Showing papers in "Frontiers in Pediatrics in 2021"

Biomarkers in COVID-19: An Up-To-Date Review

Abstract: The ongoing pandemic of coronavirus disease 2019 (COVID-19) poses several challenges to clinicians. Timely diagnosis and hospitalization, risk stratification, effective utilization of intensive care services, selection of appropriate therapies, monitoring and timely discharge are essential to save the maximum number of lives. Clinical assessment is indispensable, but laboratory markers, or biomarkers, can provide additional, objective information which can significantly impact these components of patient care. COVID-19 is not a localized respiratory infection but a multisystem disease caused by a diffuse systemic process involving a complex interplay of the immunological, inflammatory and coagulative cascades. The understanding of what the virus does to the body and how the body reacts to it has uncovered a gamut of potential biomarkers. This review discusses the different classes of biomarkers - immunological, inflammatory, coagulation, hematological, cardiac, biochemical and miscellaneous - in terms of their pathophysiological basis followed by the current evidence. Differences between children and adults are highlighted. The role of biomarkers in the diagnosis and management of Multisystem Inflammatory Syndrome in Children (MIS-C) is reviewed. The correlation of biomarkers with clinical and radiological features and the viral load, temporal evolution and the effect of treatment remain to be studied in detail. Which biomarker needs to be evaluated when and in whom, and how best this information can contribute to patient care are questions which currently lack convincing answers. With the evidence currently available broad guidelines on the rational use of available biomarkers are presented. Integrating clinical and laboratory data, monitoring trends rather than a single value, correlating with the natural course of the disease and tailoring guidelines to the individual patient and healthcare setting are essential.

Childhood and Adolescent Obesity: A Review.

Abstract: Obesity is a complex condition that interweaves biological, developmental, environmental, behavioral, and genetic factors; it is a significant public health problem. The most common cause of obesity throughout childhood and adolescence is an inequity in energy balance; that is, excess caloric intake without appropriate caloric expenditure. Adiposity rebound (AR) in early childhood is a risk factor for obesity in adolescence and adulthood. The increasing prevalence of childhood and adolescent obesity is associated with a rise in comorbidities previously identified in the adult population, such as Type 2 Diabetes Mellitus, Hypertension, Non-alcoholic Fatty Liver disease (NAFLD), Obstructive Sleep Apnea (OSA), and Dyslipidemia. Due to the lack of a single treatment option to address obesity, clinicians have generally relied on counseling dietary changes and exercise. Due to psychosocial issues that may accompany adolescence regarding body habitus, this approach can have negative results. Teens can develop unhealthy eating habits that result in Bulimia Nervosa (BN), Binge- Eating Disorder (BED), or Night eating syndrome (NES). Others can develop Anorexia Nervosa (AN) as they attempt to restrict their diet and overshoot their goal of "being healthy." To date, lifestyle interventions have shown only modest effects on weight loss. Emerging findings from basic science as well as interventional drug trials utilizing GLP-1 agonists have demonstrated success in effective weight loss in obese adults, adolescents, and pediatric patients. However, there is limited data on the efficacy and safety of other weight-loss medications in children and adolescents. Nearly 6% of adolescents in the United States are severely obese and bariatric surgery as a treatment consideration will be discussed. In summary, this paper will overview the pathophysiology, clinical, and psychological implications, and treatment options available for obese pediatric and adolescent patients.

Genetic Testing in Neurodevelopmental Disorders.

Abstract: Neurodevelopmental disorders are the most prevalent chronic medical conditions encountered in pediatric primary care. In addition to identifying appropriate descriptive diagnoses and guiding families to evidence-based treatments and supports, comprehensive care for individuals with neurodevelopmental disorders includes a search for an underlying etiologic diagnosis, primarily through a genetic evaluation. Identification of an underlying genetic etiology can inform prognosis, clarify recurrence risk, shape clinical management, and direct patients and families to condition-specific resources and supports. Here we review the utility of genetic testing in patients with neurodevelopmental disorders and describe the three major testing modalities and their yields - chromosomal microarray, exome sequencing (with/without copy number variant calling), and FMR1 CGG repeat analysis for fragile X syndrome. Given the diagnostic yield of genetic testing and the potential for clinical and personal utility, there is consensus that genetic testing should be offered to all patients with global developmental delay, intellectual disability, and/or autism spectrum disorder. Despite this recommendation, data suggest that a minority of children with autism spectrum disorder and intellectual disability have undergone genetic testing. To address this gap in care, we describe a structured but flexible approach to facilitate integration of genetic testing into clinical practice across pediatric specialties and discuss future considerations for genetic testing in neurodevelopmental disorders to prepare pediatric providers to care for patients with such diagnoses today and tomorrow.

Development of Psychological Problems Among Adolescents During School Closures Because of the COVID-19 Lockdown Phase in Italy: A Cross-Sectional Survey

Abstract: Background: Previous studies have shown that during COVID-19 pandemic, mainly due to the imposed lockdown, significant psychological problems had emerged in a significant part of the population, including older children and adolescents. School closure, leading to significant social isolation, was considered one of the most important reasons for pediatric mental health problems. However, how knowledge of COVID-19 related problems, modification of lifestyle and age, gender and severity of COVID-19 pandemic had influenced psychological problems of older children and adolescents has not been detailed. To evaluate these variables, a survey was carried out in Italy. Methods: This cross-sectional survey was carried out by means of an anonymous online questionnaire administered to 2,996 students of secondary and high schools living in Italian Regions with different COVID-19 epidemiology. Results: A total of 2,064 adolescent students (62.8% females; mean age, 15.4 ± 2.1 years), completed and returned the questionnaire. Most of enrolled students showed good knowledge of COVID-19-related problems. School closure was associated with significant modifications of lifestyle and the development of substantial psychological problems in all the study groups, including students living in Regions with lower COVID-19 incidence. However, in some cases, some differences, were evidenced. Sadness was significantly more frequent in females (84%) than males (68.2%; p < 0.001) and in the 14-19-year-old age group than the 11-13-year-old age group (79.2% vs. 70.2%; p < 0.001). Missing the school community was a significantly more common cause of sadness in girls (26.5% vs. 16.8%; p < 0.001), in southern Italy (26.45% vs. 20.2%; p < 0.01) and in the 14-19-year-old group (24.2% vs. 14.7%; p < 0.001). The multivariate regression analysis showed that male gender was a protective factor against negative feelings (p < 0.01), leading to a decrease of 0.63 points in the total negative feelings index. Having a family member or an acquaintance with COVID-19 increased the negative feelings index by 0.1 points (p < 0.05). Conclusions: This study shows that school closures because of the COVID-19 pandemic outbreak was associated with significant lifestyle changes in all the students, regardless of age and gender. Despite some differences in some subgroups, the study confirms that school closure can cause relevant mental health problems in older children and adolescents. This must be considered as a reason for the maintenance of all school activities, although in full compliance with the measures to contain the spread of the pandemic.

Coronavirus Disease 2019 in Children

Abstract: Since its appearance in Wuhan in mid-December 2019, acute respiratory syndrome coronavirus 2 (SARS-CoV-2) related 19 coronavirus disease (COVID-19) has spread dramatically worldwide. It soon became apparent that the incidence of pediatric COVID-19 was much lower than the adult form. Morbidity in children is characterized by a variable clinical presentation and course. Symptoms are similar to those of other acute respiratory viral infections, the upper airways being more affected than the lower airways. Thus far, over 90% of children who tested positive for the virus presented mild or moderate symptoms and signs. Most children were asymptomatic, and only a few cases were severe, unlike in the adult population. Deaths have been rare and occurred mainly in children with underlying morbidity. Factors as reduced angiotensin-converting enzyme receptor expression, increased activation of the interferon-related innate immune response, and trained immunity have been implicated in the relative resistance to COVID-19 in children, however the underlying pathogenesis and mechanism of action remain to be established. While at the pandemic outbreak, mild respiratory manifestations were the most frequently described symptoms in children, subsequent reports suggested that the clinical course of COVID-19 is more complex than initially thought. Thanks to the experience acquired in adults, the diagnosis of pediatric SARS-CoV-2 infection has improved with time. Data on the treatment of children are sparse, however, several antiviral trials are ongoing. The purpose of this narrative review is to summarize current understanding of pediatric SARS-CoV-2 infection and provide more accurate information for healthcare workers and improve the care of patients.

SARS-CoV-2 Infections in Italian Schools: Preliminary Findings After 1 Month of School Opening During the Second Wave of the Pandemic

Abstract: Introduction: The impact of school opening on the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is still unknown. This study aims to provide preliminary information about the number of SARS-CoV-2 cases among students attending Italian schools. Methods: Data are extracted and analyzed from an open-access, online dataset that monitor, on a daily basis, media news about SARS-CoV-2 infections of students attending Italian schools. Results: As of October 5, 2020, a total of 1,350 cases of SARS-CoV-2 infections have been registered in the Italian territory schools (involving 1,059 students, 145 teachers, and 146 other school members), for a total of 1,212 out of 65,104 (1.8%) Italian schools involved. National schools reported only one case of SARS-CoV-2 infection in more than 90% of cases, and only in one high school a cluster of more than 10 cases has been described (P = 0.015). The detection of one or more SARS-CoV-2 infections led to the closure of 192 (15.8%) entire schools, more frequently nursery/kindergartens (P < 0.0005). Discussion: Our preliminary data support low transmission of SARS-CoV-2 within schools, at least among younger students. However, entire schools are frequently closed in the fear of larger outbreaks. Continuous monitoring of school settings, hopefully through daily updated open-access datasets, is needed to better understand the impact of schools on the pandemic and provide guidelines that better consider different risks within different age groups.

Epidemiology, Clinical Features and Prognostic Factors of Pediatric SARS-CoV-2 Infection: Results From an Italian Multicenter Study

Abstract: Background: Many aspects of SARS-CoV-2 infection in children and adolescents remain unclear and optimal treatment is debated. The objective of our study was to investigate epidemiological, clinical and therapeutic characteristics of pediatric SARS-CoV-2 infection, focusing on risk factors for complicated and critical disease. Methods: The present multicenter Italian study was promoted by the Italian Society of Pediatric Infectious Diseases, involving both pediatric hospitals and general pediatricians/family doctors. All subjects under 18 years of age with documented SARS-CoV-2 infection and referred to the coordinating center were enrolled from March 2020. Results: As of 15 September 2020, 759 children were enrolled (median age 7.2 years, IQR 1.4; 12.4). Among the 688 symptomatic children, fever was the most common symptom (81.9%). Barely 47% of children were hospitalized for COVID-19. Age was inversely related to hospital admission (p < 0.01) and linearly to length of stay (p = 0.014). One hundred forty-nine children (19.6%) developed complications. Comorbidities were risk factors for complications (p < 0.001). Viral coinfections, underlying clinical conditions, age 5-9 years and lymphopenia were statistically related to ICU admission (p < 0.05). Conclusions: Complications of COVID-19 in children are related to comorbidities and increase with age. Viral co-infections are additional risk factors for disease progression and multisystem inflammatory syndrome temporarily related to COVID-19 (MIS-C) for ICU admission.

Comparison of Persistent Symptoms After COVID-19 and Other Non-SARS-CoV-2 Infections in Children.

Abstract: Introduction: The data on long COVID in children is scarce since children and adolescents are typically less severely affected by acute COVID-19. This study aimed to identify the long-term consequences of SARS-CoV-2 infection in children, and to compare the persistent symptom spectrum between COVID-19 and community-acquired infections of other etiologies. Methods: This was an ambidirectional cohort study conducted at the Children's Clinical University Hospital in Latvia. The study population of pediatric COVID-19 patients and children with other non-SARS-CoV-2-community-acquired infections were invited to participate between July 1, 2020, and April 30, 2021. Results: In total, 236 pediatric COVID-19 patients were enrolled in the study. Additionally, 142 comparison group patients were also enrolled. Median follow-up time from acute symptom onset was 73.5 days (IQR; 43-110 days) in the COVID-19 patient group and 69 days (IQR, 58-84 days) in the comparison group. Most pediatric COVID-19 survivors (70%, N = 152) reported at least one persistent symptom, but more than half of the patients (53%, N = 117) noted two or more long-lasting symptoms. The most commonly reported complaints among COVID-19 patients included persistent fatigue (25.2%), cognitive sequelae, such as irritability (24.3%), and mood changes (23.3%), as well as headaches (16.9%), rhinorrhea (16.1%), coughing (14.4%), and anosmia/dysgeusia (12.3%). In addition, 105 (44.5%) COVID patients had persistent symptoms after the 12-week cut-off point, with irritability (27.6%, N = 29), mood changes (26.7%, N = 28), and fatigue (19.2%, N = 20) being the most commonly reported ones. Differences in symptom spectrum among the various age groups were seen. Logistic regression analysis showed that long-term persistent symptoms as fever, fatigue, rhinorrhea, loss of taste and/or smell, headaches, cognitive sequelae, and nocturnal sweating were significantly associated with the COVID-19 experience when compared with the controls. Conclusions: We found that at the time of interview almost three-quarters of children reported at least one persistent symptom, but the majority of patients (53%) had two or more concurrent symptoms. The comparison group's inclusion in the study allowed us to identify that symptom persistence is more apparent with COVID-19 than any other non-SARS-CoV-2 infection. More research is needed to distinguish the symptoms of long COVID from pandemic-associated complaints. Each persistent symptom is important in terms of child well-being during COVID-19 recovery.

Hypertrophic Cardiomyopathy in Children: Pathophysiology, Diagnosis, and Treatment of Non-sarcomeric Causes.

Abstract: Hypertrophic cardiomyopathy (HCM) is a myocardial disease characterized by left ventricular hypertrophy not solely explained by abnormal loading conditions. Despite its rare prevalence in pediatric age, HCM carries a relevant risk of mortality and morbidity in both infants and children. Pediatric HCM is a large heterogeneous group of disorders. Other than mutations in sarcomeric genes, which represent the most important cause of HCM in adults, childhood HCM includes a high prevalence of non-sarcomeric causes, including inherited errors of metabolism (i.e., glycogen storage diseases, lysosomal storage diseases, and fatty acid oxidation disorders), malformation syndromes, neuromuscular diseases, and mitochondrial disease, which globally represent up to 35% of children with HCM. The age of presentation and the underlying etiology significantly impact the prognosis of children with HCM. Moreover, in recent years, different targeted approaches for non-sarcomeric etiologies of HCM have emerged. Therefore, the etiological diagnosis is a fundamental step in designing specific management and therapy in these subjects. The present review aims to provide an overview of the non-sarcomeric causes of HCM in children, focusing on the pathophysiology, clinical features, diagnosis, and treatment of these rare disorders.

SARS-CoV-2 and the Gastrointestinal Tract in Children

Abstract: Coronavirus disease 2019 (COVID-19), caused by acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is predominantly a respiratory disease. However, its significant impact on the gastrointestinal (GI) system is now well-known. SARS-CoV-2 enters cells via the angiotensin-converting enzyme-2 (ACE-2) receptor, which is abundantly expressed on lung cells, but also on enterocytes. Several etiopathogenetic mechanisms have been postulated to explain the GI involvement in COVID-19, including loss in intestinal absorption, microscopic mucosal inflammation and impaired ACE-2 function, which plays a significant role in maintaining gut homeostasis. In children the GI manifestations include anorexia, nausea, vomiting, diarrhea and abdominal pain, which may represent the earliest presenting symptoms of the disease. However, although rare, a significant GI mucosal inflammation, such as terminal ileitis mimicking an atypical appendicitis, and other GI manifestations have been reported. COVID-19 pandemic has posed a significant challenge in healthcare provision in term of ability in providing safe diagnostic procedures, face-to-face consultations, and offering comprehensive care. For instance, changes in health services have raised the risk of empirical or sub-optimal management of chronic GI disorders such as inflammatory bowel disease (IBD) due to delayed endoscopic and clinical assessment. This review will discuss the acute GI involvement in COVID-19 in children and reflect on challenges and major changes observed in clinical practice during COVID-19 pandemic by sharing both the published literature and personal experience. We also suggest potential strategies for providing optimal gastroenterology care during this unprecedented era.

The Impact of COVID-19 on Adolescent Mental Health: Preliminary Findings From a Longitudinal Sample of Healthy and At-Risk Adolescents

Abstract: Background: The COVID-19 pandemic has brought on far-reaching consequences for adolescents. Adolescents with early life stress (ELS) may be at particular risk. We sought to examine how COVID-19 impacted psychological functioning in a sample of healthy and ELS-exposed adolescents during the pandemic. Methods: A total of 24 adolescents (15 healthy, nine ELS) completed self-report measures prior to and during the COVID-19 pandemic. The effect of COVID-19 on symptoms of depression and anxiety were explored using linear mixed-effect analyses. Results: With the onset of the pandemic, healthy but not ELS-exposed adolescents evidenced increased symptoms of depression and anxiety (ps < 0.05). Coping by talking with friends and prioritizing sleep had a protective effect against anxiety for healthy adolescents (t = -3.76, p = 0.002). Conclusions: On average, this study demonstrated large increases in depression and anxiety in adolescents who were healthy prior to the COVID-19 pandemic, while ELS-exposed adolescents evidenced high but stable symptoms over time.

Not All Fibers Are Born Equal; Variable Response to Dietary Fiber Subtypes in IBD

Abstract: Diet provides a safe and attractive alternative to available treatment options in a variety of diseases; however, research has only just begun to elucidate the role of diet in chronic diseases, such as the inflammatory bowel diseases (IBD). The chronic and highly debilitating IBDs, Crohn disease and ulcerative colitis, are hallmarked by intestinal inflammation, immune dysregulation, and dysbiosis; and evidence supports a role for genetics, microbiota, and the environment, including diet, in disease pathogenesis. This is true especially in children with IBD, where diet-based treatments have shown excellent results. One interesting group of dietary factors that readily links microbiota to gut health is dietary fibers. Fibers are not digested by human cells, but rather fermented by the gut microbes within the bowel. Evidence has been mounting over the last decade in support of the importance of dietary fibers in the maintenance of gut health and in IBD; however, more recent studies highlight the complexity of this interaction and importance of understanding the role of each individual dietary fiber subtype, especially during disease. There are roughly ten subtypes of dietary fibers described to date, categorized as soluble or insoluble, with varying chemical structures, and large differences in their fermentation profiles. Many studies to date have described the benefits of the byproducts of fermentation in healthy individuals and the potential health benefits in select disease models. However, there remains a void in our understanding of how each of these individual fibers affect human health in dysbiotic settings where appropriate fermentation may not be achieved. This review highlights the possibilities for better defining the role of individual dietary fibers for use in regulating inflammation in IBD.

3D Modeling and Printing in Congenital Heart Surgery: Entering the Stage of Maturation.

Abstract: 3D printing allows the most realistic perception of the surgical anatomy of congenital heart diseases without the requirement of physical devices such as a computer screen or virtual headset It is useful for surgical decision making and simulation, hands-on surgical training (HOST) and cardiovascular morphology teaching 3D-printed models allow easy understanding of surgical morphology and preoperative surgical simulation The most common indications for its clinical use include complex forms of double outlet right ventricle and transposition of the great arteries, anomalous systemic and pulmonary venous connections, and heterotaxy Its utility in congenital heart surgery is indisputable, although it is hard to "scientifically" prove the impact of its use in surgery because of many confounding factors that contribute to the surgical outcome 3D-printed models are valuable resources for morphology teaching Educational models can be produced for almost all different variations of congenital heart diseases, and replicated in any number HOST using 3D-printed models enables efficient education of surgeons in-training Implementation of the HOST courses in congenital heart surgical training programs is not an option but an absolute necessity In conclusion, 3D printing is entering the stage of maturation in its use for congenital heart surgery It is now time for imagers and surgeons to find how to effectively utilize 3D printing and how to improve the quality of the products for improved patient outcomes and impact of education and training

Congenital Hypopituitarism During the Neonatal Period: Epidemiology, Pathogenesis, Therapeutic Options, and Outcome.

Abstract: Introduction: Congenital hypopituitarism (CH) is characterized by a deficiency of one or more pituitary hormones The pituitary gland is a central regulator of growth, metabolism, and reproduction The anterior pituitary produces and secretes growth hormone (GH), adrenocorticotropic hormone, thyroid-stimulating hormone, follicle-stimulating hormone, luteinizing hormone, and prolactin The posterior pituitary hormone secretes antidiuretic hormone and oxytocin Epidemiology: The incidence is 1 in 4,000-1 in 10,000 The majority of CH cases are sporadic; however, a small number of familial cases have been identified In the latter, a molecular basis has frequently been identified Between 80-90% of CH cases remain unsolved in terms of molecular genetics Pathogenesis: Several transcription factors and signaling molecules are involved in the development of the pituitary gland Mutations in any of these genes may result in CH including HESX1, PROP1, POU1F1, LHX3, LHX4, SOX2, SOX3, OTX2, PAX6, FGFR1, GLI2, and FGF8 Over the last 5 years, several novel genes have been identified in association with CH, but it is likely that many genes remain to be identified, as the majority of patients with CH do not have an identified mutation Clinical manifestations: Genotype-phenotype correlations are difficult to establish There is a high phenotypic variability associated with different genetic mutations The clinical spectrum includes severe midline developmental disorders, hypopituitarism (in isolation or combined with other congenital abnormalities), and isolated hormone deficiencies Diagnosis and treatment: Key investigations include MRI and baseline and dynamic pituitary function tests However, dynamic tests of GH secretion cannot be performed in the neonatal period, and a diagnosis of GH deficiency may be based on auxology, MRI findings, and low growth factor concentrations Once a hormone deficit is confirmed, hormone replacement should be started If onset is acute with hypoglycaemia, cortisol deficiency should be excluded, and if identified this should be rapidly treated, as should TSH deficiency This review aims to give an overview of CH including management of this complex condition

Best Practice Recommendations for the Diagnosis and Management of Children With Pediatric Inflammatory Multisystem Syndrome Temporally Associated With SARS-CoV-2 (PIMS-TS;Multisystem Inflammatory Syndrome in Children, MIS-C) in Switzerland

Abstract: Background: Following the spread of the coronavirus disease 2019 (COVID-19) pandemic a new disease entity emerged, defined as Pediatric Inflammatory Multisystem Syndrome temporally associated with COVID-19 (PIMS-TS), or Multisystem Inflammatory Syndrome in Children (MIS-C). In the absence of trials, evidence for treatment remains scarce. Purpose: To develop best practice recommendations for the diagnosis and treatment of children with PIMS-TS in Switzerland. It is acknowledged that the field is changing rapidly, and regular revisions in the coming months are pre-planned as evidence is increasing. Methods: Consensus guidelines for best practice were established by a multidisciplinary group of Swiss pediatric clinicians with expertise in intensive care, immunology/rheumatology, infectious diseases, hematology, and cardiology. Subsequent to literature review, four working groups established draft recommendations which were subsequently adapted in a modified Delphi process. Recommendations had to reach >80% agreement for acceptance. Results: The group achieved agreement on 26 recommendations, which specify diagnostic approaches and interventions across anti-inflammatory, anti-infectious, and support therapies, and follow-up for children with suspected PIMS-TS. A management algorithm was derived to guide treatment depending on the phenotype of presentation, categorized into PIMS-TS with (a) shock, (b) Kawasaki-disease like, and (c) undifferentiated inflammatory presentation. Conclusion: Available literature on PIMS-TS is limited to retrospective or prospective observational studies. Informed by these cohort studies and indirect evidence from other inflammatory conditions in children and adults, as well as guidelines from international health authorities, the Swiss PIMS-TS recommendations represent best practice guidelines based on currently available knowledge to standardize treatment of children with suspected PIMS-TS. Given the absence of high-grade evidence, regular updates of the recommendations will be warranted, and participation of patients in trials should be encouraged.

The Use of Whole Genome and Exome Sequencing for Newborn Screening: Challenges and Opportunities for Population Health.

Abstract: Newborn screening (NBS) is a population-based program with a goal of reducing the burden of disease for conditions with significant clinical impact on neonates. Screening tests were originally developed and implemented one at a time, but newer methods have allowed the use of multiplex technologies to expand additions more rapidly to standard panels. Recent improvements in next-generation sequencing are also evolving rapidly from first focusing on individual genes, then panels, and finally all genes as encompassed by whole exome and genome sequencing. The intersection of these two technologies brings the revolutionary possibility of identifying all genetic disorders in newborns, allowing implementation of therapies at the optimum time regardless of symptoms. This article reviews the history of newborn screening and early studies examining the use of whole genome and exome sequencing as a screening tool. Lessons learned from these studies are discussed, along with technical, ethical, and societal challenges to broad implementation.

Type I Interferonopathies in Children: An Overview

Abstract: Notable advances in gene sequencing methods in recent years have permitted enormous progress in the phenotypic and genotypic characterization of autoinflammatory syndromes. Interferonopathies are a recent group of inherited autoinflammatory diseases, characterized by a dysregulation of the interferon pathway, leading to constitutive upregulation of its activation mechanisms or downregulation of negative regulatory systems. They are clinically heterogeneous, but some peculiar clinical features may lead to suspicion: a familial "idiopathic" juvenile arthritis resistant to conventional treatments, an early necrotizing vasculitis, a non-infectious interstitial lung disease, and a panniculitis associated or not with a lipodystrophy may represent the "interferon alarm bells." The awareness of this group of diseases represents a challenge for pediatricians because, despite being rare, a differential diagnosis with the most common childhood rheumatological and immunological disorders is mandatory. Furthermore, the characterization of interferonopathy molecular pathogenetic mechanisms is allowing important steps forward in other immune dysregulation diseases, such as systemic lupus erythematosus and inflammatory myositis, implementing the opportunity of a more effective target therapy.

Promoting and Protecting Human Milk and Breastfeeding in a COVID-19 World

Abstract: The global COVID-19 pandemic has put enormous stress on healthcare systems and hospital staffing. However, through all this, families will continue to become pregnant, give birth, and breastfeed. Unfortunately, care of the childbearing family has been de-prioritized during the pandemic. Additionally, many healthcare practices during the pandemic have not been positive for the childbearing family or breastfeeding. Despite recommendations from the World Health Organization to promote early, direct breastfeeding and skin to skin contact, these and other recommendations are not being followed in the clinical setting. For example, some mothers have been forced to go through labor and birth alone in some institutions whilst some hospitals have limited or no parental visitation to infants in the NICU. Furthermore, hospitals are discharging mothers and their newborns early, limiting the amount of time that families receive expert lactation care, education, and technical assistance. In addition, some hospitals have furloughed staff or transferred them to COVID-19 wards, further negatively impacting direct care for families and their newborns. We are concerned that these massive changes in the care of childbearing families will be permanently adopted. Instead, we must use the pandemic to underscore the importance of human milk and breastfeeding as lifesaving medical interventions. We challenge healthcare professionals to change the current prenatal and post-birth practice paradigms to protect lactation physiology and to ensure that all families in need receive equal access to evidence-based lactation education, care and technical assistance.

Disappearance of Seasonal Respiratory Viruses in Children Under Two Years Old During COVID-19 Pandemic: A Monocentric Retrospective Study in Milan, Italy.

Abstract: Background: The containment measures adopted during COVID-19 pandemic have influenced the epidemiology of other respiratory viruses. Aim: We analyzed the modification of the incidence and etiology of lower respiratory tract infections (LRTIs) in young children during COVID-19 pandemic. Methods: Case series of all children under 2 years old hospitalized at a tertiary care Hospital in the Center of Milan, Italy diagnosed with LRTIs in three consecutive winter seasons (from the 1st of November to the last day of February in 2018/2019, 2019/2020 and 2020/2021). We compared the number of hospitalizations and viral detections in the 2020/2021 with the average of 2018/2019 and 2019/2020 (pre-COVID-19) using the Poisson distribution. Results: we enrolled 178 patients (66 from 2018/2019, 96 from 2019/2020, 16 from 2020/2021) 94 males (53%) and 84 females (47%), with a median (IQR) age of 5 (2-13) months. The number of hospitalizations during the 2020/2021 season was 80% lower than the average of the pre-COVID-19 seasons (16 vs. 81, p<0.001). Overall, 171 (96%) patient's nasopharyngeal aspirate (NPA) detected at least one virus (110, 64%, single-detection, 61, 36%, co-detections). In 2020/2021 we observed the disappearance of Respiratory Syncytial virus (0 vs. 54, p < 0.001), Influenza virus (0 vs. 6.5, p = 0.002), Metapneumovirus (0 vs. 8, p < 0.001), Parainfluenza viruses (0 vs. 3.5, p = 0.03) and a significant reduction of Adenovirus (2 vs. 7, p = 0.03), Bocavirus (2 vs. 7.5, p = 0.02) and Enterovirus (1 vs. 5, p = 0.04). No significant difference was found for Rhinoviruses (14 cases vs. 17, p = 0.2), other Coronaviruses (0 vs. 2, p = 0.1), and Cytomegalovirus (1 vs. 1, p = 0.7). Conclusions: We observed a striking reduction in hospitalizations due to LRTIs and a modification of the etiology, with enveloped viruses mainly affected.

Association Between the COVID-19 Pandemic and Infant Neurodevelopment: A Comparison Before and During COVID-19.

Abstract: Aim: To investigate the association between the experience of the coronavirus disease 2019 (COVID-19) pandemic and neurodevelopment of 6-month-old and 1-year-old children and explore the differences in the association by birth order. Methods: This comparison study was embedded in the Born in Guangzhou Cohort Study in China. The exposed group included 546 6-month-old and 285 1-year-old children who attended neurodevelopment assessments between March 1 and May 15, 2020, and the non-exposed group included 3,009 6-month-old and 2,214 1-year-old children during the same months from 2015 to 2019. Neurodevelopment at age 6 months and 1 year was assessed by trained clinical staff using the Ages and Stages Questionnaires, third edition (ASQ-3) and the Gesell Developmental Schedules (GDS). Results: The experience of the pandemic in 2020 was associated with a higher risk of delay in the fine motor (adjusted OR: 2.50, 95% CI: 1.25, 4.99; estimated by logistic regression) and communication (adjusted RR [aRR]: 1.13, 95% CI: 1.02, 1.25; estimated by log-binomial regression) domains at age 1 year. The association between the experience of the pandemic and communication delay at age 1 year only existed in first-born children (aRR: 1.15, 95% CI: 1.03, 1.30) but not in later-born children (aRR: 1.02, 95% CI: 0.84, 1.25). No associations were observed in any domain among 6-month-olds. Conclusion: Experiencing the COVID-19 pandemic and related public health strategies might be associated with a higher risk of delay in the development of fine motor and communication in 1-year-old children; the association observed in the communication domain only existed in first-born children.

Barriers and Facilitators for Implementing Paediatric Telemedicine: Rapid Review of User Perspectives

Abstract: Background: COVID-19 has brought to the fore an urgent need for secure information and communication technology (ICT) supported healthcare delivery, as the pertinence of infection control and social distancing continues. Telemedicine for paediatric care warrants special consideration around logistics, consent and assent, child welfare and communication that may differ to adult services. There is no systematic evidence synthesis available that outlines the implementation issues for incorporating telemedicine to paediatric services generally, or how users perceive these issues. Methods: We conducted a rapid mixed-methods evidence synthesis to identify barriers, facilitators, and documented stakeholder experiences of implementing paediatric telemedicine, to inform the pandemic response. A systematic search was undertaken by a research librarian in MEDLINE for relevant studies. All identified records were blind double-screened by two reviewers. Implementation-related data were extracted, and studies quality appraised using the Mixed-Methods Appraisal Tool. Qualitative findings were analysed thematically and then mapped to the Consolidated Framework for Implementation Research. Quantitative findings about barriers and facilitators for implementation were narratively synthesised. Results: We identified 27 eligible studies (19 quantitative; 5 mixed-methods, 3 qualitative). Important challenges highlighted from the perspective of the healthcare providers included issues with ICT proficiency, lack of confidence in the quality/reliability of the technology, connectivity issues, concerns around legal issues, increased administrative burden and/or fear of inability to conduct thorough examinations with reliance on subjective descriptions. Facilitators included clear dissemination of the aims of ICT services, involvement of staff throughout planning and implementation, sufficient training, and cultivation of telemedicine champions. Families often expressed preference for in-person visits but those who had tried tele-consultations, lived far from clinics, or perceived increased convenience with technology considered telemedicine more favourably. Concerns from parents included the responsibility of describing their child's condition in the absence of an in-person examination. Discussion: Healthcare providers and families who have experienced tele-consultations generally report high satisfaction and usability for such services. The use of ICT to facilitate paediatric healthcare consultations is feasible for certain clinical encounters and can work well with appropriate planning and quality facilities in place.

Impact of Probiotic B. infantis EVC001 Feeding in Premature Infants on the Gut Microbiome, Nosocomially Acquired Antibiotic Resistance, and Enteric Inflammation.

Abstract: Background: Preterm birth is a major determinant of neonatal survival and morbidity, but the gut microbiome and associated enteric inflammation are also key factors in neonatal development and the risk of associated morbidities. We prospectively and longitudinally followed two cohorts of preterm infants, one of which was fed activated Bifidobacterium longum subsp. infantis (B. infantis) EVC001 8 × 109 CFU daily, and the other was not fed a probiotic. Hospital feeding protocol assigned all infants born at 1500 g and/or >32 weeks corrected gestational age were not fed a probiotic. Fecal samples were opportunistically collected from 77 infants throughout the hospital stay, and subjected to shotgun metagenomic sequencing and quantification of enteric inflammation. De-identified metadata was collected from patient medical records. Results: The gut microbiome of preterm infants was typified by a high abundance of Enterobacteriaceae and/or Staphylococcaceae, and multivariate modeling identified the probiotic intervention, rather than degree of prematurity, day of life, or other clinical interventions, as the primary source of change in the gut microbiome. Among infants fed B. infantis EVC001, a high abundance of total Bifidobacteriaceae developed rapidly, the majority of which was B. infantis confirmed via subspecies-specific qPCR. Associated with this higher abundance of Bifidobacteriaceae, we found increased functional capacity for utilization of human milk oligosaccharides (HMOs), as well as reduced abundance of antibiotic resistance genes (ARGs) and the taxa that harbored them. Importantly, we found that infants fed B. infantis EVC001 exhibited diminished enteric inflammation, even when other clinical variables were accounted for using multivariate modeling. Conclusion: These results provide an important observational background for probiotic use in a NICU setting, and describe the clinical, physiological, and microbiome-associated improvements in preterm infants associated with B. infantis EVC001 feeding.

Antimicrobial Resistance Analysis of Clinical Escherichia coli Isolates in Neonatal Ward.

Abstract: Background: Escherichia coli (E. coli) column for one of the most common pathogens causing neonatal infections. The emergence of antibiotic-resistant bacteria is a major cause of treatment failure in infected newborns. The purpose of this study was to describe antibiotic and multidrug resistance of E. coli strains isolated from neonates with infection throughout the years 2009-2011. Methods: The antimicrobial susceptibility testing of E. coli strains to selected antibiotics was assessed using the E-test technique on the Mueller-Hinton agar. The antimicrobial tests included ceftazidime, cefuroxime, cefatriaxone, amoxicillin, amoxicillin-clavulanic acid, cefoperazone- sulbactam, meropenem, gentamicin, ciprofloxacin, and sulfonamides. Results: A total of 100 E. coli strains were isolated from sputum (n = 78), blood (n = 10), cerebrospinal fluid (n = 5), and umbilical discharge (n = 7) samples of hospitalized neonates at the Beijing Children's Hospital. The highest rate of E. coli resistance was found in amoxicillin (85%), followed by cefuroxime (65%), and cefatriaxone (60%), respectively. A total of 6 and 5% of all isolates were only resistant to amoxicillin/clavulanic acid and cefoperazone -sulbactam. The rates of resistance to ceftazidime, gentamicin, ciprofloxacin, and sulfonamides were 31, 20, 33, and 47%, respectively. All isolates were susceptible to meropenem. Approximately 26% of all E. coli isolates were multidrug-resistant. The detection rate of ESBL-Producing E. coli was 55%. Conclusions: Multi-drug-resistant E. coli has become an important and complex problem in clinical treatment, and it is thus essential to monitor E. coli resistance in neonates.

Adolescent Vision Health During the Outbreak of COVID-19: Association Between Digital Screen Use and Myopia Progression

Abstract: The coronavirus (COVID-19) pandemic has impacted education systems globally, making digital devices common arrangements for adolescent learning. However, vision consequences of such behavioral changes are not well-understood. This study investigates the association between duration of daily digital screen engagement and myopic progression among 3,831 Chinese adolescents during the COVID-19 pandemic. Study subjects report an average of 2.70 (SD = 1.77), 3.88 (SD = 2.23), 3.58 (SD = 2.30), and 3.42 (SD = 2.49) hours of television, computer, and smartphone for digital learning use at home, respectively. Researchers analyzed the association between digital screen use and myopic symptoms using statistical tools, and find that every 1 h increase in daily digital screen use is associated with 1.26 OR [Odds Ratio] (95% CI [Confidence Interval: 1.21-1.31, p < 0.001]) higher risks of myopic progression. Using computers (OR = 1.813, 95% CI = 1.05-3.12, p = 0.032) and using smartphones (OR = 2.02, 95% CI = 1.19-3.43, p = 0.009) are shown to be associated with higher risks of myopic progression than television use. Results from additional sensitivity tests that included inverse probability weights which accounted for heterogeneous user profile across different device type categories confirm that these findings are robust. In conclusion, this study finds that daily digital screen use is positively associated with prevalence of myopic progression and holds serious vision health implications for adolescents.

Intra-Household and Close-Contact SARS-CoV-2 Transmission Among Children - a Systematic Review

Abstract: Introduction: The outbreak of the novel coronavirus disease (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to a range of emergency measures worldwide. Early in the pandemic, children were suspected to act as drivers of the COVID-19 spread in the population, which was based on experiences with influenza virus and other respiratory pathogens. Consequently, closures of schools and kindergartens were implemented in many countries around the world, alongside with other non-pharmaceutical interventions for transmission control. Given the grave and multifaceted consequences of contact restriction measures for children, it is crucial to better understand the effect size of these incisive actions for the COVID-19 pandemic. Therefore, we systematically review the current evidence on transmission of SARS-CoV-2 to and by children. Data Sources: PubMed and preprints uploaded on medRxiv. Study Selection: Original research articles, case reports, brief communications, and commentaries were included into the analysis. Each title or abstract was independently reviewed to identify relevant articles. Studies in other languages than English were not included. Data Extraction: Two reviewers independently reviewed the selected studies. Extracted data included citation of each study, type of healthcare setting, location of the study, characteristics of patient population, and reported outcomes. Results: Data on transmission of SARS-CoV-2 on or by children is scarce. Several studies show a lower seropositivity of children compared to adults, suggesting a lower susceptibility of especially younger children. Most insight currently comes from household studies suggesting, that children are predominantly infected by their household contacts. The contagiousness however, seems to be comparable between children and adults, based on our meta-analysis of included studies. Conclusions: Larger and systematic studies are urgently needed to better understand the age dependent patterns of SARS-CoV-2 transmission and thereby design more effective non-pharmaceutical interventions to reduce disease transmission.

Evolution of Our Understanding of XIAP Deficiency

Abstract: X-linked inhibitor of apoptosis (XIAP) deficiency is a rare inborn error of immunity first described in 2006. XIAP deficiency is characterised by immune dysregulation and a broad spectrum of clinical manifestations, including haemophagocytic lymphohistiocytosis (HLH), inflammatory bowel disease (IBD), hypogammaglobulinemia, susceptibility to infections, splenomegaly, cytopaenias, and other less common autoinflammatory phenomena. Since the first description of the disease, many XIAP deficient patients have been identified and our understanding of the disease has grown. Over 90 disease causing mutations have been described and more inflammatory disease manifestations, such as hepatitis, arthritis, and uveitis, are now well-recognised. Recently, following the introduction of reduced intensity conditioning (RIC), outcomes of allogeneic haematopoietic stem cell transplantation (HSCT), the only curative treatment option for XIAP deficiency, have improved. The pathophysiology of XIAP deficiency is not fully understood, however it is known that XIAP plays a role in both the innate and adaptive immune response and in immune regulation, most notably through modulation of tumour necrosis factor (TNF)-receptor signalling and regulation of NLRP3 inflammasome activity. In this review we will provide an up to date overview of both the clinical aspects and pathophysiology of XIAP deficiency.

COVID-19 Pandemic Impact on Respiratory Infectious Diseases in Primary Care Practice in Children.

Abstract: Background: The coronavirus disease 2019 (COVID-19) pandemic led to day care and school closures and children staying home for several months. When they gradually returned, aggressive regulations were implemented in New York State to reduce viral transmission. Method: An ongoing prospective study occurring in the Rochester, NY region, focused on early childhood respiratory infectious diseases, afforded an opportunity to assess the impact of the pandemic on the incidence of these illnesses in a primary care outpatient setting. Physician-diagnosed, medically attended infection visits were assessed in two child cohorts, age 6-36 months old: from March 15 to December 31, 2020 (the pandemic period) compared to the same months in 2019 (prepandemic). Nasopharyngeal colonization by potential otopathogens during healthy/well-child and acute otitis media (AOM) visits was evaluated. Results: One hundred and forty-four children were included in the pandemic cohort and 215 in the prepandemic cohort. The pandemic cohort of children experienced 1.8-fold less frequent infectious disease visits during the pandemic (p < 0.0001). Specifically, visits for AOM were 3.7-fold lower (p < 0.0001), viral upper respiratory infections (URI) 3.8-fold lower (p < 0.0001), croup 27.5-fold lower (p < 0.0001), and bronchiolitis 7.4-fold lower (p = 0.04) than the prepandemic cohort. Streptococcus pneumoniae (p = 0.03), Haemophilus influenzae (p < 0.0001), and Moraxella catarrhalis (p < 0.0001) nasopharyngeal colonization occurred less frequently among children during the pandemic. Conclusion: In primary care pediatric practice, during the first 9 months of the COVID-19 pandemic, significant decreases in the frequency of multiple respiratory infections and nasopharyngeal colonization by potential bacterial respiratory pathogens occurred in children age 6-36 months old.

Red Blood Cell Contribution to Hemostasis

Abstract: Red Blood Cells (RBCs) have been increasingly recognized to play important roles in hemostasis and the mechanisms by which they do so continue to be elucidated. First and foremost, RBC biomechanics are the principal determinant of viscosity and flow dynamics of blood, which strongly influence all features of hemostasis. Of note, morphologic pathology, such as that found in sickle cell disease, leads to increased risk of thrombotic disease. RBC surface interactions govern signaling between platelets and RBCs and also aid in the conversion of prothrombin to thrombin. Additionally, RBCs generate microparticles which have been shown to reduce clotting time. Finally, blood clot structure and maturation are dependent on the inclusion of RBCs in forming thrombi. Here, we review the above mechanisms of RBC contribution to hemostasis.

Case Report: Neonatal Multi-System Inflammatory Syndrome Associated With SARS-CoV-2 Exposure in Two Cases From Saudi Arabia

Abstract: Background: Vertical transmission of SARS-CoV-2 is under investigation. A few reports suggest the possibility of SARS-CoV-2 transmission from mothers to their neonates. Most neonates have mild symptoms, but some develop multisystem involvement and shock. Case Presentation: We report two cases of possible SARS-CoV-2 vertical transmission from mothers to their neonates. The first case shows maternal infection with SARS-CoV-2 in the second trimester followed by recurrent infection in the third trimester right before the delivery. The infant demonstrated respiratory distress soon after delivery along with myocardial dysfunction and multi-organ system involvement. The second case shows maternal infection with SARS-COV-2 at the time of delivery with preterm labor secondary to placental abruption, with that delivery resulting in the preterm neonate requiring non-invasive ventilation with multisystem involvement in the context of persistently positive SARS-COV-2 PCR in the neonate. Both neonates were treated with IVIG along with steroids. Both neonates recovered fully and were discharged and allowed to go home. Conclusion: In neonates, COVID-19 usually presents as an asymptomatic or mild illness; some may develop a more severe course. Our two cases, however, demonstrate that multisystem involvement, although rare, is possible. This report also supports the current evidence of possible vertical transmission from mothers to their neonates. This multisystem involvement might be underreported and should be considered in neonates with respiratory distress when born to mothers suffering of COVID-19. Clinical Trial Registration: [KSUMC], identifier [No#98763298].

"The First Thousand Days" Define a Fetal/Neonatal Neurology Program.

Abstract: Gene-environment interactions begin at conception to influence maternal/placental/fetal triads, neonates, and children with short- and long-term effects on brain development. Life-long developmental neuroplasticity more likely results during critical/sensitive periods of brain maturation over these first 1,000 days. A fetal/neonatal program (FNNP) applying this perspective better identifies trimester-specific mechanisms affecting the maternal/placental/fetal (MPF) triad, expressed as brain malformations and destructive lesions. Maladaptive MPF triad interactions impair progenitor neuronal/glial populations within transient embryonic/fetal brain structures by processes such as maternal immune activation. Destructive fetal brain lesions later in pregnancy result from ischemic placental syndromes associated with the great obstetrical syndromes. Trimester-specific MPF triad diseases may negatively impact labor and delivery outcomes. Neonatal neurocritical care addresses the symptomatic minority who express the great neonatal neurological syndromes: encephalopathy, seizures, stroke, and encephalopathy of prematurity. The asymptomatic majority present with neurologic disorders before 2 years of age without prior detection. The developmental principle of ontogenetic adaptation helps guide the diagnostic process during the first 1,000 days to identify more phenotypes using systems-biology analyses. This strategy will foster innovative interdisciplinary diagnostic/therapeutic pathways, educational curricula, and research agenda among multiple FNNP. Effective early-life diagnostic/therapeutic programs will help reduce neurologic disease burden across the lifespan and successive generations.