Publications by authors named "Carlo Giaquinto"

211 Publications

Multi-Parametric Diagnostic Approach and Potential Markers of Early Onset Subclinical Cardiovascular Disease in a Cohort of Children, Adolescents and Young Adults Vertically Infected with HIV on cART.

J Clin Med 2021 Nov 22;10(22). Epub 2021 Nov 22.

Department of Women's and Children's Health, University of Padua, 35126 Padua, Italy.

Background: HIV infection and lifelong cART are responsible of an increase in cardiovascular risk. The aim of this study was to describe the subclinical cardiovascular disease and to identify early markers of cardiovascular damage in adolescents and young adults vertically infected with HIV on cART, through an innovative multi-parametric approach.

Methods: We enrolled 52 patients vertically infected with HIV. Demographic records, traditional cardiovascular risk factors, laboratory findings and echocardiographic measurements were collected in a one-year routine follow up. The echocardiographic examination included measurements of the 2D and 3D ejection fraction (EF), E/A ratio, E/E' ratio, carotid intima media thickness (cIMT), flow-mediated dilation (FMD) and global longitudinal strain (GLS).

Results: At the time of enrolment, all the patients were on cART therapy. The viral load was suppressed in 95% of them. EF was normal in 94.2% of patients (66 ± 7.2%), and GLS (mean value: -20.0 ± 2.5%) was reduced in 29% of patients. The cIMT mean value was higher than the 95th centile for sex and age in 73%, and FMD was impaired in 45% of patients. Clinically evident disease was found in three patients: dilative cardiomyopathy in one, thoracic-abdominal aneurysm Crawford type II with a bilateral carotid dilation in one and carotid plaque with 30% of stenosis in a third patient.

Conclusions: This study confirms the presence of clinical and subclinical cardiovascular disease in a very young population vertically infected with HIV, underlining the importance of an early, multi-parametric cardiovascular follow up.
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http://dx.doi.org/10.3390/jcm10225455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8623100PMC
November 2021

Size of HIV-1 reservoir is associated with telomere shortening and immunosenescence in early-treated European children with perinatally acquired HIV-1.

J Int AIDS Soc 2021 11;24(11):e25847

Section of Oncology and Immunology, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy.

Introduction: Persistence of HIV-1, causing chronic immune activation, is a key determinant of premature senescence. Early antiretroviral therapy (ART) has been associated with a reduced HIV-1 reservoir in children with perinatally acquired HIV-1 (PHIV), but its impact on the senescence process is an open question. We investigated the association between HIV-1 reservoir and biological and immune ageing profile in PHIV enrolled in the multicentre cross-sectional study CARMA (Child and Adolescent Reservoir Measurements on early suppressive ART) conducted within the EPIICAL (Early treated Perinatally HIV Infected individuals: Improving Children's Actual Life) consortium.

Methods: Between September 2017 and June 2018, CARMA enrolled 40 PHIV who started ART before 2 years of age and had undetectable viremia for at least 5 years before sampling date. Samples from 37 children with a median age of 13.8 years were available for this study. HIV-1 DNA copies on CD4 cells, relative telomere length (marker of cellular senescence) and levels of T-cell receptor rearrangement excision circle (TREC, marker of thymic output) on CD4 and CD8 cells were quantified by qPCR. Immunological profile was assessed by flow cytometry. Associations between molecular and phenotypic markers, HIV-1 reservoir and age at ART initiation were explored using a multivariable Poisson regression.

Results: Higher HIV-1 reservoir was associated (p<0.001) with telomere shortening (incidence rate ratio [IRR] = 0.15 [0.13-0.17]), immunosenescence (CD28 CD57 , IRR = 1.23 [1.21-1.26]) and immunoactivation (CD38 HLADR , IRR = 7.29 [6.58-8.09]) of CD4 cells. Late ART initiation (after 6 months of age) correlated with higher HIV-1 reservoir levels (552 [303-1001] vs. 89 [56-365] copies/10 CD4 cells, p = 0.003) and percentage of CD4 senescent cells (2.89 [1.95-6.31] vs. 1.02 [0.45-2.69, p = 0.047). TREC levels in CD8 cells were inversely associated with HIV-1 reservoir (IRR = 0.77 [0.76-0.79]) and were significantly lower in late treated PHIV (1128 [486-1671] vs. 2278 [1425-3314], p = 0.042).

Conclusions: Later ART initiation is associated with higher HIV-1 reservoir size, which correlates with increased telomere shortening and senescence of CD4 cells. Timing of ART initiation in infancy has long-term consequences on the immune and biological ageing profile of children with perinatally acquired HIV-1.
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http://dx.doi.org/10.1002/jia2.25847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8604380PMC
November 2021

Pediatric COVID-19 Therapeutics: Seizing the Right Research and Development Opportunities to Accelerate Access for Children.

Pediatr Infect Dis J 2021 Nov 16. Epub 2021 Nov 16.

From the Medicines Patent Pool, Geneva, Switzerland Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa Clinton Health Access Initiative, Boston, Massachusetts, USA Department of Women and Child Health, University of Padova, Padova, Italy World Health Organization, Geneva, Switzerland.

Children, although at lower risk of poor outcomes from COVID-19 relative to adults, still stand to benefit from therapeutic interventions. Understanding of COVID-19 clinical presentation and prognosis in children is essential to optimize therapeutic trials design. This perspective illustrates how to collectively accelerate pediatric COVID-19 therapeutic research and development, based on the experience of the Global Accelerator for Paediatric Formulations.
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http://dx.doi.org/10.1097/INF.0000000000003331DOI Listing
November 2021

Multistep antimicrobial stewardship intervention on antibiotic prescriptions and treatment duration in children with pneumonia.

PLoS One 2021 27;16(10):e0257993. Epub 2021 Oct 27.

Division of Pediatric Infectious Diseases, Department for Woman and Child Health, University of Padua, Padua, Italy.

Introduction: The Italian antimicrobial prescription rate is one of the highest in Europe, and antibiotic resistance has become a serious problem with high costs and severe consequences, including prolonged illnesses, the increased period of hospitalization and mortality. Inadequate antibiotic prescriptions have been frequently reported, especially for lower respiratory tract infections (LRTI); many patients receive antibiotics for viral pneumonia or bronchiolitis or broad-spectrum antibiotics for not complicated community-acquired pneumonia. For this reason, healthcare organizations need to implement strategies to raise physicians' awareness about this kind of drug and their overall effect on the population. The implementation of antibiotic stewardship programs and the use of Clinical Pathways (CPs) are excellent solutions because they have proven to be effective tools at diagnostic and therapeutic levels.

Aims: This study evaluates the impact of CPs implementation in a Pediatric Emergency Department (PED), analyzing antibiotic prescriptions before and after the publication in 2015 and 2019. The CP developed in 2019 represents an update of the previous one with the introduction of serum procalcitonin. The study aims to evaluate the antibiotic prescriptions in patients with community-acquired pneumonia (CAP) before and after both CPs (2015 and 2019).

Methods: The periods analyzed are seven semesters (one before CP-2015 called PRE period, five post CP-2015 called POST 1-5 and 1 post CP-2019 called POST6). The patients have been split into two groups: (i) children admitted to the Pediatric Acute Care Unit (INPATIENTS), and (ii) patients evaluated in the PED and sent back home (OUTPATIENTS). We have analyzed all descriptive diagnosis of CAP (the assessment of episodes with a descriptive diagnosis were conducted independently by two pediatricians) and CAP with ICD9 classification. All antibiotic prescriptions for pediatric patients with CAP were analyzed.

Results: A drastic reduction of broad-spectrum antibiotics prescription for inpatients has been noticed; from 100.0% in the PRE-period to 66.7% in POST1, and up to 38.5% in POST6. Simultaneously, an increase in amoxicillin use from 33.3% in the PRE-period to 76.1% in POST1 (p-value 0.078 and 0.018) has been seen. The outpatients' group's broad-spectrum antibiotics prescriptions decreased from 54.6% PRE to 17.4% in POST6. Both for outpatients and inpatients, there was a decrease of macrolides. The inpatient group's antibiotic therapy duration decreased from 13.5 days (PRE-period) to 7.0 days in the POST6. Antibiotic therapy duration in the outpatient group decreased from 9.0 days (PRE) to 7.0 days (POST1), maintaining the same value in subsequent periods. Overlapping results were seen in the ICD9 group for both inpatients and outpatients.

Conclusions: This study shows that CPs are effective tools for an antibiotic stewardship program. Indeed, broad-spectrum antibiotics usage has dropped and amoxicillin prescriptions have increased after implementing the CAP CP-2015 and the 2019 update.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0257993PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8550372PMC
October 2021

Vancomycin Use in Children and Neonates across Three Decades: A Bibliometric Analysis of the Top-Cited Articles.

Pathogens 2021 Oct 18;10(10). Epub 2021 Oct 18.

Division of Pediatric Infectious Diseases, Department of Women's and Children's Health, University of Padova, 35100 Padova, Italy.

Vancomycin is frequently prescribed in pediatrics, especially in intensive care unit settings, to treat Gram-positive bacterial infections. This work aims to collect the top-cited articles of pediatric and infectious diseases areas to gather the current evidence and gaps of knowledge on the use of vancomycin in these populations. The most relevant journals reported in the "pediatrics" and "infectious diseases" categories of the 2019 edition of Journal Citation Reports were browsed. Articles with more than 30 citations and published over the last three decades were collected. A bibliometric analysis was performed and 115 articles were retrieved. They were published in 21 journals, with a median impact factor of 4.6 (IQR 2.9-5.4). Sixty-eight of them (59.1%) belonged to "infectious diseases" journals. The most relevant topic was "bloodstream/complicated/invasive infections", followed by "antibiotic resistance/MRSA treatment". As for population distribution, 27 articles were on children only and 27 on neonates, most of which were from intensive care unit (ICU) settings. The current literature mainly deals with vancomycin as a treatment for severe infections and antibiotic resistance, especially in neonatal ICU settings. Lately, attention to new dosing strategies in the neonatal and pediatric population has become a sensible topic.
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http://dx.doi.org/10.3390/pathogens10101343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8537673PMC
October 2021

Asymptomatic and Mild SARS-CoV-2 Infections Elicit Lower Immune Activation and Higher Specific Neutralizing Antibodies in Children Than in Adults.

Front Immunol 2021 30;12:741796. Epub 2021 Sep 30.

Oncology and Immunology Section, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy.

Background: The immune response plays a pivotal role in dictating the clinical outcome in severe acute respiratory syndrome coronavirus 2 (SARSCoV2)-infected adults, but it is still poorly investigated in the pediatric population.

Methods: Of 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).

Results: Overall, 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.

Conclusions: Adults 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.
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http://dx.doi.org/10.3389/fimmu.2021.741796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8515185PMC
November 2021

Children living with HIV in Europe: do migrants have worse treatment outcomes?

HIV Med 2021 Oct 1. Epub 2021 Oct 1.

MRC Clinical Trials Unit at UCL, London, UK.

Objectives: To assess the effect of migrant status on treatment outcomes among children living with HIV in Europe.

Methods: Children aged < 18 years at the start of antiretroviral therapy (ART) in European paediatric HIV observational cohorts where ≥ 5% of children were migrants (defined as born abroad) were included. Three outcomes were considered: (i) severe immunosuppression-for-age; (ii) viraemic viral load (≥ 400 copies/mL) at 1 year after ART initiation; and (iii) AIDS/death after ART initiation. The effect of migrant status was assessed using univariable and multivariable logistic and Cox models.

Results: Of 2620 children included across 12 European countries, 56% were migrants. At ART initiation, migrant children were older than domestic-born children (median 6.1 vs. 0.9 years, p < 0.001), with slightly higher proportions being severely immunocompromised (35% vs. 33%) and with active tuberculosis (2% vs. 1%), but a lower proportion with an AIDS diagnosis (14% vs. 19%) (all p < 0.001). At 1 year after beginning ART, a lower proportion of migrant children were viraemic (18% vs. 24%) but there was no difference in multivariable analysis (p = 0.702), and no difference in severe immunosuppression (p = 0.409). However, there was a trend towards higher risk of AIDS/death in migrant children (adjusted hazard ratio = 1.51, 95% confidence interval: 0.96-2.38, p = 0.072).

Conclusions: After adjusting for characteristics at ART initiation, migrant children have virological and immunological outcomes at 1 year of ART that are comparable to those who are domestic-born, possibly indicating equity in access to healthcare in Europe. However, there was some evidence of a difference in AIDS-free survival, which warrants further monitoring.
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http://dx.doi.org/10.1111/hiv.13177DOI Listing
October 2021

Association of Treated and Untreated Gastroesophageal Reflux Disease in the First Year of Life with the Subsequent Development of Asthma.

Int J Environ Res Public Health 2021 09 13;18(18). Epub 2021 Sep 13.

Unit of Biostatistics, Epidemiology and Public Health, Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova, 35131 Padova, Italy.

Introduction: Gastroesophageal reflux disease (GERD) as well as its treatment with acid-suppressive medications have been considered possible risk factors for the development of asthma, but few studies have disentangled the role of GERD with that of its treatment. The present study aimed at estimating the association of treated and untreated GERD in the first year of life with the risk of asthma.

Methods: Retrospective cohort study including all children born between 2004 and 2015 registered in Pedianet, an Italian primary care database. We analyzed the association of children exposed to GERD (both treated and untreated) in the first year of life with the risk of developing clinically assessed asthma (clinical asthma) after 3 years. Secondary outcomes included asthma identified by anti-asthmatic medications (treated asthma) and wheezing after 3 years. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated comparing children with and without GERD, stratifying by treatment with acid-suppressive medications.

Results: Out of 86,381 children, 1652 (1.9%) were affected by GERD in the first year of life, of which 871 (53%) were treated with acid-suppressive medications. Compared with controls, children with GERD were at increased risk of clinical asthma (HR: 1.40, 95% CI 1.15-1.70). Risks were similar between treated and untreated GERD ( = 0.41). Comparable results were found for treated asthma, but no risk increase was seen for wheezing.

Discussion: Early-life GERD was associated with subsequent childhood asthma. Similar risks among children with treated and untreated GERD suggest that acid-suppressive medications are unlikely to play a major role in the development asthma.
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http://dx.doi.org/10.3390/ijerph18189633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8468622PMC
September 2021

Plasticity of the Immune System in Children Following Treatment Interruption in HIV-1 Infection.

Front Immunol 2021 29;12:643189. Epub 2021 Jul 29.

Great Ormond Street Institute of Child Health, University College London, London, United Kingdom.

It is intriguing that, unlike adults with HIV-1, children with HIV-1 reach a greater CD4 T cell recovery following planned treatment cessation. The reasons for the better outcomes in children remain unknown but may be related to increased thymic output and diversity of T cell receptor repertoires. HIV-1 infected children from the PENTA 11 trial tolerated planned treatment interruption without adverse long-term clinical, virological, or immunological consequences, once antiretroviral therapy was re-introduced. This contrasts to treatment interruption trials of HIV-1 infected adults, who had rapid changes in T cells and slow recovery when antiretroviral therapy was restarted. How children can develop such effective immune responses to planned treatment interruption may be critical for future studies. PENTA 11 was a randomized, phase II trial of planned treatment interruptions in HIV-1-infected children (ISRCTN 36694210). In this sub-study, eight patients in long-term follow-up were chosen with CD4 count>500/ml, viral load <50c/ml at baseline: four patients on treatment interruption and four on continuous treatment. Together with measurements of thymic output, we used high-throughput next generation sequencing and bioinformatics to systematically organize memory CD8 and naïve CD4 T cell receptors according to diversity, clonal expansions, sequence sharing, antigen specificity, and T cell receptor similarities following treatment interruption compared to continuous treatment. We observed an increase in thymic output following treatment interruption compared to continuous treatment. This was accompanied by an increase in T cell receptor clonal expansions, increased T cell receptor sharing, and higher sequence similarities between patients, suggesting a more focused T cell receptor repertoire. The low numbers of patients included is a limitation and the data should be interpreted with caution. Nonetheless, the high levels of thymic output and the high diversity of the T cell receptor repertoire in children may be sufficient to reconstitute the T cell immune repertoire and reverse the impact of interruption of antiretroviral therapy. Importantly, the effective T cell receptor repertoires following treatment interruption may inform novel therapeutic strategies in children infected with HIV-1.
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http://dx.doi.org/10.3389/fimmu.2021.643189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406805PMC
September 2021

Prioritizing the First Doses of SARS-CoV-2 Vaccine to Save the Elderly: The Case Study of Italy.

Front Public Health 2021 14;9:684760. Epub 2021 Jul 14.

Enrico Fermi Research Center, Rome, Italy.

SARS-CoV-2 is currently causing hundreds of deaths every day in European countries, mostly in not yet vaccinated elderly. Vaccine shortage poses relevant challenges to health authorities, called to act promptly with a scarcity of data. We modeled the mortality reduction of the elderly according to a schedule of mRNA SARS-CoV-2 vaccine that prioritized first dose administration. For the case study of Italy, we show an increase in protected individuals up to 53.4% and a decrease in deaths up to 19.8% in the cohort of over 80's compared with the standard vaccine recalls after 3 or 4 weeks. This model supports the adoption of vaccination campaigns that prioritize the administration of the first doses in the elderly.
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http://dx.doi.org/10.3389/fpubh.2021.684760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8318130PMC
August 2021

Real-World Analysis of Survival and Clinical Events in a Cohort of Italian Perinatally HIV-1 Infected Children From 2001 to 2018.

Front Pediatr 2021 16;9:665764. Epub 2021 Jul 16.

Paediatric Infectious Diseases Unit, Department of Health Sciences, Anna Meyer Children's Hospital, University of Florence, Florence, Italy.

Combined antiretroviral therapy (cART) has been associated with a steep decrease in mortality and morbidity in HIV-1 infected children. New antiretroviral molecules and drug classes have been developed and the management of HIV-infected children has improved, but recent data on survival are limited. An observational retrospective study investigating changes in mortality and morbidity was conducted on 1,091 perinatally HIV-1 infected children enrolled in the Italian Register for HIV Infection in Children and followed-up from 2001 to 2018. Three hundred and fifty-four (32%) AIDS events and 26 (2%) deaths occurred overtime. Mortality rates decreased from 0.4/100 person-years in 2001-2006 to 0.27/100 person-years in 2007-2012 and 0.07/100 person-years in 2013-2018. Notably, 92% of the dead children were born in Italy, but only 50% were followed-up since birth or within three months of age. Seventy three percent of children had started cART at age ≥6 months; 23% were treated for <30 days before death. B and C clinical events progressively decreased ( < 0.0001). Opportunistic infections significantly decreased over time, but still were the most common events in all the periods (6.76/100 person-years in 2013-2018). In the last period, severe bacterial infections were the most common ones. Cancer rates were 0.07/100; 0.17/100; 0.07/100 person-years in the three periods, respectively. Progressive reductions both in mortality and in rates of class B and C clinical events and OIs have been observed during the cART era. However, deaths were still registered; more than half of dead children were enrolled after birth and had belatedly started cART.
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http://dx.doi.org/10.3389/fped.2021.665764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8322739PMC
July 2021

Aetiology of acute respiratory infection in preschool children requiring hospitalisation in Europe-results from the PED-MERMAIDS multicentre case-control study.

BMJ Open Respir Res 2021 07;8(1)

Paediatrics and Infectious Diseases Department, La Paz University Hospital, Madrid, Spain.

Background: Both pathogenic bacteria and viruses are frequently detected in the nasopharynx (NP) of children in the absence of acute respiratory infection (ARI) symptoms. The aim of this study was to estimate the aetiological fractions for ARI hospitalisation in children for respiratory syncytial virus (RSV) and influenza virus and to determine whether detection of specific respiratory pathogens on NP samples was associated with ARI hospitalisation.

Methods: 349 children up to 5 years of age hospitalised for ARI (following a symptom-based case definition) and 306 hospital controls were prospectively enrolled in 16 centres across seven European Union countries between 2016 and 2019. Admission day NP swabs were analysed by multiplex PCR for 25 targets.

Results: RSV was the leading single cause of ARI hospitalisations, with an overall population attributable fraction (PAF) of 33.4% and high seasonality as well as preponderance in younger children. Detection of RSV on NP swabs was strongly associated with ARI hospitalisation (OR adjusted for age and season: 20.6, 95% CI: 9.4 to 45.3). Detection of three other viral pathogens showed strong associations with ARI hospitalisation: influenza viruses had an adjusted OR of 6.1 (95% CI: 2.5 to 14.9), parainfluenza viruses (PIVs) an adjusted OR of 4.6 (95% CI: 1.8 to 11.3) and metapneumoviruses an adjusted OR of 4.5 (95% CI: 1.3 to 16.1). Influenza viruses had a PAF of 7.9%, PIVs of 6.5% and metapneumoviruses of 3.0%. In contrast, most other pathogens were found in similar proportions in cases and controls, including , which was weakly associated with case status, and endemic coronaviruses.

Conclusion: RSV is the predominant cause of ARI hospitalisations in young children in Europe and its detection, as well as detection of influenza virus, PIV or metapneumovirus, on NP swabs can establish aetiology with high probability. PAFs for RSV and influenza virus are highly seasonal and age dependent.
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http://dx.doi.org/10.1136/bmjresp-2021-000887DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323363PMC
July 2021

Early ART initiation during infancy preserves natural killer cells in young European adolescents living with HIV (CARMA cohort).

J Int AIDS Soc 2021 07;24(7):e25717

Research Unit of Primary Immunodeficiency, Bambino Gesú Children's Hospital, IRCCS, Rome, Italy.

Introduction: HIV infection causes pathological changes in the natural killer (NK) cell compartment that can be only partially restored by antiretroviral therapy (ART). We investigated NK cells phenotype and function in children with perinatally acquired HIV (PHIV) and long-term viral control (five years) due to effective ART in a multicentre cross-sectional European study (CARMA, EPIICAL consortium). The impact of age at ART start and viral reservoir was also evaluated.

Methods: Peripheral blood mononuclear cells (PBMCs) from 40 PHIV who started ART within two years of life (early treated patients (ET), ≤6 months; late treated patients (LT), > 6 months), with at least five years of HIV-1 suppression (<40 HIV copies/mL), were collected between November 2017 and August 2018. NK phenotype and function were analysed by flow cytometry and transcriptional profile of PBMCs by RNA-Seq. HIV-1 DNA was measured by real-time polymerase chain reaction (Data were analysed by Spearman correlation plots and multivariable Poisson regression model (adjusted for baseline %CD4 and RNA HIV viral load and for age at ART start as an interaction term, either ET or LT) to explore the association between NK cell parameters and HIV reservoir modulated by age at ART start.

Results: A significantly higher frequency of CD56 NK cells was found in LT compared with ET. We further found in LT a positive correlation of CD56 NK cells with HIV-1 DNA. LT also displayed increased expression of the NKG2D and NKp46 activating receptors and perforin compared with ET. Moreover, CD107a and IFN-γ frequencies in non-stimulated NK were associated with HIV-1 DNA in LT patients. Finally, RNA-Seq analysis showed in LT an up-regulation of genes related to NK-activating pathways and susceptibility to apoptosis compared with ET.

Conclusions: We show that early initiation of ART during infancy preserves the NK compartment and is associated with lower HIV-1 reservoir. Such condition persists over adolescence due to long-term viral control achieved through effective ART.
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http://dx.doi.org/10.1002/jia2.25717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8264399PMC
July 2021

Left ventricular longitudinal strain alterations in asymptomatic or mildly symptomatic paediatric patients with SARS-CoV-2 infection.

Eur Heart J Cardiovasc Imaging 2021 Jul 5. Epub 2021 Jul 5.

Department for Women's and Children's Health, University Hospital of Padova, Pediatric and Congenital Cardiology Unit, Via Nicolò Giustiniani, 2, 35128 Padova, Italy.

Aims: Compared with adult patients, clinical manifestations of children's coronavirus disease-2019 (COVID-19) are generally perceived as less severe. The objective of this study was to evaluate cardiac involvement in previously healthy children with asymptomatic or mildly symptomatic severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection.

Methods And Results: We analysed a cohort of 53 paediatric patients (29 males, 55%), mean age 7.5 ± 4.7 years, who had a confirmed diagnosis of SARS-CoV-2 infection and were asymptomatic or only mildly symptomatic for COVID-19. Patients underwent standard transthoracic echocardiogram and speckle tracking echocardiographic study at least 3 months after diagnosis. Thirty-two age, sex, and body surface area comparable healthy subjects were used as control group. Left ventricular ejection fraction was within normal limits but significantly lower in the cases group compared to controls (62.4 ± 4.1% vs. 65.2 ± 5.5%; P = 0.012). Tricuspid annular plane systolic excursion (20.1 ± 3 mm vs. 19.8 ± 3.4 mm; P = 0.822) and left ventricular (LV) global longitudinal strain (-21.9 ± 2.4% vs. -22.6 ± 2.5%; P = 0.208) were comparable between the two groups. Regional LV strain analysis showed a significant reduction of the LV mid-wall segments strain among cases compared to controls. Furthermore, in the cases group, there were 14 subjects (26%) with a regional peak systolic strain below -16% (-2.5 Z score in our healthy cohort) in at least two segments. These subjects did not show any difference regarding symptoms or serological findings.

Conclusion: SARS-CoV-2 infection may affect left ventricular deformation in 26% of children despite an asymptomatic or only mildly symptomatic acute illness. A follow-up is needed to verify the reversibility of these alterations and their impact on long-term outcomes.
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http://dx.doi.org/10.1093/ehjci/jeab127DOI Listing
July 2021

Use of the Bacterial Lysate OM-85 in the Paediatric Population in Italy: A Retrospective Cohort Study.

Int J Environ Res Public Health 2021 06 26;18(13). Epub 2021 Jun 26.

Società Servizi Telematici-Pedianet, 35121 Padua, Italy.

Background: In Italy, the bacterial lysate OM-85 (Broncho-Vaxom, Broncho-Munal, Ommunal, Paxoral, Vaxoral) is registered for the prophylaxis of recurrent respiratory tract infections (RTIs) in adults and children above one year of age, but there are limited data on its use in the paediatric population. We aim to estimate the impact of OM-85 treatment on RTIs and antibiotic prescriptions in children.

Methods: This study included children aged 1 to 14 years enrolled in Pedianet, a paediatric general practice research database, from January 2007 to June 2017, having at least one prescription of OM-85. Children with less than 12 months of follow-up before (PRE period) and after (POST period) the OM-85 prescription were excluded. The frequency of antibiotic prescriptions and the frequency of RTI episodes in the PRE and POST periods were compared through the post-hoc test. Subgroup analysis was performed in children with recurrent RTIs.

Results: 1091 children received 1382 OM-85 prescriptions for a total follow-up of 619,525.5 person-years. Overall, antibiotic prescriptions decreased from a mean of 2.8 (SD (standard deviation) 2.7) prescriptions in the PRE period to a mean of 2.2 (SD 2.6) prescriptions in the POST period ( < 0.0001). RTIs decreased from a mean of 3.4 (SD 2.9) episodes in the PRE period to a mean of 2.5 (SD 2.6) episodes in the POST period ( < 0.0001). No change in antibiotic class was noted, and co-amoxiclav remained the preferred therapy in 28% of cases, followed by amoxicillin. These results were confirmed among children with recurrent RTIs.

Conclusions: OM-85 is effective in preventing both antibiotic prescriptions and RTIs in children.
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http://dx.doi.org/10.3390/ijerph18136871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8297025PMC
June 2021

Virological and immunological features of SARS-COV-2 infected children with distinct symptomatology.

Pediatr Allergy Immunol 2021 11 16;32(8):1833-1842. Epub 2021 Jul 16.

Clinical and Research Unit of Clinical Immunology and Vaccinology, Academic Department of Pediatrics (DPUO), Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Background: Although SARS-CoV-2 immunizations have started in most countries, children are not currently included in the vaccination programs; thus, it remains crucial to define their anti-SARS-CoV-2 immune response in order to minimize the risk for other epidemic waves. This study sought to provide a description of the virology ad anti-SARS-CoV-2 immunity in children with distinct symptomatology.

Methods: Between March and July 2020, we recruited 15 SARS-CoV-2 asymptomatic (AS) and 51 symptomatic (SY) children, stratified according to WHO clinical classification. We measured SARS-CoV-2 viral load using ddPCR and qPCR in longitudinally collected nasopharyngeal swab samples. To define anti-SARS-CoV-2 antibodies, we measured neutralization activity and total IgG load (DiaSorin). We also evaluated antigen-specific B and CD8+T cells, using a labeled S1+S2 protein and ICAM expression, respectively. Plasma protein profiling was performed with Olink.

Results: Virological profiling showed that AS patients had lower viral load at diagnosis (p = .004) and faster virus clearance (p = .0002) compared with SY patients. Anti-SARS-CoV-2 humoral and cellular response did not appear to be associated with the presence of symptoms. AS and SY patients showed similar titers of SARS-CoV-2 IgG, levels of neutralizing activity, and frequency of Ag-specific B and CD8+ T cells, whereas pro-inflammatory plasma protein profile was found to be associated with symptomatology.

Conclusion: We demonstrated the development of anti-SARS-CoV-2 humoral and cellular response with any regard to symptomatology, suggesting the ability of both SY and AS patients to contribute toward herd immunity. The virological profiling of AS patients suggested that they have lower virus load associated with faster virus clearance.
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http://dx.doi.org/10.1111/pai.13585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8420243PMC
November 2021

Mild SARS-CoV-2 Infections and Neutralizing Antibody Titers.

Pediatrics 2021 09 22;148(3). Epub 2021 Jun 22.

Division of Pediatric Infectious Diseases, Department for Women's and Children's Health, University of Padua, Padua, Italy.

Background: Recent evidence suggests that neutralizing antibodies (nAbs) to severe acute respiratory syndrome coronavirus 2 may persist over time; however, knowledge regarding pediatric subjects is limited.

Methods: A single-center, prospective observational study was conducted on 57 family clusters of coronavirus disease 2019, including children of neonatal and pediatric age attending the University Hospital of Padua (Italy). For each patient, blood samples were collected for both the quantification of nAbs through a plaque reduction neutralizing test and the detection of antinucleocapsid-spike protein immunoglobulin G and/or immunoglobulin M.

Results: We analyzed 283 blood samples collected from 152 confirmed coronavirus disease 2019 cases (82 parents and 70 children or older siblings of median age of 8 years, interquartile range: 4-13), presenting asymptomatic or with mildly symptomatic disease. Despite the decrease of immunoglobulin G over time, nAbs were found to persist up to 7 to 8 months in children, whereas adults recorded a modest declining trend. Interestingly, children aged <6 years, and, in particular, those aged <3 years, developed higher long-lasting levels of nAbs compared with older siblings and/or adults.

Conclusions: Mild and asymptomatic severe acute respiratory syndrome coronavirus 2 infections in family clusters elicited higher nAbs among children.
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http://dx.doi.org/10.1542/peds.2021-052173DOI Listing
September 2021

Development of a Weighted-Incidence Syndromic Combination Antibiogram (WISCA) to guide the choice of the empiric antibiotic treatment for urinary tract infection in paediatric patients: a Bayesian approach.

Antimicrob Resist Infect Control 2021 05 1;10(1):74. Epub 2021 May 1.

Division of Paediatric Infectious Diseases- Department of Women's and Children's Health, University of Padova, Padova, Italy.

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 (< 15 years) accessing the emergency rooms of Padua University-Hospital and Mestre Dell' Angelo-Hospital (Venice) between January 1st, 2016, and December 31st, 2018. WISCAs were developed by estimating the coverage of eight regimens using a Bayesian hierarchical model adjusted for age, sex, and previous antibiotic treatment or renal/urological comorbidities.

Results: 385 of 620 urine culture requests were included in the model analysis. The most frequently observed bacterium was E. coli (85% and 87%, Centre A and B). No centre effect on coverage estimates was found, and data were successfully pooled together. Coverage ranged from 77.8% (Co-trimoxazole) to 97.6% (Carbapenems). Complex cases and males had significantly lower odds of being covered by a regimen than non-complex cases and females (odds ratio (OR) 0.49 [95% HDI, 0.38-0.65], and OR: 0.73 [95% HDIs, 0.56-0.96] respectively). Children aged 3-5 years had lower odds of being covered by a regimen than other age groups, except for neonates.

Conclusions: The developed WISCAs provide highly informative estimates on coverage patterns overcoming the limitation of combination antibiograms and expanding the framework of previous Bayesian WISCA algorithm.
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http://dx.doi.org/10.1186/s13756-021-00939-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088309PMC
May 2021

A Procalcitonin and C-Reactive Protein-Guided Clinical Pathway for Reducing Antibiotic Use in Children Hospitalized with Bronchiolitis.

Children (Basel) 2021 Apr 28;8(5). Epub 2021 Apr 28.

Division of Paediatric Infectious Diseases, Department of Women's and Children's Health, University of Padova, 35100 Padova, Italy.

Despite the lack of evidence that bronchodilators, corticosteroids, and antibiotics are useful in treating bronchiolitis, their use is still widespread. This study aimed to determine the consumption of antibiotics for bronchiolitis before and after a procalcitonin-guided clinical pathway (CP) implementation. In December 2019, a CP for lower respiratory tract infection management was implemented at the Department of Women's and Children's Health at Padua University Hospital. This was a pre-post, quasi-experimental study that assessed the changes in the treatment of bronchiolitis during two bimesters preceding the CP implementation (pre-period: January 2018-February 2018 and January 2019-February 2019) and during the bimester after CP implementation (post-period January 2020-February 2020). After the CP implementation, there was a significant reduction in antibiotic prescriptions from 36.2% to 12.5% ( = 0.036) in patients hospitalized for bronchiolitis. Co-amoxiclav treatment, the antibiotic most commonly administered, decreased from 66.6% to 33.3%. Among outpatients' bronchiolitis episodes, a statistically significant decrease in beta2-agonists' use (from 18.0% to 4.4%, pre and post periods) and a quasi-significant decrease in corticosteroid use (from 8.0% to 0% pre and post periods) were observed. An evidence-based CP supported by educational lectures was associated with significant changes in the physicians' prescribing habits.
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http://dx.doi.org/10.3390/children8050351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8146464PMC
April 2021

T cell immune discriminants of HIV reservoir size in a pediatric cohort of perinatally infected individuals.

PLoS Pathog 2021 04 26;17(4):e1009533. Epub 2021 Apr 26.

Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, Florida.

The size of the latent HIV reservoir is associated with the timing of therapeutic interventions and overall health of the immune system. Here, we demonstrate that T cell phenotypic signatures associate with viral reservoir size in a cohort of HIV vertically infected children and young adults under durable viral control, and who initiated anti-retroviral therapy (ART) <2 years old. Flow cytometry was used to measure expression of immune activation (IA), immune checkpoint (ICP) markers, and intracellular cytokine production after stimulation with GAG peptides in CD4 and CD8 T cells from cross-sectional peripheral blood samples. We also evaluated the expression of 96 genes in sort-purified total CD4 and CD8 T cells along with HIV-specific CD4 and CD8 T cells using a multiplexed RT-PCR approach. As a measure of HIV reservoir, total HIV-DNA quantification by real-time PCR was performed. Poisson regression modeling for predicting reservoir size using phenotypic markers revealed a signature that featured frequencies of PD-1+CD4 T cells, TIGIT+CD4 T cells and HIV-specific (CD40L+) CD4 T cells as important predictors and it also shows that time of ART initiation strongly affects their association with HIV-DNA. Further, gene expression analysis showed that the frequencies of PD-1+CD4 T cells associated with a CD4 T cell molecular profile skewed toward an exhausted Th1 profile. Our data provide a link between immune checkpoint molecules and HIV persistence in a pediatric cohort as has been demonstrated in adults. Frequencies of PD-1+ and TIGIT+CD4 T cells along with the frequency of HIV-specific CD4 T cells could be associated with the mechanism of viral persistence and may provide insight into potential targets for therapeutic intervention.
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http://dx.doi.org/10.1371/journal.ppat.1009533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8112655PMC
April 2021

Analytical and clinical performances of a SARS-CoV-2 S-RBD IgG assay: comparison with neutralization titers.

Clin Chem Lab Med 2021 07 14;59(8):1444-1452. Epub 2021 Apr 14.

Department of Medicine-DIMED, Medical School, University of Padova, Padova, Italy.

Objectives: SARS-CoV-2 serology presents an important role in several aspects of COVID-19 pandemic. Immunoassays performances have to be accurately evaluated and correlated with neutralizing antibodies. We investigated the analytical and clinical performances of a SARS-CoV-2 RBD IgG assay, automated on a high throughput platform, and the correlation of the antibodies (Ab) levels with the plaque reduction neutralization (PRNT) Ab titers.

Methods: A series of 546 samples were evaluated by SARS-CoV-2 RBD IgG assay (Snibe diagnostics), including 171 negative and 168 positive SARS-CoV-2 subjects and a further group of 207 subjects of the COVID-19 family clusters follow-up cohort.

Results: Assay imprecision ranged from 3.98 to 12.18% being satisfactory at low and medium levels; linearity was excellent in all the measurement range. Considering specimens collected after 14 days post symptoms onset, overall sensitivity and specificity were 99.0 and 92.5%, respectively. A total of 281 leftover samples results of the PRNT test were available. An elevated correlation was obtained between the SARS-CoV-2 RBD IgG assay and the PRNT titer at univariate (=0.689) and multivariate (=0.712) analyses.

Conclusions: SARS-CoV-2 S-RBD IgG assay shows satisfactory analytical and clinical performances, and a strong correlation with sera neutralizing activity.
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http://dx.doi.org/10.1515/cclm-2021-0313DOI Listing
July 2021

The unsung virtue of thermostability.

Lancet 2021 04 23;397(10282):1346. Epub 2021 Mar 23.

University of Padua, Padua, Italy.

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http://dx.doi.org/10.1016/S0140-6736(21)00526-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987303PMC
April 2021

Impact of bronchiolitis guidelines publication on primary care prescriptions in the Italian pediatric population.

NPJ Prim Care Respir Med 2021 03 19;31(1):15. Epub 2021 Mar 19.

Division of Paediatric Infectious Diseases, Department of Women's and Children's Health, University of Padova, Padua, Italy.

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 < 0.001) after the publication of the second guideline; the highest reduction was in younger patients (from 57% to 44%, p = 0.013). Overall antibiotic prescriptions rate did not change, with 31.6% of the patients still receiving them. Our results confirm unnecessary non-evidence-based treatments in the primary care setting, with few changes after the guidelines publications.
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http://dx.doi.org/10.1038/s41533-021-00228-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979748PMC
March 2021

Virological and immunological features of SARS-CoV-2-infected children who develop neutralizing antibodies.

Cell Rep 2021 03;34(11):108852

Academic Department of Pediatrics (DPUO), Research Unit of Clinical Immunology and Vaccinology, Bambino Gesù Children's Hospital, IRCCS, 00165 Rome, Italy; Chair of Pediatrics, Department of Systems Medicine, University of Rome "Tor Vergata," 00185 Rome, Italy. Electronic address:

As the global COVID-19 pandemic progresses, it is paramount to gain knowledge on adaptive immunity to SARS-CoV-2 in children to define immune correlates of protection upon immunization or infection. We analyzed anti-SARS-CoV-2 antibodies and their neutralizing activity (PRNT) in 66 COVID-19-infected children at 7 (±2) days after symptom onset. Individuals with specific humoral responses presented faster virus clearance and lower viral load associated with a reduced in vitro infectivity. We demonstrated that the frequencies of SARS-CoV-2-specific CD4CD40L T cells and Spike-specific B cells were associated with the anti-SARS-CoV-2 antibodies and the magnitude of neutralizing activity. The plasma proteome confirmed the association between cellular and humoral SARS-CoV-2 immunity, and PRNT patients show higher viral signal transduction molecules (SLAMF1, CD244, CLEC4G). This work sheds lights on cellular and humoral anti-SARS-CoV-2 responses in children, which may drive future vaccination trial endpoints and quarantine measures policies.
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http://dx.doi.org/10.1016/j.celrep.2021.108852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962998PMC
March 2021

Untargeted and Targeted Metabolomic Profiling of Preterm Newborns with EarlyOnset Sepsis: A Case-Control Study.

Metabolites 2021 Feb 18;11(2). Epub 2021 Feb 18.

Women's and Children's Health Department, Padua University, 35128 Padua (PD), Italy.

Sepsis is a major concern in neonatology, but there are no reliable biomarkers for its early diagnosis. The aim of the study was to compare the metabolic profiles of plasma and urine samples collected at birth from preterm neonates with and without earlyonset sepsis (EOS) to identify metabolic perturbations that might orient the search for new early biomarkers. All preterm newborns admitted to the neonatal intensive care unit were eligible for this proof-of-concept, prospective case-control study. Infants were enrolled as "cases" if they developed EOS, and as "controls"if they did not. Plasma samples collected at birth and urine samples collected within 24 h of birth underwent untargeted and targeted metabolomic analysis using mass spectrometry coupled with ultra-performance liquid chromatography. Univariate and multivariate statistical analyses were applied. Of 123 eligible newborns, 15 developed EOS. These 15 newborns matched controls for gestational age and weight. Metabolomic analysis revealed evident clustering of the cases versus controls, with the glutathione and tryptophan metabolic pathways markedly disrupted in the former. In conclusion, neonates with EOS had a metabolic profile at birth that clearly distinguished them from those without sepsis, and metabolites of glutathione and tryptophan pathways are promising as new biomarkers of neonatal sepsis.
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http://dx.doi.org/10.3390/metabo11020115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7922887PMC
February 2021

The conect4children (c4c) Consortium: Potential for Improving European Clinical Research into Medicines for Children.

Pharmaceut Med 2021 03 4;35(2):71-79. Epub 2021 Feb 4.

Division of Pediatric Infectious Diseases, Department of Woman's and Child's Health, University of Padua, Padua, Italy.

The need for information about new and existing drugs used in children was recognized in the European Union (EU) with the implementation of the Paediatric Regulation in 2007. In 2017, the 10-year review of the Paediatric Regulation identified barriers to the conduct of clinical trials, including delays in setting up and completing paediatric trials. Across Europe, the difficulties with clinical research are compounded by variation within countries and between countries. Ethics and regulatory review have national specificities. This paper describes the Collaborative Network for European Clinical Trials for Children (conect4children, c4c), which addresses selected difficulties in the design and conduct of paediatric clinical trials. c4c is a time-limited public-private consortium funded by the Innovative Medicines Initiative (IMI2). The elements of c4c are as follows: expert advice providing input on study design and/or paediatric development programmes (including patient involvement activities); a network of sites following harmonised procedures coordinated by National Hubs and a single point of contact for Europe; a facility for education and training for sites and trial teams; and support for managing data used by the network and a common paediatric data dictionary. c4c does not sponsor trials. c4c is taking a phased approach with careful piloting through industry and non-industry studies intended to demonstrate the viability of the network (proof-of-viability studies). c4c uses a co-design approach involving industry and academics within a clearly defined scope. A sustainable, successor organization open to all potential service users will be open for business before the end of IMI2 funding in 2024.
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http://dx.doi.org/10.1007/s40290-020-00373-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979601PMC
March 2021

Faster Initial Viral Decay in Female Children Living With HIV.

J Pediatric Infect Dis Soc 2021 May;10(5):674-676

Pediatric Infectious Diseases Unit, Fundación para la Investigación Biomédica del Hospital 12 de Octubre, Madrid, Spain.

Limited data exist regarding sex bias and viral decay in children with HIV. We investigated the sex differences in viral decay in 25 perinatally HIV-infected children. Females presented faster phase I viral decay regardless of their age at antiretroviral therapy (ART) initiation, baseline CD4 percentages, or baseline RNA levels. Also, for each month elapsed under ART, females had faster viral decay than males.
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http://dx.doi.org/10.1093/jpids/piaa174DOI Listing
May 2021

Harmonising regulatory approval for antibiotics in children.

Lancet Child Adolesc Health 2021 02;5(2):96-98

Paediatric Infectious Diseases Research Group, Institute of Infection and Immunity, St George's University London, London, UK.

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http://dx.doi.org/10.1016/S2352-4642(20)30365-5DOI Listing
February 2021

ODYSSEY clinical trial design: a randomised global study to evaluate the efficacy and safety of dolutegravir-based antiretroviral therapy in HIV-positive children, with nested pharmacokinetic sub-studies to evaluate pragmatic WHO-weight-band based dolutegravir dosing.

BMC Infect Dis 2021 Jan 4;21(1). Epub 2021 Jan 4.

Medical Research Council Clinical Trials Unit at University College London, London, United Kingdom.

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 < 14 kg while dosing was in development.

Methods: ODYSSEY (Once-daily DTG based ART in Young people vS. Standard thErapY) is an open-label, randomised, non-inferiority, basket trial comparing the efficacy and safety of DTG + 2 nucleos(t) ides (NRTIs) versus standard-of-care (SOC) in HIV-infected children < 18 years starting first-line ART (ODYSSEY A) or switching to second-line ART (ODYSSEY B). The primary endpoint is clinical or virological failure by 96 weeks.

Results: Between September 2016 and June 2018, 707 children weighing ≥14 kg were enrolled; including 311 ART-naïve children and 396 children starting second-line. 47% of children were enrolled in Uganda, 21% Zimbabwe, 20% South Africa, 9% Thailand, 4% Europe. 362 (51%) participants were male; median age [range] at enrolment was 12.2 years [2.9-18.0]. 82 (12%) children weighed 14 to < 20 kg, 135 (19%) 20 to < 25 kg, 206 (29%) 25 to < 35 kg, 284 (40%) ≥35 kg. 128 (18%) had WHO stage 3 and 60 (8%) WHO stage 4 disease. Challenges encountered include: (i) running the trial across high- to low-income countries with differing frequencies of standard-of-care viral load monitoring; (ii) evaluating pragmatic DTG dosing in PK sub-studies alongside FDA- and EMA-approved dosing and subsequently transitioning participants to new recommended doses; (iii) delays in dosing information for children weighing 3 to < 14 kg and rapid recruitment of ART-naïve older/heavier children, which led to capping recruitment of participants weighing ≥35 kg in ODYSSEY A and extending recruitment (above 700) to allow for ≥60 additional children weighing between 3 to < 14 kg with associated PK; (iv) a safety alert associated with DTG use during pregnancy, which required a review of the safety plan for adolescent girls.

Conclusions: By employing a basket design, to include ART-naïve and -experienced children, and nested PK sub-studies, the ODYSSEY trial efficiently evaluates multiple scientific questions regarding dosing and effectiveness of DTG-based ART in children.

Trial Registration: NCT, NCT02259127 , registered 7th October 2014; EUDRACT, 2014-002632-14, registered 18th June 2014 ( https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-002632-14/ES ); ISRCTN, ISRCTN91737921 , registered 4th October 2014.
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http://dx.doi.org/10.1186/s12879-020-05672-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809782PMC
January 2021

Children's Hospital Management in the COVID-19 Era: The Reorganization of a Tertiary Care Pediatric Emergency Department in Northern Italy.

Front Pediatr 2020 19;8:594831. Epub 2020 Nov 19.

Pediatric Emergency Department, Department of Women's and Children's Health, University Hospital of Padua, Padua, Italy.

In the Veneto Region, an exponential spread of patients affected by 2019 novel Coronavirus disease (COVID-19) has been observed after February 21st. Since then, we have been evaluating children suspected or confirmed for SARS-CoV-2 infection. A protocol for pediatric hospital reorganization and children management has been developed, since the beginning of the epidemic. A pre-triage area has been created at the immediate entrance of the pediatric emergency room, for all uncritical pediatric patients. According to the epidemiologic and clinical risk factors, all children/adolescents have been addressing to one of the four different pathways created. The strict application of this protocol has been leading to quickly identification, isolation, and management of all positive children, preventing SARS-CoV-2 intrahospital spread.
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http://dx.doi.org/10.3389/fped.2020.594831DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710791PMC
November 2020
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