The Requirements of Managing Phase I Clinical Trials Risks: The British and Italian Case Studies.

Phase I clinical trials represent a critical point in drug development because the investigational medicinal product is being tested in humans for the first time. For this reason, it is essential to evaluate and identify the Maximum Tolerated Dose (MTD) and the safety of the new compound. To mitigate the possible risks associated with drug administration and treatment, the European Competent Authority issued various guidelines to provide provisions and harmonize risk management processes. In the UK and Italy, particular attention should be paid to the Medicines & Healthcare Products Regulatory Agency (MHRA) phase I accreditation scheme and the specific rules set by the Italian Drug Authority through the AIFA Determination no. 809/2015. Both reference documents are based on the concept of quality risk management while conducting phase I clinical studies. Moreover, the AIFA determination outlines specific requirements for those sites that want to conduct non-profit phase I clinical trials. Indeed, the document reports peculiar activities to the "Clinical Trial Quality Team", which is a team that should support the clinical site researchers in designing, starting, performing, and closing non-profit phase I studies. In this paper, we provide a general overview of the main European guidelines concerning the management of risks during phase I trials, focusing on the main peculiarities of the schemes and rules set by the MHRA and AIFA.

Minipuberty assessment in newborns with hypoxic ischemic encephalopathy treated with therapeutic hypothermia: a single-center case-control study.

Introduction: The aim of our single-center case-control study is to evaluate whether minipuberty occurs in patients with hypoxic ischemic encephalopathy (HIE) who underwent therapeutic hypothermia (TH). We intend to conduct this evaluation by confronting the values of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) and the values of testosterone in males and estradiol in females between newborns with HIE and in subsequent TH and healthy controls. Methods: We enrolled 40 patients (age: 56-179 days; 23 males), of whom 20 met the inclusion criteria for the case group and who underwent TH. A blood sample was taken from each patient at approximately 10 weeks of age to evaluate FSH and LH from the serum samples of all patients and to evaluate 17-beta estradiol (E2) and testosterone levels, respectively, from the serum samples of female and male patients. Results: It was found that minipuberty occurred in the case group patients, with no significant differences reported from the control group and with hormonal serum levels comparable to healthy infants of the control group (FSH 4.14 mUI/ml ± 5.81 SD vs. 3.45 mUI/ml ± 3.48 SD; LH 1.41 mUI/ml ±1.29 SD vs. 2.04 mUI/ml ±1.76 SD; testosterone in males 0.79 ng/ml ± 0.43 SD vs. 0.56 ng/ml ± 0.43 SD; 17-beta estradiol in females 28.90 pg/ml ± 16.71 SD vs. 23.66 pg/ml ± 21.29 SD). Discussion: The results of the present study may pave the way for further research and the evaluation of more possible advantages of TH.

Short-term antibiotic therapy for the most common bacterial respiratory infections in infants and children.

Overuse and misuse of antibiotics have strongly accelerated the progressive increase in bacterial antimicrobial resistance (AMR). The evidence that antimicrobial selective pressure was greater the longer the antibiotic therapy was continued has led some experts to reconsider duration of antibiotic therapy testing the use of short-term drug administration. If as effective as long-term therapy, short-term therapy could have been an easy measure to limit AMR emergence. In the present narrative review, whether present knowledge on short-term therapy of acute streptococcal pharyngitis (ASF), acute otitis media (AOM) and mild to moderate community-acquired pneumonia (CAP) allows systematic use of short-term therapy in infants and children with these diseases is discussed. Literature analysis showed that reducing the duration of antibiotic therapy for some of the most common pediatric respiratory infections could be a valid measure to contain the antibiotic abuse and the consequent impact on the emergence of AMR. Several data seem to indicate that this type of intervention is possible, as short-term therapy has been found as effective as the traditionally recommended long-term therapy in some cases of ASF, AOM and mild to moderate CAP. However, further studies are needed to better characterize infants and children who can have benefit with short-term antibiotic therapy in common bacterial respiratory infections.

Knowledge on Parental Hesitancy toward COVID-19 Vaccination of Children 5-11 Years Old.

Although vaccines are the safest and the most effective measure to prevent disease, disability, and death from various pediatric infectious diseases, parental vaccine hesitancy is a common and increasing phenomenon worldwide. To contribute to improving our knowledge on parental willingness and hesitancy toward COVID-19 vaccine administration in children aged 5-11 years, an anonymous online questionnaire was disseminated in Italy after the COVID-19 vaccine's authorization for this age group. An online survey was conducted using the Crowd Signal platform from 15 December 2021 to 15 January 2022 in Italy among parents of children 5-11 years old. A total of 3433 questionnaires were analyzed. Overall, a "Favorable" position was observed in 1459 (42.5%) parents, a "Doubtful" one in 1223 (35.6%) and a "Hesitant/Reluctant" one in 751 (21.9%). The univariate multinomial logistic regression analysis and the multivariate multinomial logistic regression analysis showed that the Hesitant/Reluctant parents were younger than 40 years of age, mostly female, with a secondary or middle school degree, an annual income below EUR 28,000, more than one child in the age range from 5 to 11 years, an underestimated consideration of the severity of COVID-19's effects, and concern regarding the COVID-19 vaccines in general. These results show that in Italy, most parents of children aged 5 to 11 were doubtful or hesitant/reluctant to vaccinate their children against the COVID-19 virus. Poor trust in health institutions as well as poor consideration of the epidemiological and clinical relevance of COVID-19 in children seem to have played the biggest roles in forming these attitudes. Moreover, the negative attitude of several parents who previously agreed to immunize their children against other childhood illnesses according to the official national pediatric immunization schedule clearly indicates that only the COVID-19 vaccine was put in doubt or rejected. All these findings lead us to conclude that to improve COVID-19 vaccination coverage in children aged 5 to 11, health authorities should increase parental education on the true clinical relevance of COVID-19 and on the importance of its prevention to hinder the evolution of the pandemic in pediatric subjects and the emergence of new variants, and its relative weight in influencing the efficacy of vaccines.

Use of Telemedicine Healthcare Systems in Pediatric Assistance at Territorial Level: Consensus Document of the Italian Society of Telemedicine (SIT), of the Italian Society of Preventive and Social Pediatrics (SIPPS), of the Italian Society of Pediatric Primary Care (SICuPP), of the Italian Federation of Pediatric Doctors (FIMP) and of the Syndicate of Family Pediatrician Doctors (SIMPeF).

Technological innovation can contribute to a reorganization of healthcare, particularly by supporting the shift in the focus of care from the hospital to the territory, through innovative citizen-centered models, and facilitating access to services in the territory. Health and social care delivery modalities, enabled by telemedicine, are crucial in this regard. The objective of this Consensus document, written by the main Italian Scientific Societies involved in the use of telemedicine in pediatrics, is to define a standard for its use at the territorial level in various declinations in the pediatric field; this paper also identifies priority areas for its application and the types of services that most require intervention and investment. The changes that are underway in digital transformation in all sectors are unstoppable, and for the digital transformation to take place in a productive sense, the contribution of not only all health professionals, but also of patients, is necessary. From this perspective, authors from different backgrounds were involved in the drafting of this Consensus and, in the future, other figures, primarily patients, are expected to be involved. In fact, this belongs to the vision of connected care, in which the citizen/patient actively participates in the treatment path so that they are assisted in a personalized, predictive and preventive way. The future scenario must be able to provide for the involvement of patients from the initial stages of planning any treatment path, even in the pediatric age, and increasing, where possible, the proximity of the health service to the families.

Use of Telemedicine Healthcare Systems in Children and Adolescents with Chronic Disease or in Transition Stages of Life: Consensus Document of the Italian Society of Telemedicine (SIT), of the Italian Society of Preventive and Social Pediatrics (SIPPS), of the Italian Society of Pediatric Primary Care (SICuPP), of the Italian Federation of Pediatric Doctors (FIMP) and of the Syndicate of Family Pediatrician Doctors (SIMPeF).

Telemedicine is considered an excellent tool to support the daily and traditional practice of the health profession, especially when referring to the care and management of chronic patients. In a panorama in which chronic pathologies with childhood onset are constantly increasing and the improvement of treatments has allowed survival for them into adulthood, telemedicine and remote assistance are today considered effective and convenient solutions both for the chronic patient, who thus receives personalized and timely assistance, and for the doctors, who reduce the need for direct intervention, hospitalizations and consequent management costs. This Consensus document, written by the main Italian Scientific Societies involved in the use of telemedicine in pediatrics, has the objectives to propose an organizational model based on the relationships between the actors who participate in the provision of a telemedicine service aimed at minors with chronic pathologies, identifying specific project links between the areas of telemedicine in the developmental age from the first 1000 days of life to the age adult. The future scenario will have to be able to integrate digital innovation in order to offer the best care to patients and citizens. It will have to be able to provide the involvement of patients from the very beginning of the design of any care pathway, increasing where possible the proximity of the health service to citizens.

Information and Training on the Use of Telemedicine in Pediatric Population: Consensus Document of the Italian Society of Telemedicine (SIT), of the Italian Society of Preventive and Social Pediatrics (SIPPS), of the Italian Society of Pediatric Primary Care (SICuPP), of the Italian Federation of Pediatric Doctors (FIMP), and of the Syndicate of Family Pediatrician Doctors (SIMPeF).

Telemedicine has entered the daily lives of doctors, although the digital skills of healthcare professionals still remain a goal to be achieved. For the purpose of a large-scale development of telemedicine, it is necessary to create trust in the services it can offer and to favor their acceptance by healthcare professionals and patients. In this context, information for the patient regarding the use of telemedicine, the benefits that can be derived from it, and the training of healthcare professionals and patients for the use of new technologies are fundamental aspects. This consensus document is a commentary that has the aim of defining the information on and training aspects of telemedicine for pediatric patients and their caregivers, as well as pediatricians and other health professionals who deal with minors. For the present and the future of digital healthcare, there is a need for a growth in the skills of professionals and a lifelong learning approach throughout the professional life. Therefore, information and training actions are important to guarantee the necessary professionalism and knowledge of the tools, as well as a good understanding of the interactive context in which they are used. Furthermore, medical skills can also be integrated with the skills of various professionals (engineers, physicists, statisticians, and mathematicians) to birth a new category of health professionals responsible for building new semiotics, identifying criteria for predictive models to be integrated into clinical practice, standardizing clinical and research databases, and defining the boundaries of social networks and new communication technologies within health services.

Association of viral load with TRAIL, IP-10, CRP biomarker signature and disease severity in children with respiratory tract infection or fever without source: A prospective, multicentre cohort study.

BACKGROUND: To investigate the association of viral load (VL) with (i) tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), interferon gamma-induced protein-10, C-reactive protein, and a combinatorial score (BV score), and (ii) clinical severity. STUDY DESIGN: In this prospective, multicentre cohort substudy, children with respiratory tract infection or fever without source were enrolled. VL for influenza virus, rhinovirus, respiratory syncytial virus, and adenovirus was measured from nasopharyngeal swabs. The reference standard diagnosis was established based on expert panel adjudication. RESULTS: Of 1140 recruited patients, 333 had a virus monodetection. VL for the aggregated data set correlated with TRAIL and IP-10 levels, with the length of oxygen therapy, and inversely with the BV score. At a single viral level, only the influenza VL yielded a correlation with TRAIL, IP-10 levels, and the BV score. Children with a viral reference standard diagnosis had significantly higher VL than those with bacterial infection (p = 0.0005). Low TRAIL (incidence rate ratio [IRR] 0.6, 95% confidence interval [CI] 0.39-0.91) and young age (IRR 0.62, 95% CI 0.49-0.79) were associated with a longer hospital stay, while young age (IRR 0.33, 95% CI 0.18-0.61), low TRAIL (IRR 0.25, 95% CI 0.08-0.76), and high VL (IRR 1.16, 95% CI 1.00-1.33) were predictive of longer oxygen therapy. CONCLUSION: These findings indicate that VL correlates with biomarkers and may serve as a complementary tool pertaining to disease severity.

Update on COVID-19 Therapy in Pediatric Age.

With the extension of the COVID-19 pandemic, the large use of COVID-19 vaccines among adults and the emergence of SARS-CoV-2 variants means that the epidemiology of COVID-19 in pediatrics, particularly among younger children, has substantially changed. The prevalence of pediatric COVID-19 significantly increased, several severe cases among children were reported, and long-COVID in pediatric age was frequently observed. The main aim of this paper is to discuss which types of treatment are presently available for pediatric patients with COVID-19, which of them are authorized for the first years of life, and which are the most important limitations of COVID-19 therapy in pediatric age. Four different antivirals, remdesivir (RVD), the combination nirmatrelvir plus ritonavir (Paxlovid), molnupiravir (MPV), and the monoclonal antibody bebtelovimab (BEB), are presently approved or authorized for emergency use for COVID-19 treatment by most of the national health authorities, although with limitations according to the clinical relevance of disease and patient's characteristics. Analyses in the literature show that MPV cannot be used in pediatric age for the risk of adverse events regarding bone growth. The other antivirals can be used, at least in older children, and RDV can be used in all children except in neonates. However, careful research on pharmacokinetic and clinical data specifically collected in neonates and children are urgently needed for the appropriate management of pediatric COVID-19.

Trends of Phase I Clinical Trials in the Latest Ten Years across Five European Countries.

BACKGROUND: Phase 1 clinical trials represent a critical phase of drug development because new candidate therapeutic agents are tested for the first time on humans. Therefore, international guidelines and local laws have been released to mitigate and control possible risks for human health in agreement with the declaration of Helsinki and the international Good Clinical Practice principles. Despite numerous scientific works characterizing the registered clinical trials on ClinicalTrials.gov, the main features and trends of registered phase 1 clinical trials in Europe have not been investigated. This study is aimed at assessing the features and the temporal trend of distribution of phase 1 clinical studies, carried out in the five largest European countries over a ten-year period (2012-2021), and to evaluate the impact of the Italian regulatory framework on the activation of such studies. METHODS: The main data and characteristics of phase 1 clinical studies registered on the ClinicalTrials.gov database for France, Germany, Italy, Spain and the United Kingdom have been investigated and subsequently compared. The above-mentioned countries were selected based on similarities in terms of demographic and Gross Domestic Product (GDP) data available on official government websites. (3) Results: A total number of 6878 phase 1 clinical trials were registered for the five selected countries in the ClinicalTrials.gov database during the ten years analyzed; the studies were predominantly randomized (39.33%) and for-profit (76.64%). The most represented area of investigations was oncology (52.15%), followed by hematology (24.99%) and immunology (12.04%). The variability observed between the analyzed countries showed that the UK, Germany and France presented the highest reduction in the number of phase 1 clinical trials, while for Spain and Italy, a stable/increased trend was observed, although with a lower number of trials registered on the ClinicalTrials.gov database. (4) Conclusions: Italy displayed the lowest number of registered phase 1 clinical trials, even though it showed a stable trend over the years. In this regard, the Italian regulatory framework must urgently be adapted to that of other European countries (Spain has been the first country to implement the new Regulation (EU) No 536/2014) and streamline the process of clinical trial application to increase the attractiveness of the country. Moreover, nonprofit phase 1 clinical trials (which represent 19.81% of the total number of phase 1 clinical trials registered in Italy vs. 80.19% of profit phase 1 clinical studies) should be promoted and supported by the institutions, even from a financial point of view, to allow independent researchers to develop new therapeutic drugs.

Microbiota profiles in pre-school children with respiratory infections: Modifications induced by the oral bacterial lysate OM-85.

To describe microbiota profiles considering potential influencing factors in pre-school children with recurrent respiratory tract infections (rRTIs) and to evaluate microbiota changes associated with oral bacterial lysate OM-85 treatment, we analyzed gut and nasopharynx (NP) microbiota composition in patients included in the OM-85-pediatric rRTIs (OMPeR) clinical trial (https://www.clinicaltrialsregister.eu/ctr-search/trial/2016-002705-19/IT). Relative percentage abundance was used to describe microbiota profiles in all the available biological specimens, grouped by age, atopy, and rRTIs both at inclusion (T0) and at the end of the study, after treatment with OM-85 or placebo (T1). At T0, Firmicutes and Bacteriodetes were the predominant genera in gut and Proteobacteria, Firmicutes, and Actinobacteria were the predominant genera in NP samples. Gut microbiota relative composition differed with age (<2 vs. ≥2 years) for Firmicutes, Proteobacteria, Actinobacteria (phyla) and Bifidobacterium, Ruminococcus, Lachnospiraceae (genera) (p < 0.05). Moraxella was more enriched in the NP of patients with a history of up to three RTIs. Intra-group changes in relative percentage abundance were described only for patients with gut and NP microbiota analysis available at both T0 and T1 for each study arm. In this preliminary analysis, the gut microbiota seemed more stable over the 6-month study in the OM-85 group, whose mean age was lower, as compared to the placebo group (p = 0.004). In this latter group, the relative abundance of Bacteroides decreased significantly in children ≥2 years. Some longitudinal significant differences in genera relative abundance were also detected in children of ≥2 years for NP Actinobacteria, Haemophilus, and Corynebacterium in the placebo group only. Due to the small number of patients in the different sub-populations, we could not identify significant differences in the clinical outcome and therefore no associations with microbiota changes were searched. The use of bacterial lysates might play a role in microbiota rearrangement, but further data and advanced analysis are needed to prove this in less heterogeneous populations with higher numbers of samples considering the multiple influencing factors such as delivery method, age, environment, diet, antibiotic use, and type of infections to ultimately show any associations with prevention of rRTIs.

Autoimmune encephalitis after herpes simplex encephalitis: A still undefined condition.

Herpes simplex encephalitis (HSE) is one of the most common sporadic viral encephalitis. Generally, HSE is characterized by a monophasic short course, although in some patients neurological relapses or worsening of deficits can develop some weeks later, when viral therapy has been discontinued and signs and symptoms of the central nervous system (CNS) damage seem to have stabilized. The second HSE stage is generally identified as autoimmune encephalitis after HSE (AEaHSE). Aim of this paper is to discuss which are the present knowledge in this regard. Literature analysis showed that AEaHSE exists, it is more common in younger children and it has different clinical manifestations according to age. All the patients with AEaHSE are positive for one or more neuronal cell-surface and synaptic antibodies, mainly anti-NMDAR antibodies, and the earlier the appearance of the antibodies the greater the risk of AEaHSE development. This means that a careful monitoring of antibody production starting from anti-NMDAR antibodies in all HSE cases could lead to the early identification of AEaHSE and the prompt administration of a potentially effective therapy. Further studies are needed to clarify which are the main pathogenetic mechanisms, whether there are differences in risk of development and clinical course of AEaHSE according to the type of antibody production, why response to immunosuppressive therapy significantly varies and whether administration of steroids to patients with HSE during the first phase of disease can play a role for reducing the risk of AEaHSE development.

Multidrug-Resistant Bacteria in Children and Adolescents with Cystic Fibrosis.

In patients with cystic fibrosis (CF), multidrug-resistant (MDR) bacteria can predispose to exacerbations, limit the effectiveness of antibiotic treatments and promote the progression of lung disease. The aim of this retrospective study was to compare pulmonary exacerbations (Pex), hospitalizations, lung function and nutritional status in a group of children and adolescents with CF colonized by MDR bacteria and in a noncolonized control group. Overall, 7/54 pediatric patients (12.9%) were colonized by MDR bacteria and enrolled (3 with Achromobacter xyloxidans, 3 with Stenotrophomonas maltophilia and 1 with Burkholderia cepacia). The control group included 14 sex- and age-matched CF patients (8/14 colonized by Staphylococcus aureus, 2/14 by Pseudomonas aeruginosa, 2/14 by both microorganisms and 2/14 germ free). At the time of enrollment and 12 months before the first detection of the MDR microorganism, children colonized by MDR bacteria showed lower body mass index (BMI) and lower FEV1/FVC compared to the control group. Over the previous year before the first detection, children colonized with MDR had more Pex compared to control group; those colonized by S. maltophilia experienced the highest number of Pex. In the 12 months following the first detection of MDR bacteria, all seven patients colonized by MDR had at least one Pex and patients colonized by S. maltophilia had the highest number (mean ± SD: 6 ± 2.6 vs. 1.7 ± 2.3). Our study suggests that CF pediatric patients infected by MDR bacteria have lower BMI, more obstructive disease and experience more exacerbations than patients without MDR bacteria. These differences are present even before being infected, suggesting that children and adolescents with more severe disease are predisposed to be colonized by MDR bacteria. S. maltophilia appeared to be the most aggressive pathogen. Further studies and the implementation of antimicrobial stewardship programs are necessary to clarify when and how to treat patients with CF and MDR bacteria in order to avoid the improper use of antibiotics and the development of antibiotic resistance.

Risks of SARS-CoV-2 Infection and Immune Response to COVID-19 Vaccines in Patients With Inflammatory Bowel Disease: Current Evidence.

Inflammatory bowel diseases (IBD), including Crohn's disease, ulcerative colitis, and unclassified inflammatory bowel disease, are a group of chronic, immune mediated conditions that are presumed to occur in genetically susceptible individuals because of a dysregulated intestinal immune response to environmental factors. IBD patients can be considered subjects with an aberrant immune response that makes them at increased risk of infections, particularly those due to opportunistic pathogens. In many cases this risk is significantly increased by the therapy they receive. Aim of this narrative review is to describe the impact of SARS-CoV-2 infection and the immunogenicity of COVID-19 vaccines in patients with IBD. Available data indicate that patients with IBD do not have an increased susceptibility to infection with SARS-CoV-2 and that, if infected, in the majority of the cases they must not modify the therapy in place because this does not negatively affect the COVID-19 course. Only corticosteroids should be reduced or suspended due to the risk of causing severe forms. Furthermore, COVID-19 seems to modify the course of IBD mainly due to the impact on intestinal disease of the psychological factors deriving from the measures implemented to deal with the pandemic. The data relating to the immune response induced by SARS-CoV-2 or by COVID-19 vaccines can be considered much less definitive. It seems certain that the immune response to disease and vaccines is not substantially different from that seen in healthy subjects, with the exception of patients treated with anti-tumor necrosis factor alone or in combination with other immunosuppressants who showed a reduced immune response. How much, however, this problem reduces induced protection is not known. Moreover, the impact of SARS-CoV-2 variants on IBD course and immune response to SARS-CoV-2 infection and COVID-19 vaccines has not been studied and deserves attention. Further studies capable of facing and solving unanswered questions are needed in order to adequately protect IBD patients from the risks associated with SARS-CoV-2 infection.

Myocarditis Following COVID-19 Vaccine Use: Can It Play a Role for Conditioning Immunization Schedules?

Myocarditis (MYO) is a relatively uncommon inflammatory disease that involves the heart muscle. It can be a very severe disease as it can lead to the development of acute or chronic heart failure and, in a not marginal number of cases, to death. Most of the cases are diagnosed in healthy people younger than 30 years of age. Moreover, males are affected about twice as much as females. Viruses are among the most common causes of MYO, but how viral infection can lead to MYO development is not precisely defined. After COVID-19 pandemic declaration, incidence rate of MYO has significantly increased worldwide because of the SARS-CoV-2 infection. After the introduction of anti-COVID-19 vaccines, reports of post-immunization MYO have emerged, suggesting that a further cause of MYO together with the SARS-CoV-2 infection could increase the risk of heart damage during pandemic. Main aim of this study is to discuss present knowledge regarding etiopathogenesis and clinical findings of MYO associated with COVID-19 vaccine administration and whether the risk of this adverse events can modify the initially suggested recommendation for the use of COVID-19 vaccines in pediatric age. Literature analysis showed that MYO is an adverse event that can follow the COVID-19 immunization with mRNA vaccines in few persons, particularly young adults, adolescents, and older children. It is generally a mild disease that should not modify the present recommendations for immunization with the authorized COVID-19 mRNA vaccines. Despite this, further studies are needed to evaluate presently undefined aspects of MYO development after COVID-19 vaccine administration and reduce the risk of development of this kind of vaccine complication. Together with a better definition of the true incidence of MYO and the exact role of the various factors in conditioning incidence variations, it is essential to establish long-term evolution of acute COVID-19 related MYO.

Antimicrobial Prophylaxis for Urologic Procedures in Paediatric Patients: A RAND/UCLA Appropriateness Method Consensus Study in Italy.

The main aim of surgical antimicrobial prophylaxis (SAP) in urologic procedures is to prevent bacteraemia, surgical site infections (SSIs), and postoperative urinary tract infections (ppUTIs). Guidelines for SAP in paediatric urology are lacking. Only some aspects of this complex topic have been studied, and the use of antibiotic prophylaxis prior to surgical procedures seems to be more often linked to institutional schools of thought or experts' opinions than to rules dictated by studies demonstrating the most correct and preferred management. Therefore, the aim of this Consensus document realized using the RAND/UCLA appropriateness method is to provide clinicians with a series of recommendations on SAP for the prevention of bacteraemia, SSIs, and ppUTIs after urologic imaging and surgical procedures in paediatric patients. Despite the few available studies, experts agree on some basilar concepts related to SAP for urologic procedures in paediatric patients. Before any urological procedure is conducted, UTI must be excluded. Clean procedures do not require SAP, with the exception of prosthetic device implantation and groin and perineal incisions where the SSI risk may be increased. In contrast, SAP is needed in clean-contaminated procedures. Studies have also suggested the safety of eliminating SAP in paediatric hernia repair and orchiopexy. To limit the emergence of resistance, every effort to reduce and rationalize antibiotic consumption for SAP must be made. Increased use of antibiotic stewardship can be greatly effective in this regard.

COVID-19 IgG/IgM patterns, early IL-6 elevation and long-term radiological sequelae in 75 patients hospitalized due to interstitial pneumonia followed up from 3 to 12 months.

BACKGROUND: COVID-19 pandemic resulted in about 165 million infections and 3.4 million deaths all over the world across 15 months. The most severe clinical presentation of COVID-19 diseases is interstitial pneumonia. METHODS: In this paper we describe clinical outcomes based on radiological features as well as the pattern of haematochemical parameters and IgG/IgM antibodies in 75 patients hospitalized due to COVID-related interstitial pneumonia not requiring intensive care assistance. Each patient underwent routine laboratory tests, including inflammatory markers and coagulation profile at baseline. Computed Tomography (CT) was performed at baseline and after 3 months to assess the persistence of radiological sequelae. A Generalized Linear Model (GLM) was used to test for each patient the association between individual haematochemical parameters at the time of hospital admission and the subsequent radiological features after three months. The presence of IgG antibodies was quantitatively determined in 70 patients at the time of hospital admission and after 3 months. A subgroup of 49 and 21 patients underwent additional dosage of IgG after 6 and 12 months, respectively. IgM serological antibodies were available for 17 patients at baseline and 61 at T3, with additional follow-up for 51 and 20 subjects after 6 and 12 months, respectively. RESULTS: Only 28 out of 75 patients discharged from the hospital were totally healed after 3 months, while 47 patients (62.7%) still presented radiological sequelae. According to the GLM model, specific haematochemical baseline parameters-such as IL-6, GPT, platelets and eosinophil count-showed a statistically significant association with the presence of radiological sequelae at month 3 highlighting an OR = 0.5, thus meaning that subjects completely healed after 3 months presented half levels of IL-6 at baseline compared to patients with sequelae. In general, IgG serum levels were always higher than IgM at the time of hospitalization (75% at T0; n = 12 out of 16 patients with data available in both visits), after 3 months (72.1%; n = 44 out of 61 pts.), after 6 months (56.8%; 25 out of 44 pts.), and one year after hospitalization (60%; 12 out of 20 pts.). Overall, IgG and IgM serum levels presented a statistically significant decreasing trend from the baseline to month 3, 6 and 12. One patient presented an increase in IgM between baseline and month 3 but negative PCR test for SARS-COV2 on throat swab. CONCLUSIONS: As supported by our findings on 75 patients, COVID-related interstitial pneumonia triggers early IgG levels (higher than IgM) that gradually decrease over 12 months. Mid-term sequelae are still detectable at lung Computed Tomography after 3 months from the hospital admission. Occasionally, it is possible to observe increase of IgM levels in presence of low concentrations of IgG and negative PCR ELISA tests for SARS-COV2 RNA. Baseline levels of IL-6 could be proposed as predictor of radiological mid/long-term sequelae after COVID-related interstitial pneumonia.

The remaining unsolved problems for rational antibiotic therapy use in pediatric community-acquired pneumonia.

INTRODUCTION: Despite availability of several official guidelines, not all the problems related to the most effective and safe use of antibiotics in children with community-acquired pneumonia (CAP) have been solved. Presently, too many children receive unneeded antibiotics or, when antibiotics are mandatory, the choice of the drug is not appropriate. AREAS COVERED: In this paper, the authors discuss the remaining unsolved problems for rational antibiotic therapy use in pediatric community-acquired pneumonia and provide their expert perspectives. EXPERT OPINION: Further improvement in pediatric CAP management could be derived from physician education on antibiotic use and a larger use, particularly in office practice, of point of care testing or new technologies (i.e. artificial intelligence) to define etiology of a lower respiratory infection. However, recommendations regarding the duration of antibiotic therapy vary largely because of the absence of reliable data on the optimal CAP treatment according to the bacterial etiology of the disease, its severity, and child characteristics. Available evidence seems to confirm that a short course of antibiotics, approximately 5 days, can be effective and lead to results not substantially different from those obtained with prolonged-course antibiotic therapy, at least in patients with mild to moderate disease.

A host signature based on TRAIL, IP-10, and CRP for reducing antibiotic overuse in children by differentiating bacterial from viral infections: a prospective, multicentre cohort study.

OBJECTIVES: Identifying infection aetiology is essential for appropriate antibiotic use. Previous studies have shown that a host-protein signature consisting of TNF-related apoptosis-induced ligand (TRAIL), interferon-γ-induced protein-10 (IP-10), and C-reactive protein (CRP) can accurately differentiate bacterial from viral infections. METHODS: This prospective, multicentre cohort study, entitled AutoPilot-Dx, aimed to validate signature performance and to estimate its potential impact on antibiotic use across a broad paediatric population (>90 days to 18 years) with respiratory tract infections, or fever without source, at emergency departments and wards in Italy and Germany. Infection aetiology was adjudicated by experts based on clinical and laboratory investigations, including multiplex PCR and follow-up data. RESULTS: In total, 1140 patients were recruited (February 2017-December 2018), of which 1008 met the eligibility criteria (mean age 3.5 years, 41.9% female). Viral and bacterial infections were adjudicated for 628 (85.8%) and 104 (14.2%) children, respectively; 276 patients were assigned an indeterminate reference standard outcome. For the 732 children with reference standard aetiology, the signature discriminated bacterial from viral infections with a sensitivity of 93.7% (95%CI 88.7-98.7), a specificity of 94.2% (92.2-96.1), positive predictive value of 73.0% (65.0-81.0), and negative predictive value of 98.9% (98.0-99.8); in 9.8% the test results were equivocal. The signature performed consistently across different patient subgroups and detected bacterial immune responses in viral PCR-positive patients. CONCLUSIONS: The findings validate the high diagnostic performance of the TRAIL/IP-10/CRP signature in a broad paediatric cohort, and support its potential to reduce antibiotic overuse in children with viral infections.

Antibiotic Resistance in Paediatric Febrile Urinary Tract Infections.

Febrile urinary tract infection (UTI) is currently considered the most frequent cause of serious bacterial illness in children in the first 2 years of life. UTI in paediatrics can irreversibly damage the renal parenchyma and lead to chronic renal insufficiency and related problems. To avoid this risk, an early effective antibiotic treatment is essential. Moreover, prompt treatment is mandatory to improve the clinical condition of the patient, prevent bacteraemia, and avoid the risk of bacterial localization in other body sites. However, antibiotic resistance for UTI-related bacterial pathogens continuously increases, making recommendations rapidly outdated and the definition of the best empiric antibiotic therapy more difficult. Variation in pathogen susceptibility to antibiotics is essential for the choice of an effective therapy. Moreover, proper identification of cases at increased risk of difficult-to-treat UTIs can reduce the risk of ineffective therapy. In this review, the problem of emerging antibiotic resistance among pathogens associated with the development of paediatric febrile UTIs and the best potential solutions to ensure the most effective therapy are discussed. Literature analysis showed that the emergence of antibiotic resistance is an unavoidable phenomenon closely correlated with the use of antibiotics themselves. To limit the emergence of resistance, every effort to reduce and rationalise antibiotic consumption must be made. An increased use of antibiotic stewardship can be greatly effective in this regard.