SARS-CoV-2-specific mucosal immune response in vaccinated versus infected children.

The anti-COVID-19 intramuscular vaccination induces a strong systemic but a weak mucosal immune response in adults. Little is known about the mucosal immune response in children infected or vaccinated against SARS-CoV-2. We found that 28% of children had detectable salivary IgA against SARS-CoV-2 even before vaccination, suggesting that, in children, SARS-CoV-2 infection may be undiagnosed. After vaccination, only receptor-binding domain (RBD)-specific IgA1 significantly increased in the saliva. Conversely, infected children had significantly higher salivary RBD-IgA2 compared to IgA1, indicating that infection more than vaccination induces a specific mucosal immune response in children. Future efforts should focus on development of vaccine technologies that also activate mucosal immunity.

Respiratory Syncytial Virus Bronchiolitis Before and After COVID-19 Pandemic: Has the Immunity Debt Been Paid Off?

BACKGROUND: Our aim was to hypothesize that the COVID-19 pandemic influenced the characteristics of viral bronchiolitis by comparing the last 3 epidemics with 3 pre-COVID-19 epidemics in infants hospitalized with bronchiolitis. METHODS: We prospectively enrolled 637 consecutive infants (median age 3.0 ± 2.1 months, 58.5% males), hospitalized for bronchiolitis during 6 consecutive annual epidemic seasons from 2017 to 2023. All parents of the children were given a structured anamnestic questionnaire. A nasopharyngeal aspirate was tested for 15 respiratory viruses. As measures of severity, we evaluated the O2 supplementation and the admission at the pediatric intensive care unit. RESULTS: A total of 166 were hospitalized with bronchiolitis in 2017-2018, 97 in 2018-2019, 69 in 2019-2020, 0 in 2020-2021, 129 in 2021-2022 and 176 in 2022-2023. Taking together the 332 bronchiolitis cases hospitalized during the 3 prepandemic seasons, they peaked between December and January; after the flat curve in 2020-2021, the cases of bronchiolitis peaked in November 2021 and in December 2022. While the 2021-2022 season registered a less severe clinical presentation, O2 supplementation and pediatric intensive care unit admissions increased in 2022-2023 with respect to the prepandemic seasons (P < 0.001). CONCLUSIONS: This study represents an important scientific demonstration of the impact of primary prevention measures on the epidemiology of viral infections; their fluctuations were related to the intensity of restrictive measures and to the changing trend of respiratory viruses. It is essential to predict the real temporal trend of bronchiolitis in order not to leave high-risk children uncovered and to guide hospitals to maintain a high level of readiness.

Age-related transcript changes in type I interferon signaling in children and adolescents with long COVID.

SARS-CoV-2 typically causes mild symptoms in children, but evidence suggests that persistent immunopathological changes may lead to long COVID (LC). To explore the interplay between LC and innate immunity, we assessed the type I interferon (IFN-I) response in children and adolescents with LC symptoms (LC; n = 28). This was compared with age-matched SARS-CoV-2 recovered participants without LC symptoms (MC; n = 28) and healthy controls (HC; n = 18). We measured the mRNA expression of IFN-I (IFN-α/ß/ε/ω), IFN-I receptor (IFNAR1/2), and ISGs (ISG15, ISG56, MxA, IFI27, BST2, LY6E, OAS1, OAS2, OAS3, and MDA5) in PBMCs collected 3-6 months after COVID-19. LC adolescents (12-17 years) had higher transcript levels of IFN-ß, IFN-ε, and IFN-ω than HC, whereas LC children (6-11 years) had lower levels than HC. In adolescents, increased levels of IFN-α, IFN-ß, and IFN-ω mRNAs were found in the LC group compared with MC, while lower levels were observed in LC children than MC. Adolescents with neurological symptoms had higher IFN-α/ß mRNA levels than MC. LC and MC participants showed decreased expression of ISGs and IFNAR1, but increased expression of IFNAR2, than HC. Our results show age-related changes in the expression of transcripts involved in the IFN-I signaling pathway in children and adolescents with LC.

Acute Bronchiolitis: The Less, the Better?

BACKGROUND: Acute bronchiolitis is a viral infection of the lower respiratory tract affecting infants aged under 12 months, variably presenting with respiratory distress, diffuse crackles and inflammatory wheezing. The main causative agent is Respiratory Syncytial Virus (RSV). The diagnosis is clinical and treatment mainly supportive. Despite the availability of more than 30 international guidelines, consistent management recommendations are lacking and considerable variability in patients' care persists among different providers. OBJECTIVE: To review and describe current knowledge about epidemiology, physiopathology, clinic, diagnosis and management of acute bronchiolitis, with particular emphasis on updated evidence and future perspectives in terms of treatment and prevention. METHODS AND RESULTS: We searched Cochrane for systematic reviews and PubMed for scientific articles published in the last 10 years, using a combination of the following search terms: "bronchiolitis", "respiratory syncytial virus", "epidemiology", "risk factors", "severity", "diagnosis", "clinic", "diagnostic imaging", "management", "asthma", "wheezing", "bronchodilator", "steroids", "hypertonic saline", "oxygen", "blood gas analysis", "HHHFNC", "rehydration", "enteral feeding", "parenteral hydration", "prevention", "vaccine" and "COVID-19 or SARS-CoV2". We accordingly performed a deep and extensive selection of the most updated and considerable literature on the matter, summarizing the most significant evidence concerning all aspects of acute bronchiolitis (epidemiology, clinic, diagnosis, management and prevention). Furthermore, we examined references and available guidelines from UK, USA, Canada, Italy and Spain. Results are extensively discussed below. CONCLUSION: Although acute bronchiolitis has been a widely known disease for decades, its therapeutic approach remained unchanged and essentially limited to respiratory and metabolic support. Despite the abundance of studies, there is no significant evidence concerning therapeutic alternatives (e.g. steroids, inhaled hypertonic solution), which are therefore not recommended. According to most recent data, "acute bronchiolitis" definition encompasses a plethora of different clinical entities related to each subject's genetic and immune predisposition. Therefore, future research should focus on the precise characterization of such subcategories in order to individualize therapeutic management and ensure the most appropriate evidence-based care.

A core outcome set for bronchiectasis in children and adolescents for use in clinical research: an international consensus study.

Improving the treatment of non-cystic fibrosis bronchiectasis in children and adolescents requires high-quality research with outcomes that meet study objectives and are meaningful for patients and their parents and caregivers. In the absence of systematic reviews or agreement on the health outcomes that should be measured in paediatric bronchiectasis, we established an international, multidisciplinary panel of experts to develop a core outcome set (COS) that incorporates patient and parent perspectives. We undertook a systematic review from which a list of 21 outcomes was constructed; these outcomes were used to inform the development of separate surveys for ranking by parents and patients and by health-care professionals. 562 participants (201 parents and patients from 17 countries, 361 health-care professionals from 58 countries) completed the surveys. Following two consensus meetings, agreement was reached on a ten-item COS with five outcomes that were deemed to be essential: quality of life, symptoms, exacerbation frequency, non-scheduled health-care visits, and hospitalisations. Use of this international consensus-based COS will ensure that studies have consistent, patient-focused outcomes, facilitating research worldwide and, in turn, the development of evidence-based guidelines for improved clinical care and outcomes. Further research is needed to develop validated, accessible measurement instruments for several of the outcomes in this COS.

Investigating the Relationship Between COVID-19 and Celiac Disease. A Dual Research Approach.

Background: Most evidence on the coronavirus disease 2019 (COVID-19) pandemic, has been obtained from web- or telephone-based surveys. In particular, few laboratory data, often incomplete, have been reported on the frequency of COVID-19-related serology at celiac disease (CD) diagnosis or on the effects of COVID-19 on the development of CD-specific autoimmunity. Objectives: The objective of this retrospective cross-sectional case/control study was to: (1) evaluate the frequency of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies in 78 children and adolescents at CD diagnosis (CD, 44 females, median age 7.4 years); (2) evaluate the frequency of IgA-anti-transglutaminase antibodies (IgA-tTGAbs) in 97 nonceliac patients (50 females, median age 9.0 years) who contracted SARS-CoV-2 infection during the pandemic (February-April 2021). As a control (CTRL) group, we analyzed 141 healthy subjects (79 females, median age 9.8 years) enrolled during the pandemic. Methods: SARS-CoV-2 IgM- and IgG-antibodies were detected by chemiluminescent microparticle immunoassays. IgA-tTGAbs were detected by a fluid-phase radioimmunoassay. Results: Six out of 78 (7.7%) CD patients tested positive for SARS-CoV-2Abs, with a frequency not significantly different from CTRL subjects (9.2%). None of the 97 nonceliac COVID-19 patients tested positive for IgA-tTG antibodies. Conclusion: These 2 distinct research approaches showed (1) similar frequencies of SARS-CoV-2 immunoreactivities in CD patients and CTRL subjects and, (2) no ability of SARS-CoV-2 to induce a CD-specific immune response, at least in the 3-4 months following SARS-CoV-2 infection.

Acute Pupillary Disorders in Children: A 10-Year Retrospective Study of 101 Patients.

BACKGROUND: To date, no study has specifically examined children with acute-onset pupillary motility disorders (APMD). Especially in the Emergency Department (ED), it is crucial to distinguish benign and transient conditions from life-threatening or urgent conditions (UCs). The aim of the study is to describe the clinical characteristics of children with APMD and their association with an increased risk of UCs. METHODS: We conducted a pediatric retrospective study of APMD referred to ED over a 10-year period. We described the characteristics in the overall sample and in two subgroups divided according to urgency of the underlying condition. Furthermore, we applied a logistic regression model to identify the variables predictive of LT condition. RESULTS: We analyzed 101 patients. In 59.4%, the APMD was isolated. In patients with extra-ocular involvement, the most frequently associated features were altered consciousness, headache, and vomiting. Exposure to toxic agents was reported in 48.5%. Urgent conditions occurred significantly more frequently in older children, presenting bilateral APMD and/or other ocular or extra-ocular manifestations. CONCLUSIONS: Our study shows that UCs most commonly occur in patients presenting with bilateral APMD and other associated features. In unilateral/isolated APMD ophthalmological examination, exclusion of toxic exposure and observation until resolution of symptoms should be recommended.

A Single Center Observational Study on Clinical Manifestations and Associated Factors of Pediatric Long COVID.

Children with SARS-CoV-2 are mostly mild symptomatic, but they may develop conditions, such as persisting symptoms, that may put them at greater risk of complications. Our aim was to evaluate the frequency and the presence of risk factors for persisting COVID-19 symptoms in children. We carried out a prospective observational study of the clinical manifestation of Long COVID at the Department of Maternal Infantile Science of a tertiary University hospital in Rome. We included 697 children (0-18 years), with previous SARS-CoV-2 infection. Children and parents were asked questions regarding persistent symptoms of COVID-19. Children with symptoms 30 days after initial diagnosis were 185/697 (26.4%). Moreover, 81/697 (11.6%) patients presented symptoms 90 days after the diagnosis. Thirty-day-persisting symptoms were mostly present in children with anosmia, atopy, asthenia, and cough in the acute phase compared with the asymptomatic children 30 days after infection. After 90 days, symptoms described were mainly neurological (47/697 children, 6.7%), and headache (19/697; 2.7%) was the most frequent manifestation. In conclusion, a relatively large proportion of the patients reported persisting symptoms that seem to be related to the symptom burden and to the atopy. Ninety days after the infection, most of the children had recovered, showing that long-term effects are not frequent. Limitations of the study include the single-center design and the lack of a control group.

No effects of COVID-19 on the development of type 1 diabetes autoimmunity and no evidence of an increased frequency of SARS-CoV-2 antibodies in newly diagnosed type 1 diabetes patients relative to healthy subjects.

AIMS: To evaluate the relationship between SARS-CoV-2 infection and autoimmunity in type 1 diabetes (T1D) and SARS-CoV-2 antibodies frequency at diagnosis of T1D during pandemic. METHODS: The presence of T1D-specific autoimmunity was evaluated in a cohort of 99 children and adolescents without diabetes that contracted SARS-CoV-2 infection. Moreover, the frequency of IgM- and IgG-SARS-CoV-2 antibodies was evaluated in 41 newly diagnosed T1D patients not yet vaccinated against SARS-CoV-2 disease, collected during the pandemic, compared to healthy subjects (CTRL). RESULTS: None of the 99 patients that contracted SARS-CoV-2 infection during the pandemic period was found positive for T1D autoantibodies. The frequency of SARS-CoV-2 antibodies was not significantly different in patients newly diagnosed with T1D (12.2%), compared with CTRL (8.4%). Among SARS-CoV-2 antibody positive T1D patients, 80% were target of diabetes autoantibodies and 60% had another concomitant autoimmune disease. Among the CTRL subjects positive for SARS-CoV-2Abs (n = 10), none was found positive for T1D autoantibodies. CONCLUSIONS: The results of the present study do not confirm, at least in the short term, a role of COVID-19 as a potential trigger of T1D autoimmunity and do not provide evidence of an increased frequency of SARS-CoV-2 antibodies in newly diagnosed T1D patients in comparison with healthy population.

Immunization technologies: Time to consider new preventative solutions for respiratory syncytial virus infections.

New technologies for the prevention of infectious diseases are emerging to address unmet medical needs, in particular, the use of long-acting monoclonal antibodies (mAb) to prevent Respiratory Syncytial Virus (RSV) lower respiratory tract disease in infants during their first RSV season. The lack of precedent for mAbs for broad population protection creates challenges in the assessment of upcoming prophylactic long-acting mAbs for RSV, with associated consequences in legislative and registration categorization, as well as in recommendation, funding, and implementation pathways. We suggest that the legislative and regulatory categorization of preventative solutions should be decided by the effect of the product in terms of its impact on the population and health-care systems rather than by the technology used or its mechanism of action. Immunization can be passive and active, both having the same objective of prevention of infectious diseases. Long-acting prophylactic mAbs work as passive immunization, as such, their recommendations for use should fall under the remit of National Immunization Technical Advisory Groups or other relevant recommending bodies for inclusion into National Immunization Programs. Current regulations, policy, and legislative frameworks need to evolve to embrace such innovative preventative technologies and acknowledge them as one of key immunization and public health tools.

Lung function after SARS-CoV-2 infection: A prospective cohort study in children.

INTRODUCTION: Although impaired lung function after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been described in adults, it is unclear whether lung function might be altered in children, especially among asymptomatic or mildly symptomatic patients. In this study, we report the results of lung function testing performed after SARS-CoV-2 infection in a large pediatric population. METHODS: The study included 589 patients with previous confirmed SARS-CoV-2 infection aged 0-18 years. Both symptomatic and asymptomatic patients during acute infection were enrolled in the study. A spirometry was performed in all cooperating patients. RESULTS: The mean age of enrolled patients was 9.6 years and the mean time from infection to enrollment was 171 days. Spirometry was performed and deemed evaluable in 433 patients. No patient had reduced forced vital capacity (FVC) and only 14 patients (3.2%) had a forced expiratory volume in the First second (FEV1) < 80%. The mean spirometry values recorded were in the normal range. There were no statistically significant differences in spirometry values between patients with respiratory symptoms during infection and those without. Similarly, there were no differences in spirometry parameters according to the time elapsed between infection and enrollment. CONCLUSION: Lung function, according to spirometry values, does not appear to be impaired long after infection in the pediatric population. The presence of respiratory symptoms during SARS-CoV-2 infection would not represent a risk factor for impaired lung function in this cohort of patients.

NRF2 Antioxidant Response and Interferon-Stimulated Genes Are Differentially Expressed in Respiratory-Syncytial-Virus- and Rhinovirus-Infected Hospitalized Children.

Respiratory diseases caused by respiratory syncytial virus (RSV) and human rhinovirus (HRV) are frequent causes of the hospitalization of children; nonetheless, RSV is responsible for the most severe and life-threatening illnesses. Viral infection triggers an inflammatory response, activating interferon (IFN)-mediated responses, including IFN-stimulated genes (ISG) expression with antiviral and immunomodulatory activities. In parallel, the reactive oxygen species (ROS) production activates nuclear factor erythroid 2-related factor 2 (NRF2), whose antioxidant activity can reduce inflammation by interacting with the NF-kB pathway and the IFN response. To clarify how the interplay of IFN and NRF2 may impact on clinical severity, we enrolled children hospitalized for bronchiolitis and pneumonia, and measured gene expression of type-I and III IFNs, of several ISGs, of NRF2 and antioxidant-related genes, i.e., glucose-6-phosphate dehydrogenase (G6PD), heme oxygenase 1 (HO1), and NAD(P)H dehydrogenase [Quinone] 1 (NQO1) in RSV- (RSV-A N = 33 and RSV-B N = 30) and HRV (N = 22)-positive respiratory samples. NRF2 and HO1 expression is significantly elevated in children with HRV infection compared to RSV (p = 0.012 and p = 0.007, respectively), whereas ISG15 and ISG56 expression is higher in RSV-infected children (p = 0.016 and p = 0.049, respectively). Children admitted to a pediatric intensive care unit (PICU) had reduced NRF2 expression (p = 0.002). These data suggest, for the first time, that lower activation of the NRF2 antioxidant response in RSV-infected infants may contribute to bronchiolitis severity.

Case report: A case of acute disseminated encephalomyelitis after SARS-CoV-2 infection in pediatric patients.

Introduction: Since the beginning, there has been enough evidence about the multi-systematic involvement of the coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Recent observations have revealed that, together with others, typical neurological manifestations are also associated with COVID-19 infection. In the first 2 years, children accounted for a few percent of cases, but with the emergence of the Omicron variant, the number of cases in the pediatric population has increased. It has been described that ~5% of the affected population suffered from severe neurological complications, such as seizure, coma, encephalitis, demyelinating disorders, and aseptic meningitis. Acute disseminated encephalomyelitis (ADEM) is an inflammatory demyelinating disease of the central nervous system. Typically, it presents in childhood and occurs 1 or 2 weeks after infection or vaccination. Case presentation: We present the case of a 12-year-old boy who developed ADEM, 10 days after an asymptomatic SARS-CoV-2 infection. Neurological symptoms began with headache, fever, irritability, paraplegia, and loss of sensitivity from the T1 level. The diagnosis of ADEM was confirmed by the typical signs found on brain MRI, whereas spinal cord MRI showed signs of transverse myelitis. The cerebrospinal fluid (CSF) testing excluded infections and did not reveal oligoclonal antibody bands (anti-MOG-negative and anti-AQP-negative). High-dose steroids (30 mg/kg/day) and IVIG (2 g/kg) were administered to the patient without any clinical improvement. The patient received a cycle of plasma exchange therapy, followed by rituximab infusion, with partial improvement. After 3 months, the magnetic resonance imaging (MRI) results demonstrated radiological improvement in accordance with the ADEM diagnosis. Conclusion: This clinical case confirms that SARS-CoV-2 infections are increasingly implicated in severe neurological consequences in both adult and pediatric patients. While the most frequent complications that were reported in children included headache, altered mental status, and encephalopathy, ~5% of the individuals suffered from severe neurological complications, leading to lifelong sequelae. All physicians must be aware of these data and detect neurological signs of severe (or not) complications that require a specific follow-up and treatment.

UPDATE - 2022 Italian guidelines on the management of bronchiolitis in infants.

Bronchiolitis is an acute respiratory illness that is the leading cause of hospitalization in young children. This document aims to update the consensus document published in 2014 to provide guidance on the current best practices for managing bronchiolitis in infants. The document addresses care in both hospitals and primary care. The diagnosis of bronchiolitis is based on the clinical history and physical examination. The mainstays of management are largely supportive, consisting of fluid management and respiratory support. Evidence suggests no benefit with the use of salbutamol, glucocorticosteroids and antibiotics with potential risk of harm. Because of the lack of effective treatment, the reduction of morbidity must rely on preventive measures. De-implementation of non-evidence-based interventions is a major goal, and educational interventions for clinicians should be carried out to promote high-value care of infants with bronchiolitis. Well-prepared implementation strategies to standardize care and improve the quality of care are needed to promote adherence to guidelines and discourage non-evidence-based attitudes. In parallel, parents' education will help reduce patient pressure and contribute to inappropriate prescriptions. Infants with pre-existing risk factors (i.e., prematurity, bronchopulmonary dysplasia, congenital heart diseases, immunodeficiency, neuromuscular diseases, cystic fibrosis, Down syndrome) present a significant risk of severe bronchiolitis and should be carefully assessed. This revised document, based on international and national scientific evidence, reinforces the current recommendations and integrates the recent advances for optimal care and prevention of acute bronchiolitis.

An overview on viral interference during SARS-CoV-2 pandemic.

Respiratory viruses represent the most frequent cause of mortality, morbidity and high healthcare costs for emergency visits and hospitalization in the pediatric age. Respiratory viruses can circulate simultaneously and can potentially infect the same host, determining different types of interactions, the so-called viral interference. The role of viral interference has assumed great importance since December 2019, when the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) came on the scene. The aim of this narrative review is to present our perspective regarding research in respiratory virus interference and discuss recent advances on the topic because, following SARS-CoV-2 restrictions mitigation, we are experimenting the co-circulation of respiratory viruses along with SARS-CoV-2. This scenario is raising many concerns about possible virus-virus interactions, both positive and negative, and the clinical, diagnostic and therapeutic management of these coinfections. Moreover, we cannot rule out that also climatic conditions and social behaviours are involved. Thus, this situation can lead to different population epidemic dynamics, including changes in the age of the targeted population, disease course and severity, highlighting the need for prospective epidemiologic studies and mathematical modelling able to predict the timing and magnitude of epidemics caused by SARS-CoV-2/seasonal respiratory virus interactions in order to adjust better public health interventions.

Pediatric COVID-19 Follow-Up with Lung Ultrasound: A Prospective Cohort Study.

During the COVID-19 pandemic, lung ultrasound (LUS) was widely used to assess SARS-CoV-2 infection. To date, there are patients with persistence of symptoms after acute infection. Therefore, it may be useful to have an objective tool to follow these patients. The aim of our study was to evaluate the presence of LUS artifacts after SARS-CoV-2 infection in children and to analyze the associations between time elapsed since infection and symptomatology during acute infection. We conducted an observational study, enrolling 607 children infected with SARS-CoV-2 in the previous twelve months. All patients performed a LUS and medical history of demographic and clinical data. We observed irregular pleural lines in 27.5%, B-lines in 16.9%, and subpleural consolidations in 8.6% of the cases. These artifacts were more frequently observed in the lower lobe projections. We have observed that the frequency of artifacts decreases with increasing time since infection. In symptomatic patients during COVID infection, B-lines (p = 0.02) were more frequently found. In our sample, some children, even after months of acute infection, have ultrasound artifacts and showed an improvement with the passage of time from the acute episode. Our study provides additional evidence about LUS in children with previous COVID-19 as a support to follow these patients in the months following the infection.

Neurological and psychological effects of long COVID in a young population: A cross-sectional study.

Aim: We evaluated the long-term clinical status of pediatric patients after testing positive for COVID-19. We hypothesized that there are similar symptoms to those that have been described in adults and children and that pediatric patients with neurophysiologic symptoms still present 3-5 months after infection have psychological consequences that interfere with their adaptive functioning. Method: We recruited 322 COVID-19-positive pediatric patients, between 1.5 and 17 years old, from the outpatient clinic for COVID-19 follow-up. Neurological symptoms were analyzed at onset, after 1 month, and after 3-5 months. A psychological assessment with standardized questionnaires was also conducted to determine the impact of the disease. Results: At the onset of COVID-19, 60% of the total sample exhibited symptoms; this decreased after 1 month (20%) but stabilized 3-5 months after disease onset (22%). Prevailing long-COVID neurological symptoms were headache, fatigue, and anosmia. In the 1.5-5-year-old subgroup, internalizing problems emerged in 12% of patients. In the 6-18-year-old subgroup, anxiety and post-traumatic stress showed significant associations with neurological symptoms of long COVID. Conclusions: These data demonstrate that long COVID presents various broad-spectrum symptoms, including psychological and long-lasting cognitive issues. If not treated, these symptoms could significantly compromise the quality of life of children and adolescents.