Echovirus 11 lineage I and other enterovirus in hospitalized children with acute respiratory infection in Southern Italy (2022- 2023).

OBJECTIVES: A new variant of echovirus 11 (E11) infection is a major health concern in neonates. Here, we describe the clinical and virological characteristics of enterovirus (EV) infections in children hospitalized with acute respiratory infection in Southern Italy. METHODS: Between July 2022-August 2023, 173 EV infections were identified. Demographic and clinical characteristics, comorbidities, and coinfections were analyzed. Genotypes were identified by sequencing of VP1. Whole-genome sequencing of five E11 strains was performed. RESULTS: Case numbers peaked in July 2022, November-December 2022, and June-July 2023. Coxsackievirus A2 was identified in 36.7%, coxsackievirus B5 in 13.8%, echovirus E11 in 9.2%, and EV-D68 in 6.4% of cases. No child had critical symptoms or a severe infection. The only neonate infected by E11 recovered fully after 5 days in hospital. Phylogenetic analysis revealed that four E11 strains were closely related to divergent lineage I E11 strains identified in France and Italy. CONCLUSIONS: The new variant of E11 was identified in children in Southern Italy. Although the cases were mild, the data suggest that transmission routes and host factors are likely to be main drivers for the development of potentially severe diseases. Systematic epidemiological/molecular surveillance will help us better understand the clinical impact of EV infections and develop preventive strategies.

Disrupted Seasonality of Respiratory Viruses: Retrospective Analysis of Pediatric Hospitalizations in Italy from 2019 to 2023.

This multicenter study in Italian hospitals highlights the epidemiologic disruptions in the circulation of the 5 main respiratory viruses from 2019 to 2023. Our data reveal a resurgence of respiratory syncytial virus and influenza during the 2022-2023 winter season, with an earlier peak in cases for both viruses, emphasizing the importance of timely monitoring.

Real-World Use of Dalbavancin for Treatment of Soft Tissue and Bone Infection in Children: Safe, Effective and Hospital-Time Sparing.

Acute bacterial skin and skin structure infections (ABSSSI) and osteoarticular infections compound the burden of morbidity, mortality and prolonged hospitalizations among gram-positive infections. Dalbavancin, a second-generation, intravenous lipoglycopeptide, due to its prolonged half-life, can be a valuable alternative in their treatment when administered as inpatient treatment at the price of an extended hospital stay. Between October 2019 and September 2023, 31 children and adolescents were treated with dalbavancin because of bone and joint infections (n = 12 patients, 39%), ABSSSI (n = 13 patients, 42%), mainly for the limbs, facial cellulitis or complicated ABSSSI (n = 6 patients, 19%), at five Italian pediatric centers. Microbiological study provided gram-positive bacterial isolate in 16 cases, in 11 cases from a positive blood culture; 9 of them were MRSA. Twenty-five patients were initially treated with a different antibiotic therapy: beta-lactam-based in 18 patients (58%), glycopeptide-based in 15 patients (48%) and daptomycin in 6 (19%). The median time that elapsed between admission and start of dalbavancin was 18 days. A total of 61 doses of dalbavancin were administered to the 31 patients: 16 received a single dose while the remaining 15 patients received between two (n = 9) and nine doses. The frequency of administration was weekly in five cases or fortnightly in nine patients. Median length of stay in hospital was 16 days. Median time to discharge after the first dose of dalbavancin was 1 day. Treatment was very well-tolerated: of the 61 administered doses, only four doses, administered to four patients, were associated with an adverse event: drug extravasation during intravenous administration occurred in two patients, with no sequelae; however, in two patients the first administration was stopped soon after infusion start: in one (ID #11), due to headache and vomiting; in another (ID #12) due to a systemic reaction. In both patients, drug infusion was not repeated. None of the remaining 29 patients reported treatment failure (resistant or recurrent disease) or an adverse effect during a median follow-up time of two months. The use of dalbavancin was safe, feasible and also effective in shortening the hospital stay in children and adolescents.

Policy of vaccination of "fragile children": Results of a survey of 14 Italian children's hospitals.

Children with chronic disease are at higher risk of invasive infectious disease, including several vaccine-preventable infections. The Italian Association of Pediatric Hospitals (AOPI) carried out a survey of immunization practices: 14/16 AOPI hospitals completed the survey; 50% of them include 100-199 beds, while 21% have <100 beds. In 12/14 hospitals (86%) all vaccinations included in the National Immunization Plan (plus influenza e COVID-19 vaccines) are available for inpatients, in selected wards (n = 4), on single pediatrician initiative (n = 3), by a centralized in-hospital immunization service (n = 2), and the remaining 3 in a "protected vaccination area" or in a COVID-19 pathway. The wards in which vaccination is more frequently offered to in-patients are: General Pediatrics, Neonatology, Pediatric Hematology & Oncology, Pediatric Diabetology, Pediatric Cardiology, and Pediatric Infectious Diseases (range, 58% to 83%). In 58% of vaccinating hospitals, <500 vaccinations/year are reported, while in 17% this number is >2,000/year. A COVID-19 vaccination team is in place for any inpatient child older than 12 years in 42% of hospitals, in 42% only for "fragile" children. A centralized in-hospital immunization service is an emerging model that may contribute to increase compliance to vaccination of fragile patients and to fight against vaccination hesitancy.

Hospitalization for bronchiolitis in children aged ≤ 1year, Southern Italy, year 2021: need for new preventive strategies?

BACKGROUND: Bronchiolitis is a major cause of hospitalization in infants, particularly in the first six months of life, with approximately 60-80% of admissions due to respiratory syncytial virus (RSV) infection. Currently, no prophylactic options are available for healthy infants. The present study aimed at describing the demographic, clinical, and epidemiological characteristics of infants hospitalized for bronchiolitis in the Apulia region of Italy in 2021. METHODS: From January to December 2021, data on children aged 0-12 months admitted for bronchiolitis in nine neonatal or pediatric units covering 61% of pediatric beds of hospitals in the Apulia region of Italy were analyzed. Demographic data, comorbidities, need for oxygen support, length of hospital stay, palivizumab administration, and outcomes were collected. For the purpose of the analysis, patients were divided into those aged 0-3 months and > 3 months. A multivariate logistic regression model was used to explore associations between the need for oxygen support and sex, age, comorbidities, history of prematurity, length of hospital stay, and palivizumab administration. RESULTS: This study included 349 children aged 0-12 months admitted for bronchiolitis, with a peak of hospitalization in November (7.4 cases/1,000 children). Of these patients, 70.5% were RSV positive, 80.2% were aged 0-3 months, and 73.1% required oxygen support. Moreover, 34.9% required observation in the sub-intensive care unit, and 12.9% in the intensive care unit. Of the infants who required intensive care, 96.9% were aged 0-3 months and 78.8% were born at term. Three patients required mechanical ventilation and one, who required Extra Corporeal Membrane Oxygenation, died. Children aged 0-3 months were more likely to show dyspnea, need oxygen support, and have a longer hospital stay. CONCLUSIONS: The present study showed that almost all of the children who required intensive care support were aged ≤ 3 months and most were born at term. Therefore, this age group remains the highest risk group for severe bronchiolitis. Preventive measures such as single-dose monoclonal antibody immunoprophylaxis, and maternal and childhood vaccination against RSV, may reduce the high public health burden of bronchiolitis.

Appropriate Use of Antibiotic and Principles of Antimicrobial Stewardship in Children.

Antibiotics account for over 10% of the overall drug expense of the National Health System in Italy in 2021. Their use in children is of particular interest on one side, because acute infections are very common in children, while they build their immunologic library of competence; on the other side, although many acute infections are expected and turn out to be of viral origin, caregivers will often ask the family doctor or primary care attending to reassure them by prescribing antibiotic treatment, although it may often be unnecessary. The inappropriate prescription of antibiotics in children may likely be a source not only of undue economic burden for the public health system but also of increasing development of antimicrobial resistance (AMR). Based on those issues, the inappropriate use of antibiotics in children should be avoided to reduce the risks of unnecessary toxicity, increase in health costs, lifelong effects, and selection of resistant organisms causing undue deaths. Antimicrobial stewardship (AMS) describes a coherent set of actions that ensure an optimal use of antimicrobials to improve patient outcomes while limiting the risk of adverse events including AMR. The aim of this paper is to spread some concept of good use of antibiotics for pediatricians or every other physician involved in the choice to prescribe, or not, antibiotics in children. Several actions could be of help in this process, including the following: (1) identify patients with high probability of bacterial infection; (2) collect samples for culture study before starting antibiotic treatment if invasive bacterial infection is suspected; (3) select the appropriate antibiotic molecule based on local resistance and narrow spectrum for the suspected pathogen(s); avoid multi-antibiotic association; prescribe correct dosage; (4) choose the best route of administration (oral vs. parenteral) and the best schedule of administration for every prescription (i.e., multiple administration for beta lactam); (5) schedule clinical and laboratory re-evaluation with the aim to consider therapeutic de-escalation; (6) stop antibiotic administration as soon as possible, avoiding the application of "antibiotic course".

Bronchiolitis 2021-2022 epidemic: multicentric analysis of the characteristics and treatment approach in 214 children from different areas in Italy.

Bronchiolitis causes a remarkable number of hospitalizations; its epidemiology follows that of respiratory syncytial virus (RSV), its main pathogen. The aim of this study was to evaluate the presenting features, treatment approach, and impact of medical therapy in four pediatric hospitals in Italy. Data on infants < 24 months of age hospitalized with bronchiolitis in the 2021-2022 season were collected. Between October 2021 and February 2022, 214 children were admitted. Median hospital stay was 5 days; none of the patients died. The distribution of the presenting features is largely comparable in the 33 (15.8%) RSV-negative versus the 176 (84.2%) RSV-positive children; also, no difference was observed in medical therapy provided: duration of oxygen therapy, administration of steroid, and duration of hospital stay. Systemic steroids, inhalation, or antibiotic therapy were given to 34.6%, 79.4%, and 49.1% of children respectively. Of the 214 patients with bronchiolitis, only 19 (8.8%) were admitted to ICU.   Conclusion: Our data suggest that, irrespective of treatments provided, RSV-positive and RSV-negative children had a similar clinical course. The results of our retrospective study further underline the need to improve adherence to existing guidelines on bronchiolitis treatment. What is Known: • Bronchiolitis is a common diseases with seasonal peak. The outcome is usually favorable but hospitalization and even ICU admission is not exceptional. What is New: • Children with RSV associated bronchiolitis do not have a different course and outcome. The analysis of the 2021-2022 cohort, following COVID pandemic peaking, did not show a different course and outcome. • Adherence to literature recommendation, i.e. to focus on oxygen and hydration therapy while avoiding unnecessary systemic therapy with steroid and antibiotics, should be improved.

Out-of-Season Epidemic of Respiratory Syncytial Virus during the COVID-19 Pandemic: The High Burden of Child Hospitalization in an Academic Hospital in Southern Italy in 2021.

Respiratory syncytial virus (RSV) infection is the most common cause of hospitalization in young children. In the last 2 years, public health measures aimed at controlling the spread of SARS-CoV-2 have affected the epidemiology and seasonality of RSV worldwide. The aim of this descriptive retrospective observational study was to describe the characteristics of children hospitalized with RSV in an academic tertiary care hospital in Southern Italy in 2021. We also investigate the seasonal trends of RSV from 2017 to 2021. The demographic characteristics, comorbidities, clinical data, and coinfections were retrospectively evaluated. Compared with previous seasons, the 2021 outbreak of RSV was characterized by an increased number of patients, with a delayed peak observed in November. Overall, 179 children, including 128 (71.5%) aged <12 months, were hospitalized for RSV infection between August and December 2021. Ten children (5.6%) were admitted to the intensive care unit (ICU), all aged <5 months. One patient (0.5%) aged <1 month with severe comorbidities died. The severity of symptoms was significantly associated with younger age, underlying chronic disease, and the length of hospital stay (p < 0.05 each). History of prematurity was not significantly associated with the presence of coinfections. Because of the high burden of RSV infection and the expected larger RSV epidemics resulting from a greater number of RSV-naïve children, systematic epidemiological and virological surveillance is needed. Appropriate pathways for access to RSV prevention in all infants should also be introduced.

Acute, Severe Hepatitis of Unknown Origin: Should We Really Be Afraid of Another Obscure Enemy of Our Children?

On 31 March 2022, Public Health Scotland was alerted to five children aged 3-5 years, presenting to the Glasgow children's hospital with severe hepatitis of unknown etiology within a 3-week period [...].

Limited Additive Diagnostic Impact of Isolated Gastrointestinal Involvement for the Triage of Children with Suspected COVID-19.

The strategy for the selection of patients with a suspected SARS-CoV-2 infection is relevant for the organization of a children's hospital to provide optimal separation into COVID-19 and non-COVID-19 areas and pathways. We analyzed the proportion of children with COVID-19 presenting with gastrointestinal (GI) symptoms in 137 consecutive patients admitted between January 2020 and August 2021. GI symptoms were present as follows: diarrhea in 35 patients (26%), vomiting in 16 (12%), and both of them in five (3%); the combination of fever, respiratory symptoms, and diarrhea was observed in 16 patients (12%). Of the 676 adult patients with COVID-19 admitted to our hospital in the same time interval, 62 (9.2%) had diarrhea, 30 (4.4%) had vomiting, and 11 (1.6%) had nausea; only one patient, a 38-year-old male, presented with isolated GI symptoms at the diagnosis. Although diarrhea was observed in one quarter of cases, one-half of them had the complete triad of fever, respiratory syndrome, and diarrhea, and only five had isolated diarrhea, of which two were diagnosed with a Campylobacter infection. The occurrence of either respiratory symptoms or gastrointestinal symptoms in our patients was not related to the patient age, while younger children were more likely to have a fever. Of the 137 patients, 73 (53%) could be tested for their serum level of SARS-CoV-2 specific IgG antibodies. The observed titer ranged between 0 (n = 3) and 1729 BAU/mL (median, 425 BAU/mL). Of 137 consecutive patients with COVID-19 admitted to our referral children's hospital, only three presented with an isolated GI manifestation. It is interesting to note that this finding turned out to be fully in keeping with what was observed on adult patients with COVID-19 in our hospital. The additive diagnostic impact of gastrointestinal involvement for the triage of children with suspected COVID-19 appears limited.

Effectiveness of Preventive Measures in Keeping Low Prevalence of SARS-CoV-2 Infection in Health Care Workers in a Referral Children's Hospital in Southern Italy.

The coronavirus disease 2019 (COVID-19) pandemic now represents a major threat to public health. Health care workers (HCW) are exposed to biological risk. Little is currently known about the risk of HCW operating in pediatric wards for SARS-CoV-2 infection. The aim is to assess the prevalence of SARS-CoV-2 infection in HCW in a third-level children's hospital in Southern Italy. An observational cohort study of all asymptomatic HCW (physician, technicians, nurses, and logistic and support operators) was conducted. HCW were screened, on a voluntary basis, for SARS-CoV-2 by RT-PCR on nasopharyngeal swab performed during the first wave of COVID-19. The study was then repeated, with the same modalities, at a 7-month interval, during the "second wave" of the COVID-19 pandemic. At the initial screening between 7 and 24 April 2020, 525 HCW were tested. None of them tested positive. At the repeated screening, conducted between 9 and 20 November 2020, 627 HCW were tested, including 61 additional ones resulting from COVID-emergency recruitment. At this second screening, eight subjects (1.3%) tested positive, thus being diagnosed as asymptomatic carriers of SARS-CoV-2. They were one physician, five nurses, and two HCW from the logistic/support services. They were employed in eight different wards/services. In all cases, the epidemiological investigation showed convincing evidence that the infection was acquired through social contacts. The study revealed a very low circulation of SARS-CoV-2 infection in HCW tested with RT-PCR. All the infections documented in the second wave of epidemic of SARS-CoV-2 were acquired outside of the workplace, confirming that in a pediatric hospital setting, HCW education, correct use of personal protective equipment, and separation of the COVID-patient pathway and staff flow may minimize the risk derived from occupational exposure.

SARS-CoV-2 Vaccination for Children-An Open Issue.

The Covid-19 pandemic is still raging [...].

SARS-CoV-2 Infection in Children in Southern Italy: A Descriptive Case Series.

At the beginning of the coronavirus-2019 (COVID-19) pandemic, Italy was one of the most affected countries in Europe. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is less frequent and less severe in children than in adults. This study analyzed the frequency of SARS-CoV-2 infection among all children aged <18 years in the Apulia region of southern Italy and the characteristics of the infected children. Clinical and demographic data were collected through the national platform for COVID-19 surveillance. Of the 166 infected children in the Apulia region, 104 (62.6%) were asymptomatic, 37 (22.3%) had mild infections, 22 (13.3%) had moderate infections, and 3 (1.8%) had severe infections. Only ten children (6.0%) were hospitalized, but none required intensive care support and none died. SARS-CoV-2 infection was transmitted mainly from parents or relatives to children. Because of school closure during the lockdown, infection was unlikely to have been transmitted among children. It is unclear whether school reopening would enhance virus spread, leading the Italian government to develop guidelines for safe school reopening. The actual role of children in virus transmission remains unclear. A sensitive surveillance system, prompt identification of cases, testing, and contact tracing will be key to reducing the further spread of infection.

Monitoring oral iron therapy in children with iron deficiency anemia: an observational, prospective, multicenter study of AIEOP patients (Associazione Italiana Emato-Oncologia Pediatrica).

Oral ferrous salts are standard treatment for children with iron deficiency anemia (IDA). The objective of our study was to monitor oral iron therapy in children, aged 3 months-12 years, with IDA. We prospectively collected clinical and hematological data of children with IDA, from 15 AIEOP (Associazione Italiana di Ematologia ed. Oncologia Pediatrica) centers. Response was measured by the increase of Hb from baseline. Of the 107 analyzed patients, 18 received ferrous gluconate/sulfate 2 mg/kg (ferrous 2), 7 ferrous gluconate/sulfate 4 mg/kg (ferrous 4), 7 ferric iron salts 2 mg/kg (ferric), 62 bis-glycinate iron 0.45 mg/kg (glycinate), and 13 liposomal iron 0.7-1.4 mg/kg (liposomal). Increase in reticulocytes was evident at 3 days, while Hb increase appeared at 2 weeks. Gain of Hb at 2 and 8 weeks revealed a higher median increase in both ferrous 2 and ferrous 4 groups. Gastro-intestinal side effects were reported in 16% (ferrous 2), 14% (ferrous 4), 6% (glycinate), and 0 (ferric and liposomal) patients. The reticulocyte counts significantly increased after 3 days from the start of oral iron supplementation. Bis-glycinate iron formulation had a good efficacy/safety profile and offers an acceptable alternative to ferrous iron preparations.

Voriconazole treatment in adults and children with hematological diseases: can it be used without measurement of plasma concentration?

Indication and timing of trough plasma-voriconazole (VCZ)-concentration (t-PVC) measurement during VCZ treatment is a debated issue. Patterns of t-PVC were prospectively evaluated in pediatric (50 courses) and adult (95 courses) hematologic patients. Efficacy patterns were defined: adequate, t-PVC always ≥1 mcg/ml; borderline, at least one t-PVC measurement <1 mcg/ml but median value of the measurements ≥1 mcg/ml; inadequate, median value of the measurements <1 mcg/ml. Toxicity patterns were defined: favorable, t-PVC always ≤5 mcg/ml; borderline, one or more t-PVC measurements >5 mcg/ml but median value of the measurements ≤5 mcg/ml; unfavorable, median value of the measurements >5 mcg/ml. In children and adults the mean t-PVCs were higher during intravenous treatments. The t-PVC efficacy pattern was adequate, borderline and inadequate in 48%, 12%, and 40% of courses, respectively, in children, and in 66.3%, 16.8%, and 16.8% of courses, respectively, in adults. Adequate efficacy pattern was more frequent in children with body weight above the median (≥25 kg) (OR 4.8; P = .011) and in adults with active hematological disease receiving intravenous therapy (OR 3.93; P = .006). Favorable toxicity pattern was more frequent in children receiving VCZ daily dosage below the median (<14 mg/kg) (OR 4.18; P = .027) and in adults with body weight below the median (<68 kg) (OR 0.22; P = .004). T-PVC measurement is generally needed, however, a non t-PVC guided approach may be considered in heavier adults receiving intravenous VCZ. The risk of supratherapeutic levels does not seem an absolute indication for t-PVC monitoring.

Retrospective study on the incidence and outcome of proven and probable invasive fungal infections in high-risk pediatric onco-hematological patients.

BACKGROUND: Invasive fungal infection (IFI) is a cause of morbidity, mortality and increased health costs in children undergoing chemotherapy or hematopoietic stem cell transplant (HSCT). METHODS: Multicenter, retrospective study to assess the incidence, outcome of proven and probable IFI (PP-IFI) in children treated for acute leukemia, non-Hodgkin lymphoma or who underwent HSCT from 2006 to 2012. RESULTS: Over the 7-year period, 127 PP-IFI were diagnosed in 123 patients, median age of 9.7 years. The 1-year cumulative incidence was 2.5% (CI 1.8-3.7) after frontline chemotherapy, 9.4% (CI 5.8-15.0) after relapse, and 5.3% (CI 3.9-7.1) after HSCT. Severe neutropenia was present in 98 (77%) patients. Culture-proven agents were Candida spp., mostly non-albicans, 28, mold 23, whereas three proven IFI were identified by histopathology. Favorable response to treatment within 3 months from diagnosis was observed in 77 (89%). The overall ninety-day probability of survival was 68% (CI 59-76). CONCLUSIONS: About two-thirds of pediatric patients with PP-IFI survived, regardless of whether the infection occurred after frontline chemotherapy, reinduction chemotherapy for disease relapse, or after HSCT. Further prospective studies are needed to define the impact of antifungal prophylaxis and early combination therapy on short-term overall survival.

Biosimilars in the management of neutropenia: focus on filgrastim.

Advances in chemotherapy and surgery allows the majority of patients to survive cancer diseases. Yet, the price may be a proportion of patients dying of complications due to treatment-induced infectious complications, such as neutropenia. With the aim of decreasing morbidity and mortality related to infectious complications, recombinant human granulocyte colony-stimulating factor (G-CSF), filgrastim, and pegylated filgrastim have been used to reduce time and degree of neutropenia. A biosimilar is a copy of an approved original biologic medicine whose data protection has expired. The patent for filgrastim expired in Europe in 2006 and in the US in 2013. This review analyses the available evidence to be considered in order to design a strategy of use of G-CSF and its biosimilars. The clinical and safety outcomes of biosimilars are well within the range of historically reported data for originator filgrastim. This underscores the clinical effectiveness and safety of biosimilar filgrastim in daily clinical practice. Biosimilars can play an important role by offering the opportunity to reduce costs, thus contributing to the financial sustainability of treatment programs.

Posaconazole oral suspension primary prophylaxis in acute leukemia and allogeneic stem cell transplant patients: can it be used without measurement of plasma concentration?

Posaconazole oral suspension (PCZ-susp) can display a variable degree of inter and intra-individual absorption. However, there is no agreement on the need of plasma-posaconazole-concentration (PPC) monitoring as a routine practice in patients receiving PCZ-susp. In this prospective, multicenter study we evaluated the variability of PPCs in hematologic patients receiving PCZ-susp prophylaxis with the aim to define conditions at different risk of subtherapeutic PPCs. Overall, 103 acute leukemia (AL) patients submitted to intensive chemotherapy (115 courses) and 46 allogeneic stem cell transplant (allo-SCT) recipients (47 courses) receiving PCZ-susp prophylaxis were considered. The adequacy of PPC pattern after the steady state (≥day 7 of treatment) in courses with two or more PPC measurements was defined as follows: inadequate pattern: PPC < 0.5 mcg/ml at least once; borderline pattern: PPC always ≥0.5mcg/ml but < 0.7 mcg/ml at least once; adequate pattern: PPC always ≥0.7 mcg/ml. The PPC pattern was evaluable in 83 and 37 AL and allo-SCT patients, respectively. It was adequate, borderline and inadequate in 63.9%, 14.5%, and 21.7% of courses, respectively, in AL, and in 62.2%, 10.8%, and 27.0% of courses, respectively, in allo-SCT. In both groups, an inadequate PPC pattern was associated with the development of diarrhea. In absence of diarrhea, the probability of an inadequate PPC pattern was 11.9% in AL and 17.2% in allo-SCT patients. PCZ-susp might be used without stringent need of PPC monitoring in patients without diarrhea.