Pertussis outbreak in neonates and young infants across Italy, January to May 2024: implications for vaccination strategies.

Since January 2024, Italy experiences a pertussis outbreak, primarily affecting neonates and unvaccinated infants at high risk of severe complications and mortality; 11 major paediatric centres noted 108 hospitalisations and three deaths by 10 May. The outbreak reflects increased circulation of Bordetella pertussis and non-adherence to immunisation recommendations during pregnancy. Public health interventions, including maternal immunisation, vaccination of infants as early as possible and post-exposure prophylaxis, are critical for reducing the burden of pertussis and preventing further mortality.

Pediatric ultrasound practice in Italy: an exploratory survey.

BACKGROUND: The aim of this exploratory survey is to describe the current state of US (ultrasound) technique across different pediatric settings nationwide. METHODS: A questionnaire was emailed to all members of the Italian Society of Pediatrics, including pediatric residents. The survey was open from December 2021 to March 2022. RESULTS: There were 1098 respondents. Seven hundred and seven pediatricians (84.1%) reported any use of US, while 51 (44.3%) residents denied it. The majority of participants (n = 956, 87.1%) reported to have a US machine available within the department, mostly cart-based (n = 516, 66.9%) and provided from 1 to 5 years prior to the survey (n = 330, 42.8%). Lung and neonatal cerebral regions were the most frequently scanned (n = 289, 18.7% and n = 218, 14.1%, respectively). The suspicion of pneumonia or respiratory distress represented the main reasons for performing US in emergency room (n = 390, 78% and n = 330, 66%, respectively). The majority of family pediatricians reported to scan lung and kidney/urinary tract regions (n = 30, 16.9%, and n = 23,12.9%, respectively). Regarding US training, the majority of respondents (n = 358, 34.6%) declared an experience-based education, with a deficient certification enabling the use of US in 71.6% (n = 552) of cases. The most common barriers included the lack of a well-defined training program (n = 627, 57.1%), unavailability of the US machine (n = 196, 17.9%) and legal responsibility concern (n = 175, 15.9%). CONCLUSIONS: Despite the growing interest on pediatric US nationally, significant barriers still limit widespread adoption. These obstacles may be addressed through the dissemination of a specific US education plan and providing additional resources.

Determinants of antibiotic prescription in children with adenovirus respiratory tract infections.

We performed this study to evaluate factors associated with antibiotic prescriptions in children with adenovirus infection, since no studies have attempted to address this aspect in the pediatric population. Retrospective study of children younger than 18 years of age tested positive for adenovirus on a syndromic nasopharyngeal test from 2018 to 2023. We compared the need of pediatric intensive care unit (PICU), invasive ventilation, and other respiratory support, viral etiologies, clinical presentations, imaging, and laboratory results in the precovid (2018-2019) and covid (2020-2022) period. The use of antibiotics was studied with multivariable logistic regression including demographic as well as clinical data as covariates. Two hundred fifty-eight patients were enrolled. One hundred fifty-eight patients received an antibiotic (mean duration 6.2 (±2.7) days (median 4; IQR: 4-7)). Presence of seizures and C-reactive protein values as predictors for antibiotic prescription (OR for seizures: 12.17; 95% CI: 1.42-103.91; p = 0.022; OR for CrP: 1.03; 95% CI: 1.01-1.04; p = 0.001). Seventy-four patients received intravenous antibiotics (74/156, 47.4%). Risk factors for intravenous antibiotic were the presence of decay (OR: 3.74; 95% CI: 1.25-11.71; p = 0.018), CrP values (OR: 1.02; 95% CI: 1.00-1.03; p = 0.001), and presence of seizures (OR: 16.34; 95% CI: 2.65-100.83; p = 0.003). Duration of intravenous antibiotics correlated with the presence of seizures (Coeff: 1.6; 95% CI: 0.41-2.89; p = 0.009) even when adjusted for CrP values.    Conclusion: The clinical presentation of adenovirus infection in children is non-specific, leading to frequent antibiotic prescription despite bacterial co-infections was rare. Higher CrP values and presenting with seizures are significantly associated with a higher risk of receiving antibiotics. Rapid microbiological tests and newer biomarkers can help clinicians to improve antibiotic prescription in this cohort of children. What is Known: • Adenovirus infection is a common cause of fever and respiratory tract infections in children. • Children with adenovirus infections frequently receive antibiotics, but determinants of this practice are poorly established. What is New: • Higher C-reactive protein values and presenting with seizures are significantly associated with antibiotic prescription. • Since the beginning of COVID-19 and implementation of rapid diagnostics, less children with adenovirus infection received antibiotics.

Cardiopulmonary Exercise Testing in Children With Long COVID: A Case-controlled Study.

BACKGROUND: Cardiopulmonary exercise testing (CPET) is a noninvasive and nonexpensive diagnostic tool, that provides a comprehensive evaluation of the pulmonary, cardiovascular, and skeletal muscle systems' integrated reactions to exercise. CPET has been extensively used in adults with Long COVID (LC), while the evidence about its role in children with this condition is scarce. METHODS: Prospective, case-controlled observational study. Children with LC and a control group of healthy children underwent CPET. CPET findings were compared within the 2 groups, and within the LC groups according to main clusters of persisting symptoms. RESULTS: Sixty-one children with LC and 29 healthy controls were included. Overall, 90.2% of LC patients (55 of 61) had a pathologic test vs 10.3% (3/29) of the healthy control. Children with LC presented a statistically significant higher probability of having abnormal values of peak VO2 (P = 0.001), AT% pred (P <0.001), VO2/HR % (P = 0.03), VO2 work slope (P = 0.002), VE/VCO2 slope (P = 0.01). The mean VO2 peak was 30.17 (±6.85) in LC and 34.37 (±6.55) in healthy patients (P = 0.007). CONCLUSIONS: Compared with healthy controls, children with LC have objective impaired functional capacity (expressed by a low VO2 peak), signs of deconditioning and cardiogenic inefficiency when assessed with CPET. As such, CPET should be routinely used in clinical practice to objectify and phenotype the functional limitations of children with LC, and to follow-up them.

The lung ultrasound in children with SARS-COV-2 infection: a national multicenter prospective study.

Coronavirus disease-19 (COVID-19) caused hospitalizations, severe disease, and deaths in any age, including in the youngest children. The aim of this multicenter national study is to characterize the clinical and the prognostic role of lung ultrasound (LU) in children with COVID-19. We enrolled children between 1 month and 18 years of age with severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection who underwent a LU within 6 h from the first medical evaluation. A total of 213 children were enrolled, 51.6% were male, median age was 2 years and 5 months (interquartile range (IQR) 4 months -11 years and 4 months). One hundred and forty-eight (69.4%) children were admitted in hospital, 9 (6.1%) in pediatric intensive care unit. We found an inverse correlation between the lung ultrasound score (LUS) and the oxygen saturation at the first clinical evaluation (r = -0.16; p = 0.019). Moreover, LUS was significantly higher in patients requiring oxygen supplementation (8 (IQR 3-19) vs 2 (IQR 0-4); p = 0.001). Among LU pathological findings, irregular pleural lines, subpleural consolidations, and pleural effusions were significantly more frequent in patients needing oxygen supplementation (p = 0.007, p = 0.006, and p = 0.001, respectively).  Conclusion: This multicenter study showed that LU in children with COVID-19 can highlight pleural line irregularities, vertical artifacts, and subpleural consolidation. Notably, children with higher LUS have a higher risk of hospitalization and need for oxygen supplementation, supporting LU as a valid and safe point-of-care first level tool for the clinical evaluation of children with COVID-19. What is Known: • Few children infected with SARS-CoV-2 develop a severe disease and need oxygen therapy. • Lung ultrasound can easily detect low respiratory tract infection during SARS-CoV-2. What is New: • Children with higher lung ultrasound score have a higher risk of need for oxygen supplementation. • Irregular pleural line, sub-pleural consolidations and pleural effusions were significantly more frequent in patients needing oxygen supplementation.

Corrigendum: Time-Trends in Air Pollution Impact on Health in Italy, 1990-2019: An Analysis from the Global Burden of Disease Study 2019.

[This corrects the article DOI: 10.3389/ijph.2023.1605959.].

Tuberculosis disease in immunocompromised children and adolescents: a pTBnet multi-centre case-control study.

BACKGROUND: In high-resource settings the survival of immunocompromised (IC) children has increased and immunosuppressive therapies are increasingly being used. This study aimed to determine the clinical characteristics, performance of diagnostic tools and outcome of IC children with TB in Europe. METHODS: Multicentre, matched case-control study within the Paediatric Tuberculosis Network European Trials Group (ptbnet), capturing TB cases <18 years diagnosed 2000-2020. RESULTS: 417 TB cases were included, comprising 139 children with IC (HIV, inborn errors of immunity, drug-induced immunosuppression and other immunocompromising conditions) and 278 non-IC children as controls. Non-respiratory TB was more frequent among cases than controls (32.4% vs. 21.2%; p = 0.013). IC patients had an increased likelihood of presenting with severe disease (57.6% vs. 38.5%; p < 0.001; OR [95% CI]: 2.073 [1.37-3.13]). Children with IC had higher rates of false-negative tuberculin skin test (31.9% vs. 6.0%; p < 0.001) and QuantiFERON-TB Gold assay (30.0% vs. 7.3%; p < 0.001) results at diagnosis. Overall, the microbiological confirmation rate was similar in IC and non-IC cases (58.3% vs. 49.3%; p = 0.083). Although the mortality in IC children was <1%, the rate of long-term sequelae was significantly higher than in non-IC cases (14.8% vs. 6.1%; p = 0.004). CONCLUSIONS: IC children with TB disease in Europe have increased rates of non-respiratory TB, severe disease, and long-term sequelae. Immune-based TB tests have poor sensitivity in those children. Future research should focus on developing improved immunological TB tests that perform better in IC patients, and determining the reasons for the increased risk of long-term sequelae, with the aim to design preventive management strategies.

Stime dell'antibiotico-resistenza in Italia e in Europa occidentale nel 2019: un'analisi comparativa basata su MICROBE.

BACKGROUND: antimicrobial resistance (AMR) will cause 10 million deaths per year worldwide by 2050, with economic costs of up to 100 trillion dollars. Antibiotic resistance (ABR) constitutes the majority of this health threat. Globally, 1.27 million people died in 2019 as a direct result of ABR. One in 5 deaths occurred in children under five, and 6 bacterial pathogens accounted for more than 70% of ABR-associated deaths. OBJECTIVES: to compare ABR estimates in terms of death and disability-adjusted life-years (DALYs) in 2019 in Italy and in Western Europe (WE) by grading the infectious syndromes and the bacterial pathogens involved, with the aim to identify the most urgent healthcare needs in Italy. DESIGN: the estimates of the burden of ABR in 2019 in WE and Italy, extracted from the Measuring Infectious Causes and Resistance Outcomes for Burden Estimation (MICROBE) tool by the Institute for Health Metrics and Evaluation (IHME; Seattle, USA), reported deaths and DALYs associated with 33 bacterial pathogens across 12 infectious syndromes, as well as deaths and DALYs associated with and attributable to ABR for 23 bacteria and 86 pathogen-drug combinations. The comparison between WE and Italy was performed in steps. First, among the 12 groups of infectious syndromes from the Global Burden of Diseases (GBD) study 2019, the most impacting in terms of deaths and DALYs were ranked based on the magnitude of rates, and the corresponding ABR-associated burden was reported. Then, the burden of the leading pathogens (bacteria, viruses, fungi, and polymicrobial infections) for all infectious syndromes was compared between the two areas. Death and DALY rates associated with ABR were reported for each bacterium, together with the percentage of ABR-attributable burden. Although it is known that Italy is one of the WE countries with the largest share of elderly, crude rates were reported instead of age-standardized rates, in order to quantify the actual burden of ABR in the two areas. SETTING AND PARTICIPANTS: Italy and Western Europe. MAIN OUTCOMES MEASURES: death and DALYs rates per 100,000 inhabitants. RESULTS: the largest difference between ABR-associated death rates in the two areas was found for bloodstream infections (25.2 and 18.8 per 100,000 in Italy and WE, respectively), followed by peritoneal and abdominal infections (15.1 and 12.2 in Italy and WE, respectively). However, the percentages of deaths and DALYs attributable to ABR were always higher in Italy for all the infections considered. Regarding pathogens, Escherichia coli accounted for the greatest burden associated to ABR, in terms of both deaths and DALYs, in both areas. The highest ABR-attributable percentage of deaths was found for Acinetobacter baumannii (28.4% in WE and 31.9% in Italy), accounting also for the highest percentage of ABR-attributable DALYs (28.4% in WE and 31.7% in Italy). The pathogen-drug combination with the highest burden associated with AMR was Escherichia coli-Aminopenicillin, while the greatest AMR-attributable burden was found for Staphylococcus aureus-Methicillin (MRSA). On average, 55.4% of Escherichia coli was resistant to Aminopenicillin in WE, with Italy ranking third (67.6%). Nordic countries showed smaller values, with Sweden in last place (32.8%). The average percentage of MRSA in WE was 16%, with Italy exceeding it by more than 13 pointsConclusions: despite similar sepsis mortality rates in Italy and other WE countries, the proportion of ABR-associated and attributable deaths was higher in Italy. Targeted strategies aimed at reducing the circulation of bacteria and resistant microorganisms together with other interventions could lead to an overall reduction in deaths associated with ABR.

Mucocutaneous Candidiasis: Insights Into the Diagnosis and Treatment.

Recent progress in the methods of genetic diagnosis of inborn errors of immunity has contributed to a better understanding of the pathogenesis of chronic mucocutaneous candidiasis (CMC) and potential therapeutic options. This review describes the latest advances in the understanding of the pathophysiology, diagnostic strategies, and management of chronic mucocutaneous candidiasis.

Management and outcomes of bronchiolitis in Italy and Latin America: a multi-center, prospective, observational study.

We aimed to describe differences in the epidemiology, management, and outcomes existing between centers located in countries which differ by geographical location and economic status during to post-pandemic bronchiolitis seasons.  This was a prospective observational cohort study performed in two academic centers in Latin America (LA) and three in Italy. All consecutive children with a clinical diagnosis of bronchiolitis were included, following the same data collection form.  Nine hundred forty-three patients have been enrolled: 275 from the two Latin American Centers (San Jose, 215; Buenos Aires, 60), and 668 from Italy (Rome, 178; Milano, 163; Bologna, 251; Catania, 76). Children in LA had more frequently comorbidities, and only rarely received palivizumab. A higher number of patients in LA had been hospitalized in a ward (64% versus 23.9%, p < 0.001) or in a PICU (16% versus 6.2%, p < 0.001), and children in LA required overall more often respiratory support, from low flow oxygen to invasive mechanical ventilation, except for CPAP which was more used in Italy. There was no significant difference in prescription rates for antibiotics, but a significantly higher number of patients treated with systemic steroids in Italy. CONCLUSIONS: We found significant differences in the care for children with bronchiolitis in Italy and LA. Reasons behind such differences are unclear and would require further investigations to optimize and homogenize practice all over the world. WHAT IS KNOWN: • Bronchiolitis is among the commest cause of morbidity and mortality in infants all over the world. WHAT IS NEW: • There are significant differences on how clinicians care for bronchiolitis in different centers and continents. Differences in care can be principally due to different local practices than differences in patients severity/presentations. • Understanding these differences should be a priority to optime and standardize bronchiolitis care globally.

Antimicrobial Stewardship in Pediatric Emergency Medicine: A Narrative Exploration of Antibiotic Overprescribing, Stewardship Interventions, and Performance Metrics.

Antibiotic overprescribing is prevalent in pediatric emergency medicine, influenced by clinician-caregiver dynamics and diagnostic uncertainties, and poses substantial risks such as increasing antibacterial resistance, adverse drug reactions, and increased healthcare expenditures. While antimicrobial stewardship programs have proven effective in optimizing antibiotic use within inpatient healthcare settings, their implementation in pediatric emergency medicine presents specific challenges. Existing biomarkers like white blood cell count, C-reactive protein, procalcitonin, and presepsin have limitations in their ability to distinguish (serious) bacterial infections from other etiologies of fever. Furthermore, rapid antigen detection tests and guidelines aimed at guiding antibiotic prescriptions for children have not consistently reduced unnecessary antibiotic use. To improve antibiotic prescribing practices, potential strategies include the utilization of decision support tools, audit and feedback, establishing follow-up procedures, implementing safety netting systems, and delivering comprehensive training and supervision. Notably, host genome signatures have also gained attention for their potential to facilitate rapid and precise diagnoses of inflammatory syndromes. Standardized metrics are crucial for evaluating antimicrobial use within pediatric healthcare settings, enabling the establishment of benchmarks for assessing antibiotic utilization, quality enhancement initiatives, and research endeavors.

Procalcitonin and Presepsin as Markers of Infectious Respiratory Diseases in Children: A Scoping Review of the Literature.

INTRODUCTION: Procalcitonin and presepsin have been suggested to be able to discriminate bacterial and viral infections, also in children. This scoping review aims to better explore the available evidence around the potential role of these biomarkers in the subgroup of children with respiratory infectious diseases. METHODS: We performed a systematic scoping review of studies published until March 2023 in the following bibliographic databases: PubMed, EMBASE, Cochrane and SCOPUS. RESULTS: In children with bacterial infection, procalcitonin values ranged from 0.5 ng/mL to 8.31 ng/dL, while in those hospitalized in an intensive care unit ranged from 0.6 ng/dL to 452.8 ng/dL with PCR from 2 ng/dL to 51.7 ng/dL. In children with viral infections, procalcitonin value values ranged from 0.2 ng/dL to 0.84 ng/dL, while in those hospitalized in an intensive care unit ranged from 0.61 ng/dL to 46.6 ng/dL. No studies on presepsin in children with respiratory infections were retrieved. CONCLUSIONS: Although the available literature is highly heterogeneous, evidence does not suggest a role of procalcitonin in accurately differentiating bacterial and viral infections in children with respiratory infections. In future, new approaches based on multiple markers may better help determine which febrile children require antibiotics.

Event rates and incidence of post-COVID-19 condition in hospitalised SARS-CoV-2 positive children and young people and controls across different pandemic waves: exposure-stratified prospective cohort study in Moscow (StopCOVID).

BACKGROUND: Long-term health outcomes in children and young people (CYP) after COVID-19 infection are not well understood and studies with control groups exposed to other infections are lacking. This study aimed to investigate the incidence of post-COVID-19 condition (PCC) and incomplete recovery in CYP after hospital discharge and compare outcomes between different SARS-CoV-2 variants and non-SARS-CoV-2 infections. METHODS: A prospective exposure-stratified cohort study of individuals under 18 years old in Moscow, Russia. Exposed cohorts were paediatric patients admitted with laboratory-confirmed COVID-19 infection between April 2 and December 11, 2020 (Wuhan variant cohort) and between January 12 and February 19, 2022 (Omicron variant cohort). CYP admitted with respiratory and intestinal infections, but negative lateral flow rapid diagnostic test and PCR-test results for SARS-CoV-2, between January 12 and February 19, 2022, served as unexposed reference cohort. Comparison between the 'exposed cohorts' and 'reference cohort' was conducted using 1:1 matching by age and sex. Follow-up data were collected via telephone interviews with parents, utilising the long COVID paediatric protocol and survey developed by the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC). The WHO case definition was used to categorise PCC. RESULTS: Of 2595 CYP with confirmed COVID-19, 1707 (65.7%) participated in follow-up interviews, with 1183/1707 (69%) included in the final 'matched' analysis. The median follow-up time post-discharge was 6.7 months. The incidence of PCC was significantly higher in the Wuhan variant cohort (89.7 cases per 1000 person-months, 95% CI 64.3-120.3) compared to post-infection sequalae in the reference cohort (12.2 cases per 1000 person-months, 95% CI 4.9-21.9), whereas the difference with the Omicron variant cohort and reference cohort was not significant. The Wuhan cohort had higher incidence rates of dermatological, fatigue, gastrointestinal, sensory, and sleep manifestations, as well as behavioural and emotional problems than the reference cohort. The only significant difference between Omicron variant cohort and reference cohort was decreased school attendance. When comparing the Wuhan and Omicron variant cohorts, higher incidence of PCC and event rates of fatigue, decreased physical activity, and deterioration of relationships was observed. The rate of incomplete recovery was also significantly higher in the Wuhan variant cohort than in both the reference and the Omicron variant cohorts. CONCLUSIONS: Wuhan variant exhibited a propensity for inducing a broad spectrum of physical symptoms and emotional behavioural changes, suggesting a pronounced impact on long-term health outcomes. Conversely, the Omicron variant resulted in fewer post-infection effects no different from common seasonal viral illnesses. This may mean that the Omicron variant and subsequent variants might not lead to the same level of long-term health consequences as earlier variants.

Utility of Rapid Nasopharyngeal Swab for Respiratory Pathogens in the Diagnosis of Viral Infections in Children Hospitalized with Fever: A Prospective Validation Study to Improve Antibiotic Use.

Introduction: Fever is among the most common reason for medical assessment and antibiotic prescription in practice. The aim of this study was to evaluate positive and negative predictive values of rapid nasopharyngeal swabs for respiratory pathogens to discriminate viral from bacterial infections. Methods: We prospectively tested children with signs and/or symptoms of infections (e.g., fever, cough, wheezing, suspected urinary tract infection) admitted to a paediatric department. Following discharge, clinical phenotypes were assigned defining a cohort of children having probable/certain viral infection, probable/certain bacterial infection, other inflammatory conditions or healthy controls. Results: In this study, 190 children were enrolled (50.5% females, median age 30.5 (8-86) months). In total, 102 patients (53.7%) were affected by respiratory viral infections, 16 (8.4%) by bacterial infections, 29 (15.3%) were healthy controls and 43 (22.6%) were affected by another pathological condition manifested with fever. In total, 84.3% of patients classified as viral infection tested positive for viruses, compared with 18.8% of patients with bacterial infection (p < 0.001), 18.6% of patients with other condition (p < 0.001) and 17.2% of control patients (p < 0.001). The positive predictive value of NPSs in the diagnosis of viral infection was 88.6% and the negative predictive value was 75.0%. Conclusion: Our findings suggest that rapid NPS tests for respiratory viruses are a useful tool to confirm viral infections in children with fever and improve antibiotic use.

Vaccines and Myocardial Injury in Patients Hospitalized for COVID-19 Infection: the CardioCOVID-Gemelli Study.

BACKGROUND: Myocardial injury is prevalent among patients hospitalized for COVID-19. However, the role of COVID-19 vaccines in modifying the risk of myocardial injury is unknown. OBJECTIVES: To assess the role of vaccines in modifying the risk of myocardial injury in COVID-19. METHODS: We enrolled COVID-19 patients admitted from March 2021 to February 2022 with known vaccination status and ≥1 assessment of hs-cTnI within 30 days from the admission. The primary endpoint was the occurrence of myocardial injury (hs-cTnI levels >99th percentile upper reference limit). RESULTS: 1019 patients were included (mean age 67.7±14.8 years, 60.8% male, 34.5% vaccinated against COVID-19). Myocardial injury occurred in 145 (14.2%) patients. At multivariate logistic regression analysis, advanced age, chronic kidney disease and hypertension, but not vaccination status, were independent predictors of myocardial injury. In the analysis according to age tertiles distribution, myocardial injury occurred more frequently in the III tertile (≥76 years) compared to other tertiles (I tertile:≤60 years;II tertile:61-75 years) (p<0.001). Moreover, in the III tertile, vaccination was protective against myocardial injury (OR 0.57, CI 95% 0.34-0.94; p=0.03), while a previous history of coronary artery disease was an independent positive predictor. In contrast, in the I tertile, chronic kidney disease (OR 6.94, 95% CI 1.31-36.79, p=0.02) and vaccination (OR 4.44, 95% CI 1.28-15.34, p=0.02) were independent positive predictors of myocardial injury. CONCLUSIONS: In patients ≥76 years, COVID-19 vaccines were protective for the occurrence of myocardial injury, while in patients ≤60 years, myocardial injury was associated with previous COVID-19 vaccination. Further studies are warranted to clarify the underlying mechanisms.

Core outcome measurement set for research and clinical practice in post-COVID-19 condition (long COVID) in children and young people: an international Delphi consensus study "PC-COS Children".

The coronavirus disease 2019 (COVID-19) pandemic substantially impacted different age groups, with children and young people not exempted. Many have experienced enduring health consequences. Presently, there is no consensus on the health outcomes to assess in children and young people with post-COVID-19 condition. Furthermore, it is unclear which measurement instruments are appropriate for use in research and clinical management of children and young people with post-COVID-19. To address these unmet needs, we conducted a consensus study, aiming to develop a core outcome set (COS) and an associated core outcome measurement set (COMS) for evaluating post-COVID-19 condition in children and young people. Our methodology comprised of two phases. In phase 1 (to create a COS), we performed an extensive literature review and categorisation of outcomes, and prioritised those outcomes in a two-round online modified Delphi process followed by a consensus meeting. In phase 2 (to create the COMS), we performed another modified Delphi consensus process to evaluate measurement instruments for previously defined core outcomes from phase 1, followed by an online consensus workshop to finalise recommendations regarding the most appropriate instruments for each core outcome. In phase 1, 214 participants from 37 countries participated, with 154 (72%) contributing to both Delphi rounds. The subsequent online consensus meeting resulted in a final COS which encompassed seven critical outcomes: fatigue; post-exertion symptoms; work/occupational and study changes; as well as functional changes, symptoms, and conditions relating to cardiovascular, neuro-cognitive, gastrointestinal and physical outcomes. In phase 2, 11 international experts were involved in a modified Delphi process, selecting measurement instruments for a subsequent online consensus workshop where 30 voting participants discussed and independently scored the selected instruments. As a result of this consensus process, four instruments met a priori consensus criteria for inclusion: PedsQL multidimensional fatigue scale for "fatigue"; PedsQL gastrointestinal symptom scales for "gastrointestinal"; PedsQL cognitive functioning scale for "neurocognitive" and EQ-5D for "physical functioning". Despite proposing outcome measurement instruments for the remaining three core outcomes ("cardiovascular", "post-exertional malaise", "work/occupational and study changes"), a consensus was not achieved. Our international, consensus-based initiative presents a robust framework for evaluating post-COVID-19 condition in children and young people in research and clinical practice via a rigorously defined COS and associated COMS. It will aid in the uniform measurement and reporting of relevant health outcomes worldwide.

Persisting Gastrointestinal Symptoms in Children with SARS-CoV-2: Temporal Evolution over 18 Months and Possible Role of Lactoferrin.

BACKGROUND AND AIM: Persisting gastrointestinal symptoms are reported to be relatively common in children with long COVID; however, their detailed characterization and long-term outcomes have not yet been described. METHODS: We performed a retrospective study aiming to investigate the temporal evolution of gastrointestinal symptoms in children with SARS-CoV-2, from acute infection to 18-months follow-up. To further investigate possible therapeutic strategies, we evaluated the role of lactoferrin in improving gastrointestinal symptoms in these children, compared with those not treated. RESULTS: A total of 1224 patients (47.7% females) were included. Of these participants, 246 (19.8%) were vaccinated and 143 (11.5%) presented with comorbidities. A total of 175 patients (14.1%) presented gastrointestinal symptoms during acute infection, 54 (4.4%) at three months, 23 (1.9%) at six months, 6 (3.3%) at twelve months, and 2 (2.3%) at eighteen months follow-up. At six months follow-up, children who were treated with 3 months oral lactoferrin had less persisting symptoms compared to those who did not receive lactoferrin, although this difference was not statistically significant (three patients (25%) in the lactoferrin group vs. fourteen patients (33.3%) not treated, p = 0.73), probably due to the low number of patients with persisting GI symptoms. CONCLUSIONS: GI symptoms are relatively common during acute SARS-CoV-2 infection in children, and a non-negligible proportion of these children reported persisting symptoms for up to 12-18 months after the acute infection. In addition, we found a trend even if statistically nonsignificant toward faster improvement of persisting gastrointestinal symptoms in children with long COVID treated with lactoferrin. Despite the limitations relating to the present study's design, given the significant burden of gastrointestinal symptoms in children with long COVID, our findings provide the basis to perform a prospective, placebo-controlled study.