Diagnosis of Multisystem Inflammatory Syndrome in Children by a Whole-Blood Transcriptional Signature.

BACKGROUND: To identify a diagnostic blood transcriptomic signature that distinguishes multisystem inflammatory syndrome in children (MIS-C) from Kawasaki disease (KD), bacterial infections, and viral infections. METHODS: Children presenting with MIS-C to participating hospitals in the United Kingdom and the European Union between April 2020 and April 2021 were prospectively recruited. Whole-blood RNA Sequencing was performed, contrasting the transcriptomes of children with MIS-C (n = 38) to those from children with KD (n = 136), definite bacterial (DB; n = 188) and viral infections (DV; n = 138). Genes significantly differentially expressed (SDE) between MIS-C and comparator groups were identified. Feature selection was used to identify genes that optimally distinguish MIS-C from other diseases, which were subsequently translated into RT-qPCR assays and evaluated in an independent validation set comprising MIS-C (n = 37), KD (n = 19), DB (n = 56), DV (n = 43), and COVID-19 (n = 39). RESULTS: In the discovery set, 5696 genes were SDE between MIS-C and combined comparator disease groups. Five genes were identified as potential MIS-C diagnostic biomarkers (HSPBAP1, VPS37C, TGFB1, MX2, and TRBV11-2), achieving an AUC of 96.8% (95% CI: 94.6%-98.9%) in the discovery set, and were translated into RT-qPCR assays. The RT-qPCR 5-gene signature achieved an AUC of 93.2% (95% CI: 88.3%-97.7%) in the independent validation set when distinguishing MIS-C from KD, DB, and DV. CONCLUSIONS: MIS-C can be distinguished from KD, DB, and DV groups using a 5-gene blood RNA expression signature. The small number of genes in the signature and good performance in both discovery and validation sets should enable the development of a diagnostic test for MIS-C.

Knowledge on Parental Hesitancy toward COVID-19 Vaccination of Children 5-11 Years Old.

Although vaccines are the safest and the most effective measure to prevent disease, disability, and death from various pediatric infectious diseases, parental vaccine hesitancy is a common and increasing phenomenon worldwide. To contribute to improving our knowledge on parental willingness and hesitancy toward COVID-19 vaccine administration in children aged 5-11 years, an anonymous online questionnaire was disseminated in Italy after the COVID-19 vaccine's authorization for this age group. An online survey was conducted using the Crowd Signal platform from 15 December 2021 to 15 January 2022 in Italy among parents of children 5-11 years old. A total of 3433 questionnaires were analyzed. Overall, a "Favorable" position was observed in 1459 (42.5%) parents, a "Doubtful" one in 1223 (35.6%) and a "Hesitant/Reluctant" one in 751 (21.9%). The univariate multinomial logistic regression analysis and the multivariate multinomial logistic regression analysis showed that the Hesitant/Reluctant parents were younger than 40 years of age, mostly female, with a secondary or middle school degree, an annual income below EUR 28,000, more than one child in the age range from 5 to 11 years, an underestimated consideration of the severity of COVID-19's effects, and concern regarding the COVID-19 vaccines in general. These results show that in Italy, most parents of children aged 5 to 11 were doubtful or hesitant/reluctant to vaccinate their children against the COVID-19 virus. Poor trust in health institutions as well as poor consideration of the epidemiological and clinical relevance of COVID-19 in children seem to have played the biggest roles in forming these attitudes. Moreover, the negative attitude of several parents who previously agreed to immunize their children against other childhood illnesses according to the official national pediatric immunization schedule clearly indicates that only the COVID-19 vaccine was put in doubt or rejected. All these findings lead us to conclude that to improve COVID-19 vaccination coverage in children aged 5 to 11, health authorities should increase parental education on the true clinical relevance of COVID-19 and on the importance of its prevention to hinder the evolution of the pandemic in pediatric subjects and the emergence of new variants, and its relative weight in influencing the efficacy of vaccines.

Can we get out of the COVID pandemic without adequate vaccination coverage in the pediatric population?

BACKGROUND: During the first and second COVID-19 pandemic waves, children, despite susceptible to SARS-CoV-2 infection, appeared at lower risk of severe disease, hospitalization, and death than adults and the elderly. Moreover, they seemed to play a minor role in the diffusion of the virus. The aim of this manuscript is to show epidemiological surveillance on COVID-19 incidence and hospitalization in the pediatric cohort in order to explain the importance of an adequate COVID-19 vaccination coverage in the pediatric population. METHODS: All subjects with documented SARS-CoV-2 infection diagnosed in Parma, Italy, between February 21st, 2020, and January, 31st, 2022, were recruited in this epidemiological surveillance. Diagnosis of infection was established in presence of at least one respiratory specimen positive for SARS-CoV-2 nucleic acid using a validated real-time reverse-transcriptase polymerase-chain-reaction (RT-PCR) assay. RESULTS: The number of COVID-19 pediatric cases remained very low and lower than that recorded in the general population between early February 2020 and the end of October 2021, despite in the last part of this period the Delta variant emerged. On the contrary, starting from November 2021, a sharp and significant increase in COVID-19 incidence in the pediatric population was evidenced. This was detected in all the age groups, although greater in the populations aged 5-11 and 12-17 years old. Interestingly, the peak in hospitalization rate was observed in children < 5 years old, for whom COVID-19 vaccination is not approved yet. At the beginning of November 2021 among people older than 18 years of age 85.7% had completed the primary series of COVID-19 vaccine. Almost all the infants and pre-school children were susceptible. Until January 31st, 2022, 80.4% of adolescents aged 11-17 years had received at least two doses of COVID-19 vaccine and only 52.4% received the booster. Among children 5-11 years old, on January 31st, 2022, only 28.5% had received at least one vaccine dose. CONCLUSIONS: Compared with adults and the elderly, presently a greater proportion of children and adolescents is susceptible to SARS-CoV-2 and could play a relevant role for the prolongation of the COVID-19 pandemic. Only a rapid increase in vaccination coverage of the pediatric populations can effectively counter this problem.

Risk factors for multisystem inflammatory syndrome in children - A population-based cohort study of over 2 million children.

Background: Although severe acute COVID-19 is rare in children, SARS-CoV-2 infection can trigger the novel post-infectious condition multisystem inflammatory syndrome in children (MIS-C). Increased knowledge on risk factors for MIS-C could improve our understanding of the pathogenesis of the condition and better guide targeted public health interventions. The aim of the study was to assess risk factors for MIS-C with the aim to identify vulnerable children. Methods: A register-based cohort study including all children and adolescents <19 years born in Sweden between March 1, 2001- December 31, 2020 was performed. Data on sociodemographic risk factors and comorbidities (sex, age, parental region of birth, parental education, asthma, autoimmune disease, chromosomal anomalies, chronic heart disease, chronic lung disease, obesity, life-limiting condition) were retrieved from national health and population registers. The outcome was MIS-C diagnosis according to the Swedish Pediatric Rheumatology Quality Register during March 1, 2020 - December 8, 2021.Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox regression analysis. Incidence rates per 100 000 person-years were calculated assuming a Poisson distribution. Findings: Among 2 117 443 children included in the study, 253 children developed MIS-C, corresponding to an incidence rate of 6·8 (95% CI: 6·0-7·6) per 100 000 person-years. Male sex (HR 1·65, 95% CI: 1·28-2·14), age 5-11 years (adjusted HR 1·44, 95% CI: 1·06-1·95 using children 0-4 years as reference), foreign-born parents (HR 2·53, 95% CI: 1·93-3·34), asthma (aHR 1·49, 95% CI: 1·00-2·20), obesity (aHR 2·15, 95% CI: 1·09-4·25) and life-limiting conditions (aHR 3·10, 95% CI: 1·80-5·33) were associated with MIS-C. Children 16-18 years had a reduced risk for MIS-C (aHR 0·45, 95% CI: 0·24-0·85). Interpretation: We report increased risks for MIS-C in children with male sex, age 5-11 years, foreign-born parents, asthma, obesity, and life-limiting condition. Knowing these risk populations might facilitate identification of children with MIS-C and potentially guide targeted public health interventions. Nevertheless, the absolute risks for MIS-C were very low. Funding: Financial support was provided from the Swedish Research Council (grant no 2018-02640), the Swedish Heart-Lung Foundation (grant no 20210416), the Asthma and Allergy Association, Ake Wiberg foundation, the Samariten Foundation, the Society of Child Care, and Region Stockholm.

Italian intersociety consensus on management of long covid in children.

BACKGROUND: Two sequelae of pediatric COVID-19 have been identified, the multisystem inflammatory syndrome in children (MIS-C) and the long COVID. Long COVID is much less precisely defined and includes all the persistent or new clinical manifestations evidenced in subjects previously infected by SARS-CoV-2 beyond the period of the acute infection and that cannot be explained by an alternative diagnosis. In this Intersociety Consensus, present knowledge on pediatric long COVID as well as how to identify and manage children with long COVID are discussed. MAIN FINDINGS: Although the true prevalence of long COVID in pediatrics is not exactly determined, it seems appropriate to recommend evaluating the presence of symptoms suggestive of long COVID near the end of the acute phase of the disease, between 4 and 12 weeks from this. Long COVID in children and adolescents should be suspected in presence of persistent headache and fatigue, sleep disturbance, difficulty in concentrating, abdominal pain, myalgia or arthralgia. Persistent chest pain, stomach pain, diarrhea, heart palpitations, and skin lesions should be considered as possible symptoms of long COVID. It is recommended that the primary care pediatrician visits all subjects with a suspected or a proven diagnosis of SARS-CoV-2 infection after 4 weeks to check for the presence of symptoms of previously unknown disease. In any case, a further check-up by the primary care pediatrician should be scheduled 3 months after the diagnosis of SARS-CoV-2 infection to confirm normality or to address emerging problems. The subjects who present symptoms of any organic problem must undergo a thorough evaluation of the same, with a possible request for clinical, laboratory and / or radiological in-depth analysis in case of need. Children and adolescents with clear symptoms of mental stress will need to be followed up by existing local services for problems of this type. CONCLUSIONS: Pediatric long COVID is a relevant problem that involve a considerable proportion of children and adolescents. Prognosis of these cases is generally good as in most of them symptoms disappear spontaneously. The few children with significant medical problems should be early identified after the acute phase of the infection and adequately managed to assure complete resolution. A relevant psychological support for all the children during COVID-19 pandemic must be organized by health authorities and government that have to treat this as a public health issue.

Anti-COVID Vaccination for Adolescents: A Survey on Determinants of Vaccine Parental Hesitancy.

Vaccine hesitancy has been considered one of the most severe threats to global health, as it represents an obstacle to achieving adequate vaccination coverage. Recent research studies aimed at investigating the propensity for anti-COVID vaccination among adults have found a high prevalence of vaccine hesitancy, but few data are available on parental vaccine hesitancy. We therefore built an anonymous online survey to investigate the factors related to the vaccine hesitancy of parents of adolescents between 12 and 17 years of age, with a special focus on demographic factors and the domains of confidence and complacency. The online survey was conducted by using the Crowd Signal platform from 15 July to 16 August 2021, in Italy. A total of 1799 analyzable questionnaires were analyzed. Overall, Favorable and Doubtful parents declared a higher level of confidence on safety and efficacy of pediatric vaccines and on confidence in health institutions than Hesitant/Reluctant ones (p-values < 0.001). The univariate multinomial logistic regression analysis and the multivariate multinomial logistic regression analysis showed that the Hesitant/Reluctant parents were younger than 40 years of age, with a secondary-school or three-year degree, free-lance, with a family income below €28,000, with an erroneous perception of the risk of COVID-19 as disease and with fear of anti-COVID vaccination. These results, which should be confirmed in a larger population and in different geographical areas, should lead Institutions and stakeholders to identify targeted communication tools to improve trust in health institutions, especially by younger parents.

Use of Monoclonal Antibody to Treat COVID-19 in Children and Adolescents: Risk of Abuse of Prescription and Exacerbation of Health Inequalities.

Monoclonal antibodies (mAbs) that neutralize SARS-CoV-2 in infected patients are a new class of antiviral agents approved as a type of passive immunotherapy. They should be administered to adults and children (≥12 years old, weighing ≥ 40 kg) with SARS-CoV-2 positivity, and who are suffering from a chronic underlying disease and are at risk of severe COVID-19 and/or hospitalization. The aim of this manuscript is to discuss the benefit-to-risk of mAb therapy to treat COVID-19 in pediatric age, according to current reports. A problem is that the authorization for mAbs use in children was given without studies previously evaluating the efficacy, safety and tolerability of mAbs in pediatric patients. Moreover, although the total number of children with chronic severe underlying disease is not marginal, the risk of severe COVID-19 in pediatric age is significantly reduced than in adults and the role of chronic underlying disease as a risk factor of severe COVID-19 development in pediatric patients is far from being precisely defined. In addition, criteria presently suggested for use of mAbs in children and adolescents are very broad and may cause individual clinicians or institutions to recommend these agents on a case-by-case basis, with an abuse in mAbs prescriptions and an exacerbation of health inequalities while resources are scarce. Several questions need to be addressed before their routine use in clinical practice, including what is their associated benefit-to-risk ratio in children and adolescents, who are the patients that could really have benefit from their use, and if there is any interference of mAb therapy on recommended vaccines. While we wait for answers to these questions from well-conducted research, an effective and safe COVID-19 vaccine for vulnerable pediatric patients remains the best strategy to prevent COVID-19 and represents the priority for public health policies.

Cutaneous Findings in SARS-CoV-2-Associated Multisystem Inflammatory Disease in Children.

Rash is a common feature of multisystem inflammatory syndrome in children (MIS-C), a postinfectious hyperinflammatory disease associated with prior severe acute respiratory syndrome coronavirus 2 infection. Because the differential diagnosis of fever and rash in children is broad, understanding clinical characteristics of MIS-C may assist with diagnosis. Here we describe the cutaneous findings observed in a series of children with MIS-C-associated rash.

Why It Is Important to Develop an Effective and Safe Pediatric COVID-19 Vaccine.

The need to cope with the medical, social, and economic storm due to the new coronavirus 2019 (COVID-19) pandemic as quickly as possible has led to the very rapid development of a huge number of vaccines. All these vaccines have been mainly developed in healthy adults and, in some cases, in the elderly. Children were marginally involved as, according to the clinical trial registry Clinical Trials.gov, only very few studies have included children among subjects to enroll, although just a few weeks after the pandemic declaration, the US Food and Drug Administration had highlighted the importance of vaccine evaluation in pediatrics. Availability of an effective and safe pediatric COVID-19 vaccine appears mandatory for several clinical and epidemiological reasons. However, as the development of an effective and safe pediatric vaccine seems far from easy, strong cooperation among governments, researchers, and pharmaceutical companies is highly desirable.

Home Management of Children With COVID-19 in the Emilia-Romagna Region, Italy.

In most children, coronavirus disease 2019 (COVID-19) is a mild or moderate disease. Moreover, in a relevant number of cases, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection remains totally asymptomatic. All these findings seem to suggest that otherwise healthy children with suspected COVID-19 might be managed in the community in most cases, thus avoiding hospital admission and closely related medical, social and economic problems, including overwhelming hospitals. Unfortunately, home management of children with suspected COVID-19 rarely occurs, and many children with suspected or laboratory-confirmed SARS-CoV-2 infection are frequently hospitalized irrespective of the severity of disease. To evaluate the role of community health houses (CHHs) in the management of children with COVID-19, 1,009 children with suspected SARS-CoV-2 infection were studied in Emilia-Romagna Region, Italy. Among them, 194 (19.2%) resulted positive for SARS-CoV-2. The majority (583, 58%) were tested at home by CHHs, while 426 (42%) were brought to the hospital for testing. The patients who were managed in the hospital had a significantly lower median age than those who were managed at home (2 vs. 12 years, p < 0.001). Exposure to SARS-CoV-2 cases within the family was significantly more frequent among those who were managed at home (82 vs. 46%, p < 0.05). The clinical findings were similar between the children who were managed at home and those who were managed in the hospital. Only one of the children managed at home (0.7%) required hospitalization; in comparison, 26 (48%) of those whose swab samples were taken at the hospital were hospitalized. Our research shows for the first time the importance of CHHs in the management of COVID-19 in children; because of the high frequency of mild to moderate cases, management by CHHs can reduce the care load in hospitals, providing enormous advantages on the familial, medical, social, and economic levels. These findings could be useful for suggesting a territorial rather than hospital-based strategy in pediatrics in the case of a new wave of the epidemic.