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Abstract In this work our aim was to identify early biomarkers in plasma samples associated with mortality in children with perinatal HIV treated early in life, to potentially inform early intervention targeting this vulnerable group. 20/215 children (9.3%) with perinatal HIV, enrolled within 3 months of age died prematurely within the first year of the study, despite early ART initiation. Using a propensity score, we selected 40 alive study participants having similar clinical and virological records compared to the deceased group. 13 HIV unexposed (HU) healthy children were additionally used as controls. Baseline plasma samples were analyzed using a targeted proteomic approach, and to assess pathogen-associated and damage-associated molecular patterns (PAMPs, DAMPs) levels. Data from deceased participants were compared to both control groups, with multivariate logistic regression models used to evaluate the association between mortality and plasma proteins. We developed a machine learning model to predict mortality risk, finding that IL-6 and CXCL11 not only were higher in deceased children than Matched-children with HIV (p

Abstract The significant impact of acute respiratory tract infections on healthcare systems is well-documented, given their contribution to emergency department admissions, hospitalizations, and increased use of antibiotics and other medications. However, further research is needed to understand the burden of acute respiratory tract infections in pediatric community care to develop effective public health interventions and improve child health outcomes. Real-world data were retrieved from Pedianet, an Italian network of over 200 family pediatricians. Acute respiratory tract infection visits were identified and analysed using an infection-duration algorithm to extract individual cases. The number of follow-up visits per 100 cases was calculated to assess the burden on the Italian National Health Service. Comparisons were made overall and stratified by type of acute respiratory tract infections and epidemiological season. A total of 1,402,953 acute respiratory infections-related visits were recorded, with an overall rate of 12 visits per 100 cases. Upper respiratory tract infections had an average of 9 visits per 100 cases. Lower respiratory tract infections exhibited a higher burden, with 29 visits per 100 cases. Pneumonia showed a declining trend in the pre-pandemic era (62 to 48 visits) but rebounded in the post-COVID-19 years (32 to 42 visits). This study underscores the importance of monitoring and managing acute respiratory infections, especially lower respiratory tract infections, in pediatric care.

Background: Urinary tract infections (UTIs) are the most common bacterial infections in children. The high variability in pathogen susceptibility rates leads to the lack of clear guidelines for empiric and targeted therapies. In this view, local microbiological surveillance and locally adapted stewardship interventions need to be implemented. Objective: The study aims to describe the results of a pediatric antimicrobial stewardship program on antibiotic prescriptions for UTIs over 8 years in a pediatric general ward of a tertiary center. Design: This quasi-experimental study was conducted between 2015 and 2022, with two different implementations, one in 2018 and one in 2021. Methods: Demographic, clinical, microbiological, and therapeutic data were retrieved from the electronic clinical records of included patients. The primary outcomes were adherence to local guidelines for empiric therapies and the adequacy of targeted therapy. Secondary outcomes were evaluating antibiotic prescription patterns stratified by antibiotics during hospital stay and at discharge, and assessing the microbiological characteristics of UTI episodes. Results: During the study period, 7038 patients were admitted to the pediatric acute care unit (PACU), and 264 (3.7%) were included in this study. Adherence to local guidelines was highest immediately after the interventions, and it slightly decreased thereafter. Use of cephalosporins remained high throughout the 8 years but the changing microbiological scenario observed led to changing recommendations within the study period. An increase in E. coli strains resistant to co-amoxiclav was observed in the last years. Oral second-line agent consumption remained high but was adequate considering the prevalence of resistant bacteria. Conclusion: The variability of antimicrobial consumption reflects the changing resistance patterns for UTIs pathogens, underlying the importance of locally adapted, persevering antimicrobial stewardship interventions.

Abstract Background The COVID-19 pandemic has put the provision of health services globally at risk. In Sub-Saharan Africa, it had a major impact on HIV services. However, there is a lack of data on the post-pandemic period. This study aims to evaluate the resumption of HIV services and retention in care for adolescents and young people in the period following the COVID-19 pandemic. Methods A retrospective cohort study was conducted using interrupted time series analysis. Three periods were considered: pre-pandemic (form June 2019 to March 2020), pandemic (form April 2020 to March 2022) post-pandemic (from April 2022 to March 2023). Six outcome measures were considered: number of outpatient visits, HIV tests, HIV positivity ratio, the antiretroviral treatment (ART) non-adherence ratio, recall ratio, and the return ratio for adolescent and young adults on ART. Results During the study period, 447,515 outpatient visits and 126,096 HIV tests were recorded. After a reduction at the beginning of the pandemic period, both visits and tests increased during the pandemic (p

Abstract Background Guidelines about febrile neutropenia in paediatric patients are not homogeneous; the best empiric treatment of this condition should be driven by local epidemiology. The Weighted-Incidence Syndromic Combination Antibiogram (WISCA) addresses the need for disease-specific local susceptibility evidence that could guide empiric antibiotic prescriptions based on outcome estimates of treatment regimens obtained as a weighted average of pathogen susceptibilities. This study developed a WISCA model to inform empirical antibiotic regimen selection for febrile neutropenia (FN) episodes in onco-haematological paediatric patients treated at two Italian paediatric tertiary centres. Methods We included blood cultures from patients with a bloodstream infection and neutropenia admitted to the Paediatric Haematology-Oncology wards in Padua and Genoa Hospitals from 2016 to 2021. WISCAs were developed by estimating the coverage of 20 antibiotics as monotherapy and of 21 combined regimens with a Bayesian probability distribution. Results We collected 350 blood cultures, including 196 g-negative and 154 g-positive bacteria. Considering the most used antibiotic combinations, such as piperacillin–tazobactam plus amikacin, the median coverage for the pool of bacteria collected in the study was 78%. When adding a glycopeptide, the median coverage increased to 89%, while the replacement of piperacillin–tazobactam with meropenem did not provide benefits. The developed WISCAs showed that no monotherapy offered an adequate coverage rate for the identified pathogens. Conclusions The application of WISCA offers the possibility of maximizing the clinical utility of microbiological surveillance data derived from large hospitals to inform the choice of the best empiric treatment while contributing to spare broad-spectrum antibiotics.

Background/Objectives: Seasonal influenza annually puts a significant burden on the pediatric population, especially the youngest, causing severe illness and death. Additionally, associated healthcare costs cause a significant financial strain on healthcare systems. While vaccination is the most effective prevention method, its cost-effectiveness for healthy children remains unassessed. Methods: Using the Pedianet database spanning from 2009 to 2019, we analyzed influenza cases among 6-month-olds to 14-year-olds in Italy. Data included influenza-related medical visits, prescriptions, exams, emergency visits, hospitalizations, and costs. Adverse events and quality-adjusted life years (QALYs) were considered from the existing literature. A static decision-tree model compared annual vaccination strategies, assessing probabilities for influenza or influenza-like illnesses by vaccination status. Incremental cost-effectiveness ratios (ICERs) were calculated, along with sensitivity analyses and cost-effectiveness acceptability curve generation. Results: Mean total influenza costs for vaccinated children averaged EUR 18.6 (range 0–3175.9, including EUR 15.79 for the influenza vaccination), whereas costs for unvaccinated children were consistently lower at around EUR 4.6 (range 0–3250.1). The average ICER for years where vaccine and virus strains are matched was EUR 29,831 per QALY, which is below the EUR 40,000 threshold set by the Italian National Health Services. The ICER values range from EUR 13,736 (2017/2018) to EUR 72,153 (2013/2014). Averted influenza costs averaged EUR 23 per case, with fluctuations over the years. In most observed years, influenza vaccination was cost-effective from the healthcare providers’ standpoint. The exception was 2009–2010, due to a mismatch between vaccine and virus strains. Conclusions: This study highlights the economic viability of influenza vaccination, especially when virus and vaccine strains align. It demonstrates the potential of vaccination programs in preserving children’s health and well-being while managing healthcare costs.

BackgroundChildhood obesity is a significant public health problem representing the most severe challenge in the world. Antibiotic exposure in early life has been identified as a potential factor that can disrupt the development of the gut microbiome, which may have implications for obesity. ObjectiveThis study aims to evaluate the risk of developing obesity among children exposed to antibiotics early in life. MethodsAn Italian retrospective pediatric population-based cohort study of children born between 2004 and 2018 was adopted using the Pedianet database. Children were required to be born at term, with normal weight, and without genetic diseases or congenital anomalies. We assessed the timing of the first antibiotic prescription from birth to 6, 12, and 24 months of life and the dose-response relationship via the number of antibiotic prescriptions recorded in the first year of life (none, 1, 2, and ≥3 prescriptions). Obesity was defined as a BMI z score >3 for children aged ≤5 years and >2 for children aged >5 years, using the World Health Organization growth references. The obese incidence rate (IR) × 100 person-years and the relative 95% CI were computed using infant sex, area of residence, preschool and school age, and area deprivation index, which are the covariates of interest. A mixed-effect Cox proportional hazards model was used to estimate the hazard ratio and 95% CI for the association between antibiotic exposure in early life and child obesity between 24 months and 14 years of age, considering the family pediatricians as a random factor. Several subgroup and sensitivity analyses were performed to assess the robustness of our results. ResultsAmong 121,540 children identified, 54,698 were prescribed at least an antibiotic within the first year of life and 26,990 were classified as obese during follow-up with an incidence rate of 4.05 cases (95% CI 4.01-4.10) × 100 person-year. The risk of obesity remained consistent across different timings of antibiotic prescriptions at 6 months, 1 year, and 2 years (fully adjusted hazard ratio [aHR] 1.07, 95% CI 1.04-1.10; aHR 1.06, 95% CI 1.03-1.09; and aHR 1.07, 95% CI 1.04-1.10, respectively). Increasing the number of antibiotic exposures increases the risk of obesity significantly (P trend

Abstract Introduction In Sofala province (Mozambique), young people living with HIV (YPLHIV) are estimated at 7% among people aged 15–24 years. Even though the COVID-19 pandemic threatened HIV health services, data on the impact of COVID-19 on YPLHIV people are lacking. This study aimed at exploring the seroprevalence of SARS-CoV-2 and associated factors among young people based on their HIV status. Methods A cross-sectional study was conducted, including people aged 18–24 attending a visit at one of the adolescent-friendly health services in Sofala province between October and November 2022. People vaccinated against SARS-COV-2 or YPLHIV with WHO stage III-IV were excluded. A SARS-CoV-2 antibodies qualitative test and a questionnaire investigating socio-demographic and clinical characteristics were proposed. SARS-CoV-2 seroprevalence was calculated with Clopper-Pearson method. The odds ratio (OR) of a positive SARS-CoV-2 antibodies test was estimated through multivariable binomial logistic regression. Results In total, 540 young people including 65.8% women and 16.7% YPLHIV participated in the survey.. The mean age was 20.2 years (SD 2.0). Almost all the sample (96.1%) reported adopting at least one preventive measure for COVID-19. The weighted seroprevalence of SARS-CoV-2 in the whole sample was 46.8% (95%CI 42.6–51.2) and 35.9% (95%CI 25.3–47.5) in YPLHIV. The adjusted OR of testing positive at the SARS-CoV-2 antibodies test was higher in students compared to workers (aOR:2.02[0.95CI 1.01–4.21]) and in those with symptoms (aOR:1.52[0.95CI 1.01–2.30]). There were no differences based on HIV status(aOR:0.663[95%CI 0.406–1.069]). Overall, COVID-19 symptoms were reported by 68 (28.2%) people with a positive serological SARS-CoV-2 test and by 7 (21.7%) YPLHIV (p = 0.527). No one required hospitalization. Conclusions SARS-CoV-2 seroprevalence was 46.8% without differences in risk of infection or clinical presentation based on HIV status. This result may be influenced by the exclusion of YPLHIV with advanced disease. The higher risk among students suggests the schools’ role in spreading the virus. It’s important to continue monitoring the impact of COVID-19 on YPLHIV to better understand its effect on screening and adherence to treatment.

IntroductionInitiation of antiretroviral treatment (ART) in patients early after HIV-infection and long-term suppression leads to low or undetectable levels of HIV RNA and cell-associated (CA) HIV DNA and RNA. Both CA-DNA and CA-RNA, overestimate the size of the HIV reservoir but CA-RNA as well as p24/cell-free viral RNA can be indicators of residual viral replication. This study describes HIV RNA amounts and levels of cytokines/soluble markers in 40 well-suppressed adolescents who initiated ART early in life and investigated which viral markers may be informative as endpoints in cure clinical trials within this population.MethodsForty adolescents perinatally infected with HIV on suppressive ART for >5 years were enrolled in the CARMA study. HIV DNA and total or unspliced CA-RNA in PBMCs were analyzed by qPCR/RT-qPCR and dPCR/RT-dPCR. Cell-free HIV was determined using an ultrasensitive viral load (US-VL) assay. Plasma markers and p24 were analyzed by digital ELISA and correlations between total and unspliced HIV RNA and clinical markers, including age at ART, Western Blot score, levels of cytokines/inflammation markers or HIV CA-DNA, were tested.ResultsCA-RNA was detected in two thirds of the participants and was comparable in RT-qPCR and RT-dPCR. Adolescents with undetectable CA-RNA showed significantly lower HIV DNA compared to individuals with detectable CA-RNA. Undetectable unspliced CA-RNA was positively associated with age at ART initiation and Western Blot score. We found that a higher concentration of TNF-α was predictive of higher CA-DNA and CA-RNA. Other clinical characteristics like US-VL, time to suppression, or percent CD4+ T-lymphocytes were not predictive of the CA-RNA in this cross-sectional study.ConclusionsLow CA-DNA after long-term suppressive ART is associated with lower CA-RNA, in concordance with other reports. Patients with low CA-RNA levels in combination with low CA-DNA and low Western Blot scores should be further investigated to characterize candidates for treatment interruption trials. Unspliced CA-RNA warrants further investigation as a marker that can be prioritized in paediatric clinical trials where the sample volume can be a significant limitation.

Summary: Background: Post Coronavirus disease (COVID) and other post-viral infection syndromes present an overlap of pathogenesis, onset, progression, and symptom profile. We aimed to systematically describe studies on post-viral conditions and determine the entity of post COVID compared to other post-viral conditions in children. Methods: We conducted a systematic search of the Embase, MEDLINE, Cochrane Library, and GoogleScholar databases (January 1946–3 November 2023), according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. The main outcomes were differences in condition duration, symptom type, and development of chronic symptoms. This systematic review was registered on PROSPERO (CRD42023401789). Findings: 35/5051 studies were included, with 42,934 children, adolescents and young adults (0–20 years old) overall. Twenty-eight studies focused on post COVID symptoms, followed by five papers on Respiratory Syncytial Virus (RSV) and Rhinovirus, one study on Epstein–Barr Virus (EBV), and one on gastrointestinal viruses. Studies on post COVID mainly reported data on older children/adolescents, describing long-lasting symptoms, including fatigue, neurologic, cardiorespiratory, musculoskeletal, mental health, and gastrointestinal symptoms. The maximum described symptoms duration was eighteen months, with an average follow-up of seven months. The development of chronic symptoms was reported by 30 studies (93.8%) for 10,473/28,474 patients (36.8%). Recovery was achieved in 18,001/28,474 cases (63.2%). The study on EBV reported persistent fatigue in adolescents for a similar duration (6 months, 46% chronic). Studies on RSV and Rhinovirus were mainly done in children under three years, with development of recurrent wheezing (up to 3 years). Interpretation: Post-viral fatigue was a shared feature between post COVID and post EBV conditions. A better understanding of post COVID as a unique condition, sharing features with other post-viral syndromes, is needed. The healthcare burden and socio-economic consequences for children and their families warrant further investigation and development of appropriate healthcare management plans. The foremost requirement is the establishment of consistent and shareable definitions, as well as a consensus on outcomes, to effectively evaluate follow-up and quantify the burden of different viral infections. Funding: EU Horizon, EDCTP, NIH.

Background: Despite growing scientific knowledge of Zika virus (ZIKV) infection, questions remain regarding ZIKV infection in pregnancy and congenital ZIKV syndrome (CZS). Methods: The ZIKAction Paediatric Registry is an international registry of children with documented ZIKV exposure in utero and/or with confirmed or suspected CZS. Its aim is to characterize these children (i.e., clinical, radiological, neurodevelopmental features) and describe outcomes, longer-term sequelae and management through retrospective case note review. This analysis described the maternal and perinatal characteristics of children in the Registry’s Bahia arm, assessed their neuroimaging, ophthalmic, hearing and electroencephalography abnormalities by microcephaly classification and reported on hospitalisations. Children born in 2015-2018 and enrolled 2020-2021 in three public health facilities in Salvador were included. Results: Of 129 (57% female) children, 15 (11·6%) had laboratory-confirmed congenital ZIKV infection and 114 (88·4%) suspected CZS. At delivery, 15 (11·6%) were normocephalic, 30 (23·3%) moderately microcephalic, and 84 (65·1%) severely microcephalic. Median birth head circumference z-score was -3·51 [IQR, -4·69,-2·73]. During follow-up, all children had abnormal neuroimaging, 80·3% (94/117) abnormal electroencephalogram, 62·2% (77/120) ophthalmic abnormalities, and 27·4% (34/124) hearing impairment. Microcephaly classification was significantly associated with gestational age, and ophthalmological and electroencephalography abnormalities. Of 125 children with hospitalisation data, 52 (41·6%) had been hospitalised by most recent follow-up, at median age of 15·8 [4·0, 34·4] months; infections were the leading cause. Conclusion: Congenital ZIKV infection is an emerging disease with a varied and incompletely understood spectrum. Continued long-term follow-up is essential to understand longer-term prognosis and to inform future health and educational needs.

Objectives: We compared age-stratified SARS-CoV-2 symptomatology of wild-type/Alpha vs Omicron BA.1/BA.2 variant infected individuals and the impact of COVID-19 booster vaccination on Omicron symptom burden. Methods: Data from three European prospective household cohorts were used (April 2020 to April 2021 and January to March 2022). Standardized outbreak protocols included (repeated) polymerase chain reaction testing, paired serology, and daily symptom scoring for all household members. Comparative analyses were performed on 346 secondary household cases from both periods. Results: Children

Abstract Introduction Dolutegravir‐based antiretroviral therapy (ART) is the preferred antiretroviral treatment for children and adolescents living with HIV. A large surveillance study in Botswana previously raised concerns about an association between pre‐conception dolutegravir and neural tube defects. Before these concerns were subsequently resolved, we set up a sub‐study to look at the effect of dolutegravir on levels of folate and vitamin B12 in children and adolescents within the randomized ODYSSEY trial, as folate and vitamin B12 are known to play a crucial role in neural tube development. Methods We conducted the sub‐study among Ugandan ODYSSEY participants and compared folate and vitamin B12 between children randomized to dolutegravir‐based ART (DTG) and non‐dolutegravir‐based standard‐of‐care treatment (SOC). Plasma folate was measured at enrolment and week 4 on stored samples; in addition, plasma and red blood cell (RBC) folate and vitamin B12 were assayed at week ≥96 in prospectively collected samples. RBC mean corpuscular volume (MCV) was measured 24‐weekly in all ODYSSEY participants. Samples analysed in the sub‐study were collected between September 2016 and October 2020. Results A total of 229 children aged ≥6 years were included in the sub‐study with median age at trial enrolment of 12.3 (interquartile range [IQR] 9.0, 14.7) years, and CD4 count of 501 (IQR 228, 695); 112 (49%) children were male. Most participants (225/229, 98%) had plasma folate results at enrolment and 214 (93%) children had results available for RBC folate, vitamin B12 and plasma folate at week ≥96. MCV results were analysed on 679 children aged ≥6 years enrolled in ODYSSEY. At week 4, mean plasma folate was significantly higher in the dolutegravir arm than in SOC (difference [DTG‐SOC] 1.6 ng/ml, 95% CI 0.8, 2.3; p

IntroductionCOVID-19 features changed with the Omicron variant of SARS-CoV-2 in adults. This study aims to describe COVID-19 symptoms in children and adolescents during the Parental, Delta, and Omicron erasMethodsA single-centre, prospective observational study was conducted on individuals aged 0–20 years attending the University Hospital of Padua (Italy) from April 2020 to December 2022. COVID-19 cases were defined by positive SARS-CoV-2 molecular detection and/or serology; patient/family symptoms and virological positivity were considered to determine the infection onset. Variables were summarized and compared using appropriate tests of descriptive statisticsResultsA total of 509 cases [46% female, median age eight years (IQR: 4–12)] were studied. Three-hundred-eighty-seven (76%), 52 (10%), and 70 (14%) subjects experienced COVID-19 during the Parental, Delta, and Omicron waves, respectively. All subjects developed an asymptomatic/mild COVID-19. Overall, the most frequent symptoms were fever (47%) and rhinitis (21%), which showed a significant increasing incidence from the Parental to Omicron waves (p

The WHO Model List of Essential Medicines for Children (EMLc) has not been systematically revised in the last few years. We conducted a survey addressed to healthcare professionals prescribing, preparing, or administering medicines to children and a narrative review to identify problematic paediatric formulations or missing medicines in all therapeutic fields to inform the review of the EMLc in 2023. A total of 285 physicians (63%), 28 nurses (6%) and 142 pharmacists (31%), mostly working in the hospital setting, reported at least one problematic medicine. 290 medicines were reported as missing (completely or the child-appropriate formulation). The top three most mentioned were ciprofloxacin together with phenobarbital and omeprazole. 387 medicines were reported as problematic (34% were oral liquid formulations, 34% tablets, 18% parenteral preparations. Mostly of the products were antibacterials (27%), cardiovascular medicines (11%) and antivirals (11%). The obtained responses show the perspective of healthcare workers working around the world, particularly in the European region (25%), in the African region (24%), and in the Region of the Americas (19%), with limited representation from Northern Africa and the Middle East. Our results need to be analysed with the outputs of other ongoing works before specific products can enter the WHO-hosted Global Accelerator for Paediatric formulations network prioritisation process. Efforts to develop appropriate formulations for children should be accelerated so that the uncertainties associated with off-label drug preparation and use are minimised, and therapeutic benefits are optimised.

Summary: Background: Integrase inhibitor (INSTI) with boosted darunavir (DRV/r), a regimen with a high-resistance barrier, avoiding NRTI toxicities, might be a switching option in children living with HIV (CLWHIV). Methods: SMILE is a randomised non-inferiority trial evaluating safety and antiviral efficacy of once-daily INSTI + DRV/r vs. continuing on current standard-of-care (SOC) triple ART (2NRTI + boosted PI/NNRTI) in virologically-suppressed CLWHIV aged 6–18 years. The primary outcome is the proportion with confirmed HIV-RNA ≥50 copies/mL by week 48, estimated by Kaplan–Meier method. Non-inferiority margin was 10%. Registration number for SMILE are: ISRCTN11193709, NCT #: NCT02383108. Findings: Between 10th June 2016 and 30th August 2019, 318 participants were enrolled from Africa 53%, Europe 24%, Thailand 15% and Latin America 8%, 158 INSTI + DRV/r [153 Dolutegravir (DTG); 5 Elvitegravir (EVG)], 160 SOC. Median (range) age was 14.7 years (7.6–18.0); CD4 count 782 cells/mm3 (227–1647); 61% female. Median follow-up was 64.3 weeks with no loss to follow-up. By 48 weeks, 8 INSTI + DRV/r vs. 12 SOC had confirmed HIV-RNA ≥50 copies/mL; difference (INSTI + DRV/r-SOC) −2.5% (95% CI: −7.6, 2.5%), showing non-inferiority. No major PI or INSTI resistance mutations were observed. There were no differences in safety between arms. By week 48, difference (INSTI + DRV/r-SOC) in mean CD4 count change from baseline was −48.3 cells/mm3 (95% CI: −93.4, −3.2; p = 0.036). Difference (INSTI + DRV/r-SOC) in mean HDL change from baseline was −4.1 mg/dL (95% CI: −6.7, −1.4; p = 0.003). Weight and Body Mass Index (BMI) increased more in INSTI + DRV/r than SOC [difference: 1.97 kg (95% CI: 1.1, 2.9; p

Saliva is a promising matrix with several purposes. Our aim is to verify if salivary anti-SARS-CoV-2 antibody determination is suitable for monitoring immune responses. One hundred eighty-seven subjects were enrolled at University-Hospital Padova: 105 females (56.1%) and 82 males (43.9%), 95 (50.8%) children and 92 (49.2%) adults. Subjects self-collected saliva using Salivette; nineteen subjects collected three different samples within the day. A serum sample was obtained for all individuals. The N/S anti-SARS-CoV-2 salivary IgG (sal-IgG) and serum anti-SARS-CoV-2 S-RBD IgG (ser-IgG) were used for determining anti-SARS-CoV-2 antibodies. The mean (min–max) age was 9.0 (1–18) for children and 42.5 (20–61) for adults. Of 187 samples, 63 were negative for sal-IgG (33.7%), while 7 were negative for ser-IgG (3.7%). Spearman’s correlation was 0.56 (p < 0.001). Sal-IgG and ser-IgG levels were correlated with age but not with gender, comorbidities, prolonged therapy, previous SARS-CoV-2 infection, or time from last COVID-19 infection/vaccination. The repeatability ranged from 23.8% (7.4 kAU/L) to 4.0% (3.77 kAU/L). The linearity of the assay was missed in 4/6 samples. No significant intrasubject differences were observed in sal-IgG across samples collected at different time points. Sal-IgG has good agreement with ser-IgG. Noninvasive saliva collection represents an alternative method for antibody measurement, especially in children.

Respiratory tract infections (RTIs) are the most common infectious syndromes, primarily caused by viruses. The primary objective was to compare the illness courses between historical RTIs and recent SARS-CoV-2 infections. The study cohort consisted of RTI cases evaluated at the Pediatric Emergency Departments of Padua and Bologna, discharged or admitted with microbiologically confirmed viral RTI between 1 November 2018 and 30 April 2019 (historical period) and 1 March 2020 and 30 April 2021 (recent period). We evaluated the risk of oxygen or respiratory support, hospitalization, antibiotic therapy, and complications among different viral infections. The odds ratio (OR) and the 95% confidence intervals (CIs) were estimated through mixed-effect logistic regression models, including a random intercept on the individual and hospital. We identified 767 RTIs: 359 in the historical period compared with 408 SARS-CoV-2 infections. Infections of SARS-CoV-2 had a lower risk of being admitted (OR 0.04, 95% CI 0.03–0.07), receiving respiratory support (OR 0.19, 95% CI 0.06–0.58), needing antibiotic therapy (OR 0.35, 95% CI 0.22–0.56) and developing complications (OR 0.27, 95% CI 0.14–0.51) compared to all other viral RTIs. COVID-19 in children is clinically similar to other viral RTIs but is associated with a less severe infection course. Thus, most prevention strategies implemented for SARS-CoV-2 should still be considered during RSV and Influenza epidemics.

Abstract Norovirus is a leading cause of epidemic acute gastroenteritis. More than 30 genotypes circulate in humans, some are common, and others are only sporadically detected. Here, we investigated whether serology can be used to determine which genotypes infect children. We established a multiplex protein microarray with structural and non-structural norovirus antigens that allowed simultaneous antibody testing against 30 human GI and GII genotypes. Antibody responses of sera obtained from 287 children aged

Abstract Background The World Health Organization (WHO) risk assessment algorithm for vertical transmission of HIV (VT) assumes the availability of maternal viral load (VL) result at delivery and early viral control 4 weeks after initiating antiretroviral treatment (ART). However, in many low-and-middle-income countries, VL is often unavailable and mothers’ ART adherence may be suboptimal. We evaluate the inclusion of the mothers’ self-reported adherence into the established WHO-algorithm to identify infants eligible for enhanced post-natal prophylaxis when mothers’ VL result is not available at delivery. Methods We used data from infants with perinatal HIV infection and their mothers enrolled from May-2018 to May-2020 in Mozambique, South Africa, and Mali. We retrospectively compared the performance of the WHO-algorithm with a modified algorithm which included mothers’ adherence as an additional factor. Infants were considered at high risk if born from mothers without a VL result in the 4 weeks before delivery and with adherence

BackgroundBronchiolitis is the most common lower respiratory tract infection (LRTI) in children and is mainly caused by the Respiratory Syncytial Virus (RSV). Bronchiolitis presents seasonally and lasts about five months, usually between October to March, with peaks of hospitalizations between December and February, in the Northern Hemisphere. The burden of bronchiolitis and RSV in primary care is not well understood.Materials and methodsThis retrospective analysis used data from Pedianet, a comprehensive paediatric primary care database of 161 family paediatricians in Italy. We evaluated the incidence rates (IR) of all-cause bronchiolitis (ICD9-CM codes 466.1, 466.11 or 466.19), all-cause LRTIs, RSV-bronchiolitis and RSV-LRTIs in children from 0 to 24 months of age, between January 2012 to December 2019. The role of prematurity (

Abstract Background Early start of highly active antiretroviral therapy (HAART) in perinatally HIV-1 infected children is the optimal strategy to prevent immunological and clinical deterioration. To date, according to EMA, only 35% of antiretroviral drugs are licenced in children 25%. At last check, during the off label regimen, the 80% (40/50) of patients had an undetectable VL, and 90% (45/50) of them displayed CD4 + T lymphocyte percentage > 25%. The most widely used off-label drugs were: dolutegravir/abacavir/lamivudine (16%; 8/50), emtricitbine/tenofovir disoproxil (22%; 11/50), lopinavir/ritonavir (20%; 10/50) and elvitegravir/cobicistat/emtricitabine/ tenofovir alafenamide (10%; 10/50). At logistic regression analysis, detectable VL before starting the current HAART regimen was a risk factor for receiving an off-label therapy (OR: 2.41; 95% CI 1.13–5.19; p = 0.024). Moreover, children

BackgroundThe success of pediatric COVID-19 vaccination strongly depends on parents' willingness to vaccinate their children. To date, the role of socioeconomic position (SEP) in pediatric COVID-19 vaccination has not been thoroughly examined. ObjectiveWe evaluated the association between COVID-19 vaccination and SEP in a large pediatric cohort. MethodsA case-control study design nested into a pediatric cohort of children born between 2007 and 2017, living in the Veneto Region and followed up to at least January 1, 2022, was adopted. Data on children were collected from the Pedianet database and linked with the regional COVID-19 registry. Each child vaccinated with at least one dose of any COVID-19 vaccine between July 1, 2021, and March 31, 2022, was matched by sex, year of birth, and family pediatrician to up to 5 unvaccinated children. Unvaccinated children with a positive outcome on the swab test within 180 days before the index date were excluded from the analyses. Children were geo-referenced to determine their area deprivation index (ADI)—a social and material deprivation measure calculated at the census block level and consisting of 5 socioeconomic items. The index was then categorized in quintiles based on the regional ADI level. The association between ADI quintiles and vaccination status was measured using conditioned logistic regression models to estimate odds ratios and the corresponding 95% CIs. Quantile-g-computation regression models were applied to develop a weighted combination of the individual items to estimate how much each component influenced the likelihood of vaccination. All analyses were stratified by age at vaccination (5-11 and 12-14 years). ResultsThe study population consisted of 6475 vaccinated children, who were matched with 32,124 unvaccinated children. Increasing area deprivation was associated with a lower probability of being vaccinated, with approximately a linear dose-response relationship. Children in the highest deprivation quintile were 36% less likely to receive a COVID-19 vaccine than those with the lowest area deprivation (95% CI 0.59-0.70). The results were similar in the 2 age groups, with a slightly stronger association in 5-11–year-old children. When assessing the effects of the weighted combination of the individual items, a quintile increase was associated with a 17% decrease in the probability of being vaccinated (95% CI 0.80-0.86). The conditions that influenced the probability of vaccination the most were living on rent, being unemployed, and being born in single-parent families. ConclusionsThis study has shown a significant reduction in the likelihood of receiving a COVID-19 vaccine among children living in areas characterized by a lower SEP. Findings were robust among multiple analyses and definitions of the deprivation index. These findings suggest that SEP plays an important role in vaccination coverage, emphasizing the need to promote targeted public health efforts to ensure global vaccine equity.

BackgroundDue to the growing evidence of the efficacy of intravenous (IV) cefazolin with an early switch to oral cefalexin in uncomplicated pediatric osteomyelitis (OM) and septic arthritis (SA) in children, we changed our guidelines for empiric antibiotic therapy in these conditions. This study aims at evaluating the impact of the guidelines' implementation in reducing broad-spectrum antibiotic prescriptions, duration of IV antibiotic treatment and hospital stay, treatment failure and recurrence.Materials and methodsThis is a retrospective, observational, quasi-experimental study. The four years pre-intervention were compared to the six years, ten months post-intervention (January 2012, through December 2015; January 2016, through October 31st, 2022). All patients aged 3 months to 18 years with OM or SA were evaluated for inclusion. Each population was divided into three groups: pre-intervention, post-intervention not following the guidelines, and post-intervention following the guidelines. Differences in antibiotic prescriptions such as Days of Therapy (DOT), activity spectrum and Length of Therapy (LOT), length of hospital stay (LOS), broad-spectrum antibiotics duration (bsDOT), treatment failure and relapse at six months were analyzed as outcomes.ResultsOf 87 included patients, 48 were diagnosed with OM (8 pre-intervention, 9 post-intervention not following the guidelines and 31 post-intervention following the guidelines) and 39 with SA (9 pre-intervention, 12 post-intervention not following the guidelines and 18 post-intervention following the guidelines). In OM patients, IV DOT, DOT/LOT ratio, and bsDOT were significantly lower in the guidelines group, with also the lowest proportion of patients discharged on IV treatment. Notably, significantly fewer cases required surgery in the post-intervention groups. Considering SA, LOS, IV DOT, DOT/LOT ratio, and bsDOT were significantly lower in the guidelines group. The treatment failure rate was comparable among all groups for both OM and SA. There were no relapse cases. The overall adherence was between 72 and 100%.ConclusionsThe implementation of guidelines was effective in decreasing the extensive use of broad-spectrum antibiotics and combination therapy for both OM and SA. Our results show the applicability, safety, and efficacy of a narrow-spectrum IV empirical antibiotic regimen with cefazolin, followed by oral monotherapy with first/second-generation cephalosporins, which was non-inferior to broad-spectrum regimens.

Background: Antibiotics remain the most prescribed medicine in children worldwide, but half of the prescriptions are unnecessary or inappropriate, leading to an increase in antibiotic resistance. This study aims to systemically review the effects of different Antimicrobial Stewardship Programmes (ASPs) on reducing the rates of both antibiotic prescriptions and changes in antimicrobial resistance, and on the economic impact in paediatric emergency departments (PED) and primary care settings. Materials and methods: Embase, MEDLINE, and Cochrane Library were systematically searched, combining Medical Subject Heading and free-text terms for ‘children’ and ‘antimicrobial’ and ‘stewardship’. The search strategy involved restrictions on dates (from 1 January 2007 to 30 December 2020) but not on language. Randomized controlled trials, controlled and non-controlled before and after studies, controlled and non-controlled interrupted time series, and cohort studies were included for review. The review protocol was registered at the PROSPERO International Prospective Register of Systematic Reviews: Registration Number CRD42021270630. Results: Of the 47,158 articles that remained after removing duplicates, 59 were eligible for inclusion. Most of the studies were published after 2015 (37/59, 62.7%) and in high-income countries (51/59, 86.4%). Almost half of the studies described the implementation of an ASP in the primary care setting (28/59, 47.5%), while 15 manuscripts described the implementation of ASPs in EDs (15/59, 25.4%). More than half of the studies (43/59, 72.9%) described the implementation of multiple interventions, whereas few studies considered the implementation of a single intervention. Antibiotic prescriptions and compliance with guidelines were the most frequent outcomes (47/59, 79.7% and 20/59, 33.9%, respectively). Most of the articles reported an improvement in these outcomes after implementing an ASP. Meanwhile, only very few studies focused on health care costs (6/59, 10.2%) and antimicrobial resistance (3/59 5.1%). Conclusion: The implementation of ASPs has been proven to be feasible and valuable, even in challenging settings such as Emergency Departments and Primary care.

Background The impact of the COVID-19 pandemic on paediatric populations varied between high-income countries (HICs) versus low-income to middle-income countries (LMICs). We sought to investigate differences in paediatric clinical outcomes and identify factors contributing to disparity between countries.Methods The International Severe Acute Respiratory and Emerging Infections Consortium (ISARIC) COVID-19 database was queried to include children under 19 years of age admitted to hospital from January 2020 to April 2021 with suspected or confirmed COVID-19 diagnosis. Univariate and multivariable analysis of contributing factors for mortality were assessed by country group (HICs vs LMICs) as defined by the World Bank criteria.Results A total of 12 860 children (3819 from 21 HICs and 9041 from 15 LMICs) participated in this study. Of these, 8961 were laboratory-confirmed and 3899 suspected COVID-19 cases. About 52% of LMICs children were black, and more than 40% were infants and adolescent. Overall in-hospital mortality rate (95% CI) was 3.3% [=(3.0% to 3.6%), higher in LMICs than HICs (4.0% (3.6% to 4.4%) and 1.7% (1.3% to 2.1%), respectively). There were significant differences between country income groups in intervention profile, with higher use of antibiotics, antivirals, corticosteroids, prone positioning, high flow nasal cannula, non-invasive and invasive mechanical ventilation in HICs. Out of the 439 mechanically ventilated children, mortality occurred in 106 (24.1%) subjects, which was higher in LMICs than HICs (89 (43.6%) vs 17 (7.2%) respectively). Pre-existing infectious comorbidities (tuberculosis and HIV) and some complications (bacterial pneumonia, acute respiratory distress syndrome and myocarditis) were significantly higher in LMICs compared with HICs. On multivariable analysis, LMIC as country income group was associated with increased risk of mortality (adjusted HR 4.73 (3.16 to 7.10)).Conclusion Mortality and morbidities were higher in LMICs than HICs, and it may be attributable to differences in patient demographics, complications and access to supportive and treatment modalities.

Modern HIV-1 treatment effectively suppresses viral amplification in people living with HIV. However, the persistence of HIV-1 DNA as proviruses integrated into the human genome remains the main barrier to achieving a cure. Next-generation sequencing (NGS) offers increased sensitivity for characterising archived drug resistance mutations (DRMs) in HIV-1 DNA for improved treatment options. In this study, we present an ultra-sensitive targeted PCR assay coupled with NGS and a robust pipeline to characterise HIV-1 DNA DRMs from buffy coat samples. Our evaluation supports the use of this assay for Pan-HIV-1 analyses with reliable detection of DRMs across the HIV-1 Pol region. We propose this assay as a new valuable tool for monitoring archived HIV-1 drug resistance in virologically suppressed individuals, especially in clinical trials investigating novel therapeutic approaches.

Background: Possible cardiac impairment after SARS-CoV-2 mRNA vaccination is a common driver of parental vaccine hesitancy. We performed a comprehensive echocardiographic evaluation of biventricular function in vaccinated children with or without previous COVID-19 compared to healthy controls. Methods: We conducted a single-center, prospective, case–control study enrolling children and adolescents aged 5–18 years attending the pediatric clinic of the University Hospital of Padua from April to June 2022. Three months after receiving the primary mRNA vaccination or booster dose, the patients underwent a cardiac assessment, including standard echocardiography and speckle-tracking echocardiography (STE). A pre-pandemic historical cohort of age- and gender-matched healthy children were used as a control. Results: A total of 39 post-VACCINE cases (24, 61% female), mean age 12.6 ± 2.6 years (range 8–17), were enrolled in the study. Ninety percent (N = 35) of patients were previously healthy. No differences in left ventricular diameters, left ventricular ejection fraction (LVEF), and tricuspid annular plane systolic excursion (TAPSE) were observed between cases and controls. Global longitudinal strain (GLS) was in the normal range in all individuals, with no differences between post-VACCINE cases and controls (−21.7 ± 2.3% vs. 21.2 ± 1.8%; p = 0.338). However, GLS was found to be slightly but significantly reduced in post-VACCINE children with a previous COVID-19 compared to naïve-vaccinated individuals (post-VACCINE+COVID-19: −19.9 ± 1.1% vs. post-VACCINE-only: −22.0 ± 2.3%; p = 0.002). Conclusions: We did not observe an impairment in GLS or in other indices of LV structure or function after mRNA COVID-19 vaccination.

As a synergistic treatment approach with systemic antimicrobial therapy or a systemic antibiotic-sparing strategy, the local administration of antimicrobial agents has been proposed as an alternative route for complicated infections. With the rationale of concentrating the active principle in the desired target site, avoiding potentially toxic systemic levels and bypassing anatomical and physiological barriers, local irrigation or infusion of antibiotics may effectively shorten the antimicrobial therapy course and reduce both infection-related and systemic therapy-related complications. Although evidence from the adult population supports its use in selected patients with an acceptable safety profile, data specifically focused on the pediatric population are limited. To provide a rapid and easily accessible tool for clinical practice, we synthesized the most relevant evidence on the use of local antimicrobial agents in common severe infections in children: meningitis, mediastinitis, pleural infections, recurrent urinary infections, and peritonitis. A literature search was performed using predefined combined keywords through an electronic research database (PubMed). Described molecules, dosages, routes, treated age groups, and related efficacy have been summarized for prompt application to clinical practice. It should, however, be noted that the evidence for the pediatric population remains limited, and the local administration of several molecules remains off-label. A careful multidisciplinary and patient-tailored evaluation, as well as a rational use of available guidelines, should always be the basis of clinical decision making in settings where local administration of antibiotics may be considered.

To determine the extent of exposure to Zika virus (ZIKV) and chikungunya virus (CHIKV) in Jamaica, we collected serum from 584 pregnant women during 2017–2019. We found that 15.6% had antibodies against ZIKV and 83.6% against CHIKV. These results indicate potential recirculation of ZIKV but not CHIKV in the near future.

BackgroundThere is growing evidence of the benefits of mobile health technology, which include symptom tracking apps for research, surveillance, and prevention. No study has yet addressed arbovirus symptom tracking in pregnancy. ObjectiveThis study aimed to evaluate the use of a smartphone app (ZIKApp) to self-report arbovirus symptoms and pregnancy complications and to assess compliance with daily symptom diaries during pregnancy in a cohort of women in an arbovirus-endemic, subtropical, middle-income country (Jamaica). MethodsPregnant women aged ≥16 years, having a smartphone, and planning on giving birth at the recruiting center were enrolled between February 2020 and July 2020. ZIKApp comprised a daily symptom diary based on algorithms to identify potential episodes of arbovirus infection and pregnancy complications. Sociodemographic, epidemiological, and obstetric information was collected at enrollment, with additional review of medical records, and users’ perception was collected through an exit survey. Descriptive analyses and logistic regression analysis of possible factors associated with diary adherence were performed. ResultsOf the 173 women enrolled, 157 (90.8%) used ZIKApp for a median duration of 155 (IQR 127-173) days until pregnancy end, 6 (3.5%) used the app for 34 years versus those aged 25 to 29 years (adjusted odds ratio 3.14, 95% CI 1.10-8.98) and 2-fold higher odds for women with tertiary versus secondary education (adjusted odds ratio 2.26, 95% CI 1.06-4.83). Of the 161 women who ever made a diary entry, 5454 individual symptom reports were made (median 17 per woman; IQR 4-42; range 0-278); 9 (5.6%) women reported symptom combinations triggering a potential arbovirus episode (none had an adverse pregnancy outcome) and 55 (34.2%) reported painful uterine contractions or vaginal bleeding, mainly in the month before delivery. Overall, 51.8% (71/137) of the women rated the app as an excellent experience and were less likely to be poor diary adherers (P=.04) and 99.3% (138/139) reported that the app was easy to understand and use. ConclusionsThis pilot found a high adherence to ZIKApp. It demonstrated the feasibility and usability of the app in an arbovirus-endemic region, supporting its future development to contribute to surveillance and diagnosis of arbovirus infections in pregnancy and to optimize maternal care.

ABSTRACT Reliable and accurate quantification of cell-associated HIV DNA (CA HIV DNA) is critical for early infant diagnosis, clinical management of patients under therapy, and to inform new therapeutics efficacy. The present study assessed the variability of CA HIV DNA quantification obtained from various assays and the value of using reference materials to help harmonize the measurements. Using a common set of reagents, our multicenter collaborative study highlights significant variability of CA HIV DNA quantification and lower limit of quantification across assays. The quantification of CA HIV DNA from a panel of infected PBMCs can be harmonized through cross-subtype normalization but assay calibration with the commonly used 8E5 cell line failed to reduce quantification variability between assays, demonstrating the requirement to thoroughly evaluate reference material candidates to help improve the comparability of CA HIV DNA diagnostic assay performance. IMPORTANCE Despite a global effort, HIV remains a major public health burden with an estimated 1.5 million new infections occurring in 2020. HIV DNA is an important viral marker, and its monitoring plays a critical role in the fight against HIV: supporting diagnosis in infants and underpinning clinical management of patients under therapy. Our study demonstrates that HIV DNA measurement of the same samples can vary significantly from one laboratory to another, due to heterogeneity in the assay, protocol, and reagents used. We show that when carefully selected, reference materials can reduce measurement variability and harmonize HIV DNA quantification across laboratories, which will help contribute to improved diagnosis and clinical management of patients living with HIV.

Abstract Background To evaluate the ability of Weighted-Incidence Syndromic Combination Antibiograms (WISCA) to inform the selection of empirical antibiotic regimens for suspected paediatric community-acquired urinary tract infections. Methods Data were collected from outpatients (

Abstract In Italy, two clinical practice guidelines for the diagnosis and treatment of bronchiolitis were published in October 2014 and December 2015. We evaluated prescriptions for bronchiolitis in children aged 0–24 months before (December 2012–December 2014), in between (December 2014–December 2015) and after (December 2015–December 2018) the guidelines publications. Data were retrieved from the Pedianet database; the measured outcomes were prescriptions rates of antibiotics, corticosteroids, β2-agonists, and other respiratory drugs. In 1011 out of 1581 episodes, patients received at least one treatment, with a total of 2003 prescriptions. The rate of treated bronchiolitis decreased from 66% to 57% (p

Using electronic data from a large population-based network of Family Paediatricians (Pedianet), we aimed to describe the use of topical antimicrobials, including ozenoxacin 1% cream, in impetigo in children in Italy. We included 2929 children aged 6 months–14 years from 2016 to 2019 with at least one episode of impetigo treated with topical antimicrobials. Overall, 3051 cases of impetigo were included in the analysis. Treatment started in most cases on the same day as the impetigo diagnosis and lasted around eight days. In about 8% of the cases, a systemic antibiotic was prescribed after the topical antimicrobial, usually after 4–14 days. In this study, ozenoxacin was used in 8% of the cases. Treatment duration was significantly shorter for patients prescribed ozenoxacin compared to the whole study population (median of six vs. seven days, respectively). In contrast, the rate of treatment failure was similar. Very few adverse reactions were identified.

Abstract Background Dolutegravir (DTG)-based antiretroviral therapy (ART) is highly effective and well-tolerated in adults and is rapidly being adopted globally. We describe the design of the ODYSSEY trial which evaluates the efficacy and safety of DTG-based ART compared with standard-of-care in children and adolescents. The ODYSSEY trial includes nested pharmacokinetic (PK) sub-studies which evaluated pragmatic World Health Organization (WHO) weight-band-based DTG dosing and opened recruitment to children

BackgroundIdentifying subphenotypes within heterogeneous diseases may have an impact in terms of therapeutic options. In this study, we aim to assess different subphenotypes in children living with human immunodeficiency virus (HIV-1), according to the clinical, virological, and immunological characteristics.MethodsWe collected clinical and sociodemographic data, baseline viral load (VL), CD4 and CD8 count and percentage, age at initiation of ART, HIV DNA reservoir size in peripheral blood mononuclear cells (PBMCs), cell-associated RNA (CA-RNA), ultrasensitive VL, CD4 subsets (T effector CD25+, activated memory cells, Treg cells), humoral-specific HIV response (T-bet B cells), innate response (CD56dim natural killer (NK) cells, NKp46+, perforin), exhaustion markers (PD-1, PD-L1, DNAM), CD8 senescence, and biomarkers for T-lymphocyte thymic output (TREC) and endothelial activation (VCAM). The most informative variables were selected using an unsupervised lasso-type penalty selection for sparse clustering. Hierarchical clustering was performed using Pearson correlation as the distance metric and WARD.D2 as the clustering method. Internal validation was applied to select the best number of clusters. To compare the characteristics among clusters, boxplot and Kruskal Wallis test were assessed.ResultsThree subphenotypes were discovered (cluster1: n=18, 45%; cluster2: n=11, 27.5%; cluster3: n=11, 27.5%). Patients in cluster1 were treated earlier, had higher baseline %CD4, low HIV reservoir size, low western blot score, higher TREC values, and lower VCAM values than the patients in the other clusters. In contrast, cluster3 was the less favorable. Patients were treated later and presented poorer outcomes with lower %CD4, and higher reservoir size, along with a higher percentage of CD8 immunosenescent cells, lower TREC, higher VCAM cytokine, and a higher %CD4 PD-1. Cluster2 was intermediate. Patients were like those of cluster1, but had lower levels of t-bet expression and higher HIV DNA reservoir size.ConclusionsThree HIV pediatric subphenotypes with different virological and immunological features were identified. The most favorable cluster was characterized by a higher rate of immune reconstitution and a slower disease progression, and the less favorable with more senescence and high reservoir size. In the near future therapeutic interventions for a path of a cure might be guided or supported by the different subphenotypes.

ImportanceThe Padova Chart for Health in Children (PCHC) aims to gather the evidence of healthcare promotion and protection for chidren and adolescents (i.e., aged

BackgroundDosing recommendations for anti-infective medicines in children with pre-existing kidney dysfunction are derived from adult pharmacokinetics studies and adjusted to kidney function. Due to neonatal/pediatric age and kidney impairment, modifications in renal clearance and drug metabolism make standard anti-infective dosing for children and neonates inappropriate, with a risk of drug toxicity or significant underdosing. The aim of this study was the systematic description of the use of anti-infective medicines in pediatric patients with pre-existing kidney impairment.MethodsA systematic review of the literature was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The EMBASE, Medline and Cochrane databases were searched on September 21st, 2021. Studies in all languages reporting data on pre-defined outcomes (pharmacokinetics-PK, kidney function, safety and efficacy) regarding the administration of anti-infective drugs in children up to 18 years with pre-existing kidney dysfunction were included.Results29 of 1,792 articles were eligible for inclusion. There were 13 case reports, six retrospective studies, nine prospective studies and one randomized controlled trial (RCT), reporting data on 2,168 pediatric patients. The most represented anti-infective class was glycopeptides, with seven studies on vancomycin, followed by carbapenems, with five studies, mostly on meropenem. Antivirals, aminoglycosides and antifungals counted three articles, followed by combined antibiotic therapy, cephalosporins, lipopeptides with two studies, respectively. Penicillins and polymixins counted one study each. Nine studies reported data on patients with a decreased kidney function, while 20 studies included data on kidney replacement therapy (KRT). Twenty-one studies reported data on PK. In 23 studies, clinical outcomes were reported. Clinical cure was achieved in 229/242 patients. There were four cases of underdosing, one case of overdosing and 13 reported deaths.ConclusionThis is the first systematic review providing evidence of the use of anti-infective medicines in pediatric patients with impaired kidney function or requiring KRT. Dosing size or interval adjustments in pediatric patients with kidney impairment vary according to age, critical illness status, decreased kidney function and dialysis type. Our findings underline the relevance of population PK in clinical practice and the need of developing predictive specific models for critical pediatric patients.

Impetigo is a common skin infection in children. The worldwide prevalence in children is estimated to be 12%, but this may be lower since high-income countries are under-represented. This research aims to evaluate the incidence, prevalence, and management of children with non-bullous impetigo (NBI) residing in Italy. This retrospective cohort study included children up to 14 years of age enrolled in the Pedianet database from January 2004 to June 2018. Events were identified searching ICD9-CM codes (684 and 694.3) and free text fields for a diagnosis of NBI reported during a primary care visit. Diagnoses were manually validated, and events registered within 30-days after the index date were considered follow-ups. Incidence (IR) and prevalence (PR) rates of NBI were stratified by sex, age group, and calendar year. Topical and systemic antibiotic treatments were grouped based on ATC codes. 15,136 NBI episodes occurred in a total cohort of 225,979 children. The overall IR of NBI was 9.5 per 1,000 person-years, and children aged 1–4 years had the highest IR (13.2 per 1,000 person-years). A significant decrease in NBI IR from 13 per 1,000 person-years in 2004 to 7.46 per 1,000 person-years in 2018 (p < 0.0001) was noted. Most of the episodes were treated; systemic antibiotics were preferred over topical.ConclusionThe prevalence of NBI in children in Italy is less than one third than the global estimate and the trend in time is decreasing. Over prescriptions of systemic antibiotics pose a threat to the diffusion of antimicrobial resistance.

BackgroundDespite a successful antiretroviral therapy (ART), adolescents living with perinatally acquired HIV (PHIV) experience signs of B-cell hyperactivation with expansion of ‘namely’ atypical B-cell phenotypes, including double negative (CD27-IgD-) and termed age associated (ABCs) B-cells (T-bet+CD11c+), which may result in reduced cell functionality, including loss of vaccine-induced immunological memory and higher risk of developing B-cells associated tumors. In this context, perinatally HIV infected children (PHIV) deserve particular attention, given their life-long exposure to chronic immune activation.MethodsWe studied 40 PHIV who started treatment by the 2nd year of life and maintained virological suppression for 13.5 years, with 5/40 patients experiencing transient elevation of the HIV-1 load in the plasma (Spike). We applied a multi-disciplinary approach including immunological B and T cell phenotype, plasma proteomics analysis, and serum level of anti-measles antibodies as functional correlates of vaccine-induced immunity.ResultsPhenotypic signs of B cell hyperactivation were elevated in subjects starting ART later (%DN T-bet+CD11c+ p=0.03; %AM T-bet+CD11c+ p=0.02) and were associated with detectable cell-associated HIV-1 RNA (%AM T-bet+CD11c+ p=0.0003) and transient elevation of the plasma viral load (spike). Furthermore, B-cell hyperactivation appeared to be present in individuals with higher frequency of exhausted T-cells, in particular: %CD4 TIGIT+ were associated with %DN (p=0.008), %DN T-bet+CD11c+ (p=0.0002) and %AM T-bet+CD11c+ (p=0.002) and %CD4 PD-1 were associated with %DN (p=0.048), %DN T-bet+CD11c+ (p=0.039) and %AM T-bet+CD11c+ (p=0.006). The proteomic analysis revealed that subjects with expansion of these atypical B-cells and exhausted T-cells had enrichment of proteins involved in immune inflammation and complement activation pathways. Furthermore, we observed that higher levels of ABCs were associated a reduced capacity to maintain vaccine-induced antibody immunity against measles (%B-cells CD19+CD10- T-bet+, p=0.035).ConclusionWe identified that the levels of hyperactivated B cell subsets were strongly affected by time of ART start and associated with clinical, viral, cellular and plasma soluble markers. Furthermore, the expansion of ABCs also had a direct impact on the capacity to develop antibodies response following routine vaccination.

BackgroundTo date, there's no evidence of an increased risk of SARS-CoV-2 infection or more severe COVID-19 in patients with inflammatory bowel disease (IBD). However, whether COVID-19 alters the clinical course of IBD or whether IBD treatment affects the immunological response to SARS-CoV-2 is still under investigation, especially in children.AimTo assess the serological response to SARS-CoV-2 in children with IBD, and to evaluate the impact of COVID-19 on the clinical course of IBD.Material and MethodsThis prospective study enrolled children (0–18 years) followed-up at the University Hospital of Padova for IBD, who acquired a confirmed SARS-CoV-2 infection between 02.2020 and 02.2021. The anti-SARS-CoV-2 S-RBD IgG titer was evaluated at 3 months after infection and compared to that of a control group of healthy children matched for age, sex, and COVID-19 severity.ResultsTwelve children with IBD (M = 5; median age 14 years) contracted COVID-19 during the study period. 11/12 patients were under immunomodulatory treatment (4/12 steroids; 6/12 azathioprine; 3/12 anti-TNFs; 2 vedolizumab; 1 ustekinumab). SARS-CoV-2 infection remained asymptomatic in 4/12 children and caused mild COVID-19 in the remaining 8. Mean anti-SARS-CoV-2 IgG S-RBD titer was similar between IBD patients and controls (27.3 ± 43.8 vs. 36.8 ± 35.3 kAU/L, p = ns). No children experienced IBD flares nor required gastroenterological support during the infection period.DiscussionChildren with IBD can mount a protective humoral response against SARS-CoV-2, which is comparable to that of their healthy peers regardless of ongoing immunomodulatory treatment. This study also supports the favorable course of PIBD during COVID-19 and vice-versa.

Logistic regression (LR) is the most common prediction model in medicine. In recent years, supervised machine learning (ML) methods have gained popularity. However, there are many concerns about ML utility for small sample sizes. In this study, we aim to compare the performance of 7 algorithms in the prediction of 1-year mortality and clinical progression to AIDS in a small cohort of infants living with HIV from South Africa and Mozambique. The data set (n = 100) was randomly split into 70% training and 30% validation set. Seven algorithms (LR, Random Forest (RF), Support Vector Machine (SVM), K-Nearest Neighbor (KNN), Naïve Bayes (NB), Artificial Neural Network (ANN), and Elastic Net) were compared. The variables included as predictors were the same across the models including sociodemographic, virologic, immunologic, and maternal status features. For each of the models, a parameter tuning was performed to select the best-performing hyperparameters using 5 times repeated 10-fold cross-validation. A confusion-matrix was built to assess their accuracy, sensitivity, and specificity. RF ranked as the best algorithm in terms of accuracy (82,8%), sensitivity (78%), and AUC (0,73). Regarding specificity and sensitivity, RF showed better performance than the other algorithms in the external validation and the highest AUC. LR showed lower performance compared with RF, SVM, or KNN. The outcome of children living with perinatally acquired HIV can be predicted with considerable accuracy using ML algorithms. Better models would benefit less specialized staff in limited resources countries to improve prompt referral in case of high-risk clinical progression.

Background: Methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant coagulase-negative Staphylococci (MR-CoNS), and vancomycin-resistant Enterococci (VRE) are increasing worldwide and represent a threat for the limited treatment options in pediatric patients and neonates compared to adults. Recommendations in pediatrics are mainly extrapolated from adults’ studies. Methods: A literature search for the treatment of these pathogens in children (

(1) Background: SARS-CoV-2 infection is notably mild in children, though comorbidities may increase the risk of hospitalization and may represent a risk for increased disease severity. There is an urgent need for targeted therapies with an acceptable efficacy and safety profile. To date, most of the medicines for COVID-19-specific treatment are prescribed off-label for children due to a lack of clinical trials and consequent evidence in this population. (2) Methods: This was a retrospective, observational study investigating the safety of treatments for the prevention of severe COVID-19 in fragile pediatric patients who received monoclonal antibodies and antivirals for mild-to-moderate symptoms between December 2021 and July 2022. (3) Results: Thirty-two patients were included. Monoclonal antibodies were prescribed to 62%, intravenous antivirals to 22%, and oral antivirals to 16% of children. Sotrovimab was the most frequently prescribed drug among monoclonal antibodies and overall (59%). The second most prescribed drug was remdesivir (22%). No severe adverse drug reaction was reported. There was no progression to severe disease and no death cases due to COVID-19 or drug administration. At drug-type stratification, resolution of symptoms and swab positivity time showed no difference between the two groups at 7 and 28 days. Off-label prescriptions were 84% overall, and in similar proportions between the two groups. (4) Conclusions: in this small sample, antivirals seemed safe and showed no differences in efficacy as compared to MAbs for the early treatment of COVID-19 in fragile children, thus representing a valuable choice, even when administered off-label.

BackgroundThe immune response plays a pivotal role in dictating the clinical outcome in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected adults, but it is still poorly investigated in the pediatric population.MethodsOf 209 enrolled subjects, 155 patients were confirmed by PCR and/or serology as having coronavirus disease 2019 (COVID-19). Blood samples were obtained at a median of 2.8 (interquartile, 2.1–3.7) and 6.1 (5.3–7.2) months after baseline (symptom onset and/or first positive virus detection). The immune profiles of activation, senescence, exhaustion, and regulatory cells were analyzed by flow cytometry. Neutralizing antibodies (nAbs) were detected by a plaque reduction neutralization test. In available nasopharyngeal swabs at baseline, SARS-CoV-2 levels were quantified by digital droplet PCR (ddPCR).ResultsOverall, COVID-19 patients had higher levels of immune activation, exhaustion, and regulatory cells compared to non-COVID-19 subjects. Within the COVID-19 group, activated and senescent cells were higher in adults than in children and inversely correlated with the nAbs levels. Conversely, Tregs and Bregs regulatory cells were higher in COVID-19 children compared to adults and positively correlated with nAbs. Higher immune activation still persisted in adults after 6 months of infection, while children maintained higher levels of regulatory cells. SARS-CoV-2 levels did not differ among age classes.ConclusionsAdults displayed higher immune activation and lower production of anti-SARS-CoV-2 nAbs than children. The different immune response was not related to different viral load. The higher expression of regulatory cells in children may contribute to reduce the immune activation, thus leading to a greater specific response against the virus.

Zika virus (ZIKV) is a vector-borne flavivirus with a known teratogenic effect, yet the full spectrum has not been delineated. Studies on endemic areas tried to characterize the clinical outcomes of ZIKV intrauterine exposure. We aimed to describe early neurodevelopmental outcomes on prenatally ZIKV-exposed children in a non-endemic ZIKV area. This is a prospective observational cohort study conducted from May 2016 to December 2021 at Hospital Universitari Vall d’Hebron in Barcelona, Catalonia, Spain. We monitored for up to 24 months 152 children extracted from a pregnant women cohort with suspected ZIKV infection; eleven women (11/150; 7.3%) fulfilled the criteria for a confirmed ZIKV infection. Among the 152 children included, we describe two cases of congenital ZIKV syndrome (CZS) born from women with a confirmed ZIKV infection. Additionally, we describe five cases of other potentially ZIKV-related outcomes (OPZROs), all with normal birth cranial circumference and born to women with probable ZIKV infection. The low exposed prevalence of adverse outcomes in asymptomatic children at birth in a non-endemic area suggests that close follow-up should be addressed by primary care pediatricians instead of pediatric specialists. Further studies are needed to assess the effects of ZIKV intrauterine exposure beyond two years of life.

Compared to adults, severe or fatal COVID-19 disease is much less common in children. However, a higher risk for progression has been reported in infants. Different pediatric COVID-19 severity scores are reported in the literature. Methods: Subjects under 90 days of age admitted to 35 Italian institutions for COVID-19 were included. The severity of COVID-19 was scored as mild/moderate or severe/critical following the classification reported in the literature by Venturini, Dong, Kanburoglu, and Gale. To assess the diagnostic accuracy of each classification system, we stratified all enrolled patients developing a posteriori severity score based on clinical presentation and outcomes and then compared all different scores analyzed. Results: We included 216 infants below 90 days of age. The most common symptom was fever, followed by coryza, poor feeding, cough, and gastrointestinal manifestations. According to Venturini, Dong, Kanburoglu, and Gale’s severity scores, 18%, 6%, 4.2%, and 29.6% of infants presented with severe/critical disease, respectively. A correlation analysis between these four scores and the a posteriori severity score assigned to all enrolled subjects was performed, and a crescent strength of correlation from Gale (R = 0.355, p < 0.001) to Venturini (R = 0.425, p < 0.001), Dong (R = 0.734, p < 0.001), and Kanburoglu (R = 0.859, p < 0.001) was observed. Conclusions: The percentage of infants with severe COVID-19 varies widely according to the score systems. A unique clinical score should be designed for neonates and infants with COVID-19.

Fever is one of the most common causes of medical evaluation of children, and early discrimination between viral and bacterial infection is essential to reduce inappropriate prescriptions. This study aims to systematically review the effects of point-of-care tests (POCTs) and rapid tests for respiratory tract infections on changing antibiotic prescription rate, length of stay, duration of therapy, and healthcare costs. Embase, MEDLINE, and Cochrane Library databases were systematically searched. All randomized control trials and non-randomized observational studies meeting inclusion criteria were evaluated using the NIH assessment tool. A meta-analysis was performed to assess the effects of rapid influenza diagnostic tests and film-array respiratory panel implementation on selected outcomes. From a total of 6440 studies, 57 were eligible for the review. The analysis was stratified by setting and POCT/rapid test type. The most frequent POCTs or rapid tests implemented were the Rapid Influenza Diagnostic Test and film-array and for those types of test a separate meta-analysis assessed a significant reduction in antibiotic prescription and an improvement in oseltamivir prescription. Implementing POCTs and rapid tests to discriminate between viral and bacterial infections for respiratory pathogens is valuable for improving appropriate antimicrobial prescriptions. However, more studies are needed to assess these findings in pediatric settings.

Despite widespread childhood immunization programs, pneumococcal disease (PD) continues to be associated with significant clinical and economic burden worldwide. This retrospective study assessed the PD-related economic burden in children from the Veneto region of Italy following the introduction of a 13-valent pneumococcal conjugate vaccine (PCV13) to the Italian immunization schedule in 2010. Between 2010 and 2017, the annual incidences of pneumonia, acute otitis media (AOM), and invasive pneumococcal disease (IPD), as well as syndromic-disease-related episodes, declined. In our analysis of data from regional expenditure and healthcare resource utilization (HCRU) databases related to children < 15 years of age, we found that regional expenditures decreased between 2010 and 2017 for pneumonia (EUR 8.88 to EUR 3.59 million), AOM (EUR 3.78 to EUR 2.76 million), and IPD (EUR 1.40 to EUR 1.00 million). Despite reductions in PD-related expenditure following the introduction of PCV13, there continues to be an economic burden associated with PD in Veneto, Italy.