True prevalence of long COVID in children: a narrative review

Contrary to what is true for adults, little is known about pediatric long COVID (LC). Studies enrolling children are relatively few and extremely heterogeneous. This does not allow to draw definitive conclusions on the frequency and pathogenesis of pediatric LC and limits the development of appropriate and effective measures to contain the clinical, social and economic impact of this condition on the pediatric population. Depending on the methods used to collect and analyze data, studies have found that the incidence rate of pediatric LC may vary from about 25% to less than 5%. However, despite true prevalence of pediatric LC cannot be exactly defined, studies comparing children with previous COVID-19 and uninfected controls have shown that most of the clinical manifestations detected in infected children, mainly mood symptoms, mental health disorders and heart abnormalities could be diagnosed with similar frequency and severity in uninfected subjects also. This seems to indicate that SARS-CoV-2 is the cause of pediatric LC only in a part of children and other factors play a relevant role in this regard. Pandemic itself with the persistent disruption of child lives may have caused persistent stress in all the pediatric population causing mood symptoms, mental health disorders or several organ and body system functional alterations, regardless SARS-CoV-2 infection. These suppositions suggest the need for long-term physical control of all the children after COVID-19 especially when they were already suffering from an underlying disease or have had a severe disease. Moreover, attention should be paid to the assessment of change in children’s emotional and behavioral functioning in order to assure adequate interventions for the best emotional and behavioral well being. However, whatever its origin, it seems highly likely that the prevalence of the pediatric LC is set to decline in the future. Preliminary observations seem to suggest that recently developed SARS-CoV-2 variants are associated with less severe COVID-19. This suggests that, as already seen in adults, a lower number of pediatric virus-associated LC cases should occur. Furthermore, the use of COVID-19 vaccines, reducing incidence and severity of SARS-CoV-2 infection, may reduce risk of LC development. Finally, elimination of restrictive measures should significantly reduce mood symptoms and mental health disorders

Effects of COVID-19-targeted non-pharmaceutical interventions on pediatric emergency department use: a quasi-experimental study interrupted time-series analysis in North Italian hospitals, 2017 to 2022

BackgroundThe use of Non-Pharmaceutical Interventions (NPIs) during the COVID-19 pandemic is debated. Understanding the consequences these measures may have on vulnerable populations including children and adolescents is important.MethodsThis is a multicenter, quasi-experimental before-after study involving 12 hospitals of the North Italian Emilia-Romagna Region, with NPI implementation as the intervention event. The 3 years preceding NPI implementation (in March 2020) constituted the pre-pandemic phase. The subsequent 2 years were further subdivided into a school closure phase (SC) and a subsequent mitigation measures phase (MM) with milder restrictions. Interrupted Time Series (ITS) regression analysis was used to calculate PED Standardized Incidence Rate Ratios (SIRR) on the diagnostic categories exhibiting the greatest frequency and/or variation.ResultsIn the 60 months of the study there were 765,215 PED visits. Compared to the pre-pandemic rate, overall PED presentations dropped by 58 and 39% during SC and MM, respectively. “Symptoms, signs and Ill-defined conditions,” “Injury and poisoning” and “Diseases of the Respiratory System” accounted for 74% of the reduction. A different pattern was instead seen for “Mental Disorders,” which exhibited the smallest decrease during SC, and is the only category which rose already at the end of SC. ITS analysis confirmed the strong decrease during SC (level change, IRR 0.17, 95%CI 0.12–0.27) and a significant increase in MM (slope change, IRR 1.23, 95%CI 1.13–1.33), with the sharpest decline (−94%) and rise (+36%) observed in the “Diseases of the Respiratory System” category. Mental Disorders showed a significant increasing trend of 1% monthly over the whole study period exceeding pre-pandemic levels at the end of MM. Females and adolescents showed higher increasing rates both in SC and MM.ConclusionNPIs appear to have influenced PED attendance in different ways according to diagnostic categories, mirroring different mechanisms of action. These effects are beneficial in some cases and harmful in others, and establishing a clear balance between pros and cons is a difficult task for public health decision makers. The role of NPIs on PED use appropriateness deserves investigation. The rise in pediatric mental disorders independent of the pandemic makes interventions addressing these issues urgent

Effetti dell’ambiente materno precoce e dell’espressione di NPY-1r in area limbica su comportamento e riproduzione di topi femmine KO condizionali

Il fenotipo di un organismo, cioè l’insieme delle sue caratteristiche morfologiche e funzionali, è determinato dall’espressione del suo patrimonio genetico e dalle influenze dell’ambiente circostante. Nei mammiferi l’ambiente materno precoce riveste un ruolo fondamentale nel regolare lo sviluppo postnatale e il fenotipo. Studi condotti su roditori hanno dimostrato come la qualità delle cure materne influenzi comportamento, risposta allo stress e metabolismo della progenie in età adulta. Nel modello murino caratterizzato dalla delezione condizionale (ristretta ai neuroni eccitatori del prosencefalo) del gene NPY-1r, che codifica per il recettore Y1 del neuropeptide Y (NPY), è stato dimostrato che gli effetti della delezione genica si manifestavano solo nei maschi allevati da madri adottive ad alto grado di cure materne; in questa condizione i topi knockout (NPY1rrfb) mostrano minor peso corporeo, aumento del comportamento ansioso in età adulta, minori livelli plasmatici di leptina, minor quantità di tessuto adiposo e ridotta espressione dell’mRNA codificante per NPY-1r rispetto ai topi controllo (NPY2lox). Studi condotti nel nostro laboratorio hanno dimostrato che gli effetti della delezione genica e/o dell’ambiente materno precoce dipendono anche dal sesso; le femmine presentano pochi (o nessuno) effetti comportamentali e metabolici rispetto ai maschi. Il presente studio ha lo scopo di esaminare il comportamento emozionale, riproduttivo e materno di femmine knockout (NPY1rrfb) e di controllo (NPY2lox) allevate da madri con diverso grado di cure materne per valutare l’impatto dell’inattivazione condizionale di NPY-1r in area limbica e delle cure materne in risposta al challenge riproduttivo. Dall’incrocio di tre diverse linee murine abbiamo ottenuto una prole costituita da topi NPY1rrfb e NPY2lox dati in adozione, alla nascita, a madri di quattro diversi ceppi caratterizzati da un diverso grado di cure materne. In età adulta le femmine NPY1rrfb e NPY2lox sono state accoppiate con maschi di ceppo C57Bl/6J e sottoposte a diversi test comportamentali, prima e durante la gravidanza: anedonia, esplorazione di un’arena, test di costruzione del nido, per valutare il comportamento simil-depressivo, ansioso e di motivazione materna. Al parto è stato registrato numero, sesso e peso dei piccoli e valutata la crescita e sopravvivenza delle nidiate. Le femmine NPYrfb hanno avuto una significativa riduzione del successo riproduttivo (la percentuale di femmine che al PND 6 ha almeno un piccolo) rispetto ai controlli. Inoltre, i piccoli nati dalle femmine NPYrfb mostrano alla nascita un peso corporeo minore rispetto ai piccoli delle femmine di controllo. A differenza di quanto osservato nei maschi, in cui gli effetti della delezione genica di NPY-1r sono riscontrabili solo quando la prole è allevata da madri ad alto grado di cure materne, in questo studio è emerso che la delezione genica influenza la riproduzione nelle femmine e che questo effetto non sembra dipendere dalla qualità delle cure materne ricevute. Per comprendere se la riduzione del successo riproduttivo nelle femmine NPYrfb sia attribuibile alla mancanza di motivazione materna o a una ridotta stimolazione da parte dei piccoli, in uno studio successivo ho utilizzato la procedura di adozione incrociata tra femmine NPYrfb e NPY2lox che non ha fornito però dati conclusivi. Sono tutt’ora in corso le analisi sull’espressione del recettore NPY-1r in diverse aree cerebrali e le analisi immunoistochimiche su NPY ed altri neuropeptidi, oltre allo studio delle reti perineuronali, che potrebbero contribuire alla comprensione delle cause alla base della riduzione del successo riproduttivo osservato e del ruolo del sistema NPY limbico/recettore Y1 nella modulazione del comportamento riproduttivo.The phenotype is the set of morphological and functional traits of an organism, resulting from the interaction between genotype and environmental factors. In mammals, early maternal environment plays a key role in the regulation of postnatal phenotypic development. Several studies in rodent models showed the influence of maternal cares on behavior, stress response and metabolism in adult offspring. In the mouse model characterized by a conditional deletion of Y1 receptor of neuropeptide Y (NPY) gene in excitatory neurons of the forebrain, the gene deletion affected only male mice reared by high maternal care foster dams; knockout males (NPY1rrfb) showed lower body weight, higher level of anxious behavior, lower plasmatic leptin levels, less abdominal adipose tissue and lower levels of NPY-1r mRNA expression compared to controls (NPY2lox). Further studies conducted in our laboratory have demonstrated that the effects of conditional inactivation of NPY-1r and early maternal behavior were sex related. Indeed, NPY-1r KO females display only mild or no effects on behavior and metabolism when compared to male mice. The aim of the present study was to investigate if and how limbic inactivation of NPY-1r and/or early maternal environment affect emotional, reproductive and maternal behavior of females. The generation of NPY1rrfb and NPY2lox offspring was achieved by mating three different genetically modified mouse lines. At birth, litters were fostered to dams of four different strains characterized by different levels of maternal behavior. As adults, NPY1rrfb and NPY2lox females were mated with C57Bl/6J male mice. Before and during pregnancy females were subjected to different behavioural tests: sucrose preference test (anhedonia), open field and nest-building test were performed to evaluate depression-like, anxious and maternal motivation behavior. At delivery pups were sexed and weighed, and body weight growth and survival of offspring were monitored during the first postnatal week. NPYrfb females showed decreased reproductive success compared to control females. Moreover, although no differences were observed in litter size, NPYrfb females’ litters showed lower body weight at birth compared to control females’ litters. At difference with previous data on males, the effects of NPY-1r gene inactivation on female reproduction was affected by gene deletion regardless of the foster mother strains. To assess whether the decreased reproductive success of NPYrfb females was due to a lack in maternal motivation or to decreased pups stimulation we performed a cross fostering experiment between NPYrfb and NPY2lox females. The data achieved by this experiment are not definitive. Currently analyses of NPY-1r mRNA expression in several brain areas, of immunohistochemistry of NPY and other peptides, and of perineuronal nets are still in progress. These data studies can contribute to understand the mechanisms involved in the decreased reproductive success of NPY1r KO females and the role of the limbic NPY system/Y1 receptor in the modulation of reproductive behavior

Epidemiology of Respiratory Infections during the COVID-19 Pandemic

To face the COVID-19 outbreak, a wide range of non-pharmaceutical interventions (NPIs) aimed at limiting the spread of the virus in communities, such as mask-wearing, hand hygiene, social distancing, travel restrictions, and school closures, were introduced in most countries. Thereafter, a significant reduction of new asymptomatic and symptomatic COVID-19 cases occurred, although there were differences between countries according to the type and duration of the NPIs. In addition, the COVID-19 pandemic has been accompanied by significant variations in the global incidence of diseases due to the most common non-SARS-CoV-2 respiratory viruses and some bacteria. In this narrative review, the epidemiology of the most common non-SARS-CoV-2 respiratory infections during the COVID-19 pandemic is detailed. Moreover, factors that could have had a role in modifying the traditional circulation of respiratory pathogens are discussed. A literature analysis shows that NPIs were the most important cause of the general reduction in the incidence of influenza and respiratory syncytial virus infection in the first year of the pandemic, although the different sensitivity of each virus to NPIs, the type and duration of measures used, as well as the interference among viruses may have played a role in modulating viral circulation. Reasons for the increase in the incidences of Streptococcus pneumoniae and group A Streptococcus infections seem strictly linked to immunity debt and the role played by NPIs in reducing viral infections and limiting bacterial superimposed infections. These results highlight the importance of NPIs during pandemics, the need to monitor the circulation of infectious agents that cause diseases similar to those caused by pandemic agents, and the need to make efforts to improve coverage with available vaccines

Update on COVID-19 Therapy in Pediatric Age

With the extension of the COVID-19 pandemic, the large use of COVID-19 vaccines among adults and the emergence of SARS-CoV-2 variants means that the epidemiology of COVID-19 in pediatrics, particularly among younger children, has substantially changed. The prevalence of pediatric COVID-19 significantly increased, several severe cases among children were reported, and long-COVID in pediatric age was frequently observed. The main aim of this paper is to discuss which types of treatment are presently available for pediatric patients with COVID-19, which of them are authorized for the first years of life, and which are the most important limitations of COVID-19 therapy in pediatric age. Four different antivirals, remdesivir (RVD), the combination nirmatrelvir plus ritonavir (Paxlovid), molnupiravir (MPV), and the monoclonal antibody bebtelovimab (BEB), are presently approved or authorized for emergency use for COVID-19 treatment by most of the national health authorities, although with limitations according to the clinical relevance of disease and patient’s characteristics. Analyses in the literature show that MPV cannot be used in pediatric age for the risk of adverse events regarding bone growth. The other antivirals can be used, at least in older children, and RDV can be used in all children except in neonates. However, careful research on pharmacokinetic and clinical data specifically collected in neonates and children are urgently needed for the appropriate management of pediatric COVID-19

Myocarditis Following COVID-19 Vaccine Use: Can It Play a Role for Conditioning Immunization Schedules?

Myocarditis (MYO) is a relatively uncommon inflammatory disease that involves the heart muscle. It can be a very severe disease as it can lead to the development of acute or chronic heart failure and, in a not marginal number of cases, to death. Most of the cases are diagnosed in healthy people younger than 30 years of age. Moreover, males are affected about twice as much as females. Viruses are among the most common causes of MYO, but how viral infection can lead to MYO development is not precisely defined. After COVID-19 pandemic declaration, incidence rate of MYO has significantly increased worldwide because of the SARS-CoV-2 infection. After the introduction of anti-COVID-19 vaccines, reports of post-immunization MYO have emerged, suggesting that a further cause of MYO together with the SARS-CoV-2 infection could increase the risk of heart damage during pandemic. Main aim of this study is to discuss present knowledge regarding etiopathogenesis and clinical findings of MYO associated with COVID-19 vaccine administration and whether the risk of this adverse events can modify the initially suggested recommendation for the use of COVID-19 vaccines in pediatric age. Literature analysis showed that MYO is an adverse event that can follow the COVID-19 immunization with mRNA vaccines in few persons, particularly young adults, adolescents, and older children. It is generally a mild disease that should not modify the present recommendations for immunization with the authorized COVID-19 mRNA vaccines. Despite this, further studies are needed to evaluate presently undefined aspects of MYO development after COVID-19 vaccine administration and reduce the risk of development of this kind of vaccine complication. Together with a better definition of the true incidence of MYO and the exact role of the various factors in conditioning incidence variations, it is essential to establish long-term evolution of acute COVID-19 related MYO

Risks of SARS-CoV-2 Infection and Immune Response to COVID-19 Vaccines in Patients With Inflammatory Bowel Disease: Current Evidence

Inflammatory bowel diseases (IBD), including Crohn's disease, ulcerative colitis, and unclassified inflammatory bowel disease, are a group of chronic, immune mediated conditions that are presumed to occur in genetically susceptible individuals because of a dysregulated intestinal immune response to environmental factors. IBD patients can be considered subjects with an aberrant immune response that makes them at increased risk of infections, particularly those due to opportunistic pathogens. In many cases this risk is significantly increased by the therapy they receive. Aim of this narrative review is to describe the impact of SARS-CoV-2 infection and the immunogenicity of COVID-19 vaccines in patients with IBD. Available data indicate that patients with IBD do not have an increased susceptibility to infection with SARS-CoV-2 and that, if infected, in the majority of the cases they must not modify the therapy in place because this does not negatively affect the COVID-19 course. Only corticosteroids should be reduced or suspended due to the risk of causing severe forms. Furthermore, COVID-19 seems to modify the course of IBD mainly due to the impact on intestinal disease of the psychological factors deriving from the measures implemented to deal with the pandemic. The data relating to the immune response induced by SARS-CoV-2 or by COVID-19 vaccines can be considered much less definitive. It seems certain that the immune response to disease and vaccines is not substantially different from that seen in healthy subjects, with the exception of patients treated with anti-tumor necrosis factor alone or in combination with other immunosuppressants who showed a reduced immune response. How much, however, this problem reduces induced protection is not known. Moreover, the impact of SARS-CoV-2 variants on IBD course and immune response to SARS-CoV-2 infection and COVID-19 vaccines has not been studied and deserves attention. Further studies capable of facing and solving unanswered questions are needed in order to adequately protect IBD patients from the risks associated with SARS-CoV-2 infection

Ropeginterferon phase 2 randomized study in low-risk polycythemia vera: 5-year drug survival and efficacy outcomes

: In patients with low-risk polycythemia vera, exposure to low-dose Ropeginterferon alfa-2b (Ropeg) 100 μg every 2 weeks for 2 years was more effective than the standard treatment of therapeutic phlebotomy in maintaining target hematocrit (HCT) (< 45%) with a reduction in the need for phlebotomy without disease progression. In the present paper, we analyzed drug survival, defined as a surrogate measure of the efficacy, safety, adherence, and tolerability of Ropeg in patients followed up to 5 years. During the first 2 years, Ropeg and phlebotomy-only (Phl-O) were discontinued in 33% and 70% of patients, respectively, for lack of response (12 in the Ropeg arm vs. 34 in the Phl-O arm) or adverse events (6 vs. 0) and withdrawal of consent in (3 vs. 10). Thirty-six Ropeg responders continued the drug for up to 3 years, and the probability of drug survival after a median of 3.15 years was 59%. Notably, the primary composite endpoint was maintained in 97%, 94%, and 94% of patients still on drug at 3, 4, and 5 years, respectively, and 60% of cases were phlebotomy-free. Twenty-three of 63 Phl-O patients (37%) failed the primary endpoint and were crossed over to Ropeg; among the risk factors for this failure, the need for more than three bloodletting procedures in the first 6 months emerged as the most important determinant. In conclusion, to improve the effectiveness of Ropeg, we suggest increasing the dose and using it earlier driven by high phlebotomy need in the first 6 months post-diagnosis