were screened for 84 single nucleotide polymorphisms in 18 immune relevant genes. We found 3 markers in chemokine (C-X-C motif) ligand 10 (CXCL10, 4q21, 11,101 C>T, P=.007; 1642 C

Antifungal management in cancer patients.

Invasive fungal infections (IFI) are a major cause of morbidity and mortality in cancer patients receiving myelotoxic chemotherapy. Established risk factors are previous fungal infection, neutropenia exceeding 10 days, older age, active cancer, corticosteroid therapy, administration of broad spectrum antibiotics, allogeneic HSCT, central venous catheter and organ dysfunction. The strategies to manage IFI comprise chemoprophylaxis, preemptive, empirical and directed antifungal therapy. Benefit of antifungal prophylaxis has been proven for fluconazole (400 mg/d) in allogeneic transplant recipients, and for posaconazole (600 mg/d) in patients during AML/MDS induction chemotherapy as well as in patients with GvHD. Pre-emptive therapy based on sensitive diagnostic non-culture methods needs further validation in larger randomized studies before becoming a standard. Empirical antifungal therapy is well established and should consist of either liposomal amphotericin B, itraconazole, voriconazole, or caspofungin. In patients with documented invasive aspergillosis, therapy with voriconazole is the treatment of choice. Liposomal amphotericin B is a good alternative candidate and caspofungin is reserved for salvage treatment. Invasive candidiasis should be treated with caspofungin or one of the lipid based amphotericin B formulations. Since non-albicans species are increasingly observed, the use of fluconazole is reserved for "stable", non-neutropenic patients.

Diagnostic and prognostic impact of urinary catecholamines in neuroblastoma patients.

BACKGROUND: Urinary catecholamine metabolites are well-known to be elevated in patients with neuroblastoma. Some investigators have described different patterns in favorable and unfavorable cases. However, extended studies have not been published. PROCEDURE: We investigated urinary catecholamine patterns and their correlation to stage, biological features, and outcome in 114 consecutively clinically diagnosed neuroblastoma patients. RESULTS: Sensitivity of vanillylmandelic acid (VMA), homovanillic acid (HVA), and dopamine (DA) was 80.7, 71.9, and 61.3%, respectively. In 91.2% of patients at least one parameter was above normal. High VMA levels were associated with favorable biological features, high DA levels were predominantly found in biologically unfavorable disease. Whereas patients with normal HVA levels had a significant better outcome, the other parameters showed no significant association with prognosis. For disseminated neuroblastoma of infancy, DA/VMA ratio proved to be helpful for the discrimination of stage 4 versus stage 4s. CONCLUSION: Urinary catecholamines appear to be useful to give a first but important hint about the biological behavior and thus the prognosis of the underlying disease. Particularly DA/VMA ratio may serve as a tool for "biological grading"-especially in disseminated disease of infancy. In addition, it may be speculated that HVA negativity and low DA/VMA ratio may be helpful for the decision of a "wait and see" strategy in selected neuroblastoma patients with localized disease.