High Cardiac Troponin Levels in Infants with Acute SARS-CoV-2 Infection: A Prospective Comparative Study.

OBJECTIVE: To investigate the specific role of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in inducing elevation of marker of myocardial injury in infants with acute coronavirus disease 2019 (COVID-19). STUDY DESIGN: A prospective, multicentric 3-arm comparative study (March 2020 through March 2022) enrolling 152 infants hospitalized for COVID-19, 79 children with acute infections other than SARS-CoV-2, and 71 healthy controls. Determination of high-sensitivity cardiac troponin (hs-cTn) levels was the primary outcome. RESULTS: The proportion of children with hs-cTn values above the upper limit of normal (44 [28.9%]), as well as with a 3-fold increased value (20 [13.2%]) were significantly higher in the COVID-19 group than those in both control groups. The risk of presenting a 3-fold increased hs-cTn value was higher in children with SARS-CoV-2 infection compared with either healthy children (OR, 5.23; 95% CI, 1.19-23.02) or those with other infections (OR, 11.89; 95% CI, 1.56-89.79). In children with COVID-19, hs-cTn elevation was associated with neither clinical nor biochemical characteristics, nor perinatal risk factors, but with an age of <3 months (P < .001). After adjustment for age, sex, and underlying clinical conditions, elevated hs-cTn was independently associated with COVID-19 in a multivariable regression model. All children showed a progressive reduction of hs-cTn until normalization over time, without clinical, ECG, or echocardiographic manifestations up to 1 year of follow-up. CONCLUSIONS: Infants with acute SARS-CoV-2 infection may show a subclinical and transient alteration of myocardial injury markers, especially in the first months of life. hs-cTn levels normalized during follow-up and were not associated with cardiac functional impairment; nevertheless, long-term consequences are unknown and should be followed carefully.

Bacterial-like inflammatory response in children with adenovirus leads to inappropriate antibiotic use: a multicenter cohort study.

PURPOSE: To compare the clinical severity of Human Adenovirus (HAdV) infection with other viral diseases in a cohort of children, evaluating presentation, therapy, and outcome. METHODS: We conducted a retrospective multicenter cohort study in Italian children hospitalized from January to December 2023 for respiratory symptoms. The study included children with HAdV infection presenting primarily with respiratory symptoms. Patients with isolated gastrointestinal involvement or coinfection with bacteria were excluded. RESULTS: A total of 171 children were enrolled: 98 with HAdV infection (age 44.3 ± 37.9 months) and 73 with other viruses (age 20.4 ± 27.2 months). In the first group, 57.1% had a coinfection with one or more additional viruses. The most common symptoms were fever (89.8%), cough (73.5%) and sore throat (52%). Respiratory distress and hypoxemia were more frequent in the non-HAdV group. Children with HAdV infection demonstrated significantly higher C-reactive protein levels (50.8 ± 54.2 vs. 16.5 ± 33.8 mg/L, p < 0.001), experienced a longer duration of fever (4.9 ± 3.6 vs. 3.4 ± 2.3 days, p = 0.009) and were more likely to receive antibiotic treatment (77.6% vs. 27.4%, p < 0.001). No differences were observed in hospitalization stay, rate of complications, and ICU admission. CONCLUSIONS: Interestingly, our data suggests that HAdV-infected children exhibit a more pronounced inflammatory response despite experiencing less severe respiratory symptoms compared to other viruses. The presence of prolonged fever and a strong inflammatory response often leads to antibiotic overuse during the initial phase, when the viral etiology is yet to be confirmed. Early and accurate identification of HAdV infection is crucial to optimize treatment strategies and minimize unnecessary antibiotic use.

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

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

Perception, knowledge and attitude towards childhood fever: A survey among final-year medical students.

AIMS: Undue concerns about the consequences of fever and its inappropriate management have been documented worldwide among physicians. However, no data exist on medical students. We investigated the perception, knowledge and attitude towards childhood fever among final-year medical students. METHODS: Between June and September 2021, final-year medical students of six Italian universities were invited to complete an online survey on their conceptions and attitude towards pharmacological and non-pharmacological management of childhood fever. History of relevant personal or second-hand experience with childhood fever was also addressed. Both quantitative and qualitative approaches were used. RESULTS: Of 1095 (69%) final-year medical students, 756 completed the survey. Many students believe that high fever might cause brain damage, would recommend physical methods and alternate two drugs for fever. Most students do not think that fever has mainly beneficial effects. In Northern Italy, students are less likely to believe that fever might lead to brain damage (OR 0.55, 95% CI 0.33-0.94), and in Southern Italy students are more likely to advise physical methods (OR 1.77, 95% CI 1.22-2.57) and less likely to believe that fever has mainly beneficial effects (OR 0.55, 95% CI 0.39-0.77). History of a relevant personal episode of fever during childhood was not associated with these outcomes. CONCLUSIONS: Misconceptions about fever are common among final-year medical students in Italy. Cultural factors rather than individually learned traits might underlie these beliefs. Medical students are a promising target for educational interventions to improve childhood fever management.

Effects of COVID-19 pandemic on pediatric tuberculosis: decrease in notification rates and increase in clinical severity.

The outbreak of COVID-19 resulted in a decrease in tuberculosis notification rates globally. We compared tuberculosis incidence rates and disease severity in children seen in our centre prior and during COVID-19 pandemic.We performed a cohort study enrolling children aged under 18 years who received a diagnosis of tuberculosis (January 1st, 2010-December 31st, 2021) at our Pediatric Infectious Diseases Unit. Disease severity was evaluated based on: the classification proposed by Wiseman et al., smear positivity, presence of symptoms at presentation, lung cavitation, extrapulmonary disease, respiratory failure and need for intensive care support. Overall, 168 children (50.6% female, median age 69 months, IQR 95.4) received a diagnosis of tuberculosis, 156 (92.8%) between 2010-2019, before COVID-19 outbreak, and 12 (7.2%) between 2020-2021, during the pandemic. The annual tuberculosis notification rate dropped by 73% in 2021 (0.38/100000, 95%CI 0.1-0.96) compared with 2019 (1.46/100000, 95%CI 0.84-2.37). Compared to the pre-pandemic period, the proportion of children classified as severe was higher in 2020-2021 (5, 41.6% vs 23, 15.7%, p = 0.006) with a higher rate of respiratory failure (2, 16.7%, vs 4, 2.6%, p = 0.01) and an increased need for intensive care support (1, 8.3% vs 1, 0.6%, p = 0.01).   Conclusion: During COVID-19 pandemic we observed a reduction in tuberculosis notification rate in pediatric population and a significant increase in disease severity. This scenario may be the consequence of a delay in diagnosis and an underreporting of cases, rather than the effect of a reduced transmission of tuberculosis. Children reached health-care services only in the need of urgent medical attention. What is Known: • COVID-19 pandemic had a huge impact on national health care systems, resulting in a reduction of access to medical care. What is New: • In Campania Region, Italy, a low tuberculosis incidence country, we witnessed a 75% reduction in tuberculosis notification rate during pandemic. In parallel we demonstrated a significant increase in disease severity, suggesting that the reduction in notification rate may be attributed to an underreporting of cases and consequential diagnostic delay, rather than a reduced transmission of infection.

Off-label use of combined antiretroviral therapy, analysis of data collected by the Italian Register for HIV-1 infection in paediatrics in a large cohort of children.

BACKGROUND: Early start of highly active antiretroviral therapy (HAART) in perinatally HIV-1 infected children is the optimal strategy to prevent immunological and clinical deterioration. To date, according to EMA, only 35% of antiretroviral drugs are licenced in children < 2 years of age and 60% in those aged 2-12 years, due to the lack of adequate paediatric clinical studies on pharmacokinetics, pharmacodynamics and drug safety in children. METHODS: An observational retrospective study investigating the rate and the outcomes of off-label prescription of HAART was conducted on 225 perinatally HIV-1 infected children enrolled in the Italian Register for HIV Infection in Children and followed-up from 2001 to 2018. RESULTS: 22.2% (50/225) of included children were receiving an off-label HAART regimen at last check. Only 26% (13/50) of off-label children had an undetectable viral load (VL) before the commencing of the regimen and the 52.0% (26/50) had a CD4 + T lymphocyte percentage > 25%. At last check, during the off label regimen, the 80% (40/50) of patients had an undetectable VL, and 90% (45/50) of them displayed CD4 + T lymphocyte percentage > 25%. The most widely used off-label drugs were: dolutegravir/abacavir/lamivudine (16%; 8/50), emtricitbine/tenofovir disoproxil (22%; 11/50), lopinavir/ritonavir (20%; 10/50) and elvitegravir/cobicistat/emtricitabine/ tenofovir alafenamide (10%; 10/50). At logistic regression analysis, detectable VL before starting the current HAART regimen was a risk factor for receiving an off-label therapy (OR: 2.41; 95% CI 1.13-5.19; p = 0.024). Moreover, children < 2 years of age were at increased risk for receiving off-label HAART with respect to older children (OR: 3.24; 95% CI 1063-7.3; p = 0.001). Even if our safety data regarding off-label regimens where poor, no adverse event was reported. CONCLUSION: The prescription of an off-label HAART regimen in perinatally HIV-1 infected children was common, in particular in children with detectable VL despite previous HAART and in younger children, especially those receiving their first regimen. Our data suggest similar proportions of virological and immunological successes at last check among children receiving off-label or on-label HAART. Larger studies are needed to better clarify efficacy and safety of off-label HAART regimens in children, in order to allow the enlargement of on-label prescription in children.

HIV-1 Tat-induced diarrhea is improved by the PPARalpha agonist, palmitoylethanolamide, by suppressing the activation of enteric glia.

BACKGROUND: Diarrhea is a severe complication in HIV-1-infected patients with Trans-activator of transcription (HIV-1 Tat) protein being recognized as a major underlying cause. Beside its direct enterotoxic effects, Tat protein has been recently shown to affect enteric glial cell (EGC) activity. EGCs regulate intestinal inflammatory responses by secreting pro-inflammatory molecules; nonetheless, they might also release immune-regulatory factors, as palmytoilethanolamide (PEA), which exerts anti-inflammatory effects by activating PPARα receptors. We aimed at clarifying whether EGCs are involved in HIV-1 Tat-induced diarrhea and if PEA exerts antidiarrheal activity. METHODS: Diarrhea was induced by intracolonic administration of HIV-1 Tat protein in rats at day 1. PEA alone or in the presence of peroxisome proliferator-activated receptor (PPAR) antagonists was given intraperitoneally from day 2 to day 7. S100B, iNOS, NF-kappaB, TLR4 and GFAP expression were evaluated in submucosal plexi, while S100B and NO levels were measured in EGC submucosal plexi lysates, respectively. To verify whether PEA effects were PPARα-mediated, PPARα-/- mice were also used. After 7 days from diarrhea induction, endogenous PEA levels were measured in submucosal plexi homogenates deriving from rats and PPARα-/- mice. RESULTS: HIV-1 Tat protein induced rapid onset diarrhea alongside with a significant activation of EGCs. Tat administration significantly increased all hallmarks of neuroinflammation by triggering TLR4 and NF-kappaB activation and S100B and iNOS expression. Endogenous PEA levels were increased following HIV-1 Tat exposure in both wildtype and knockout animals. In PPARα-/- mice, PEA displayed no effects. In wildtype rats, PEA, via PPARα-dependent mechanism, resulted in a significant antidiarrheal activity in parallel with marked reduction of EGC-sustained neuroinflammation. CONCLUSIONS: EGCs mediate HIV-1 Tat-induced diarrhea by sustaining the intestinal neuroinflammatory response. These effects are regulated by PEA through a selective PPARα-dependent mechanism. PEA might be considered as an adjuvant therapy in HIV-1-induced diarrhea.

Factors Affecting Outcome of Tuberculosis in Children in Italy: An Ecological Study.

INTRODUCTION: Tuberculosis is a major problem in children depending on their families for management and a re-emerging disease in low incidence countries, where foreign-born cases account for a large proportion of cases. METHODS: We investigated socioeconomic features of families and their impact on management and outcome of children with tuberculosis disease seen at a tertiary care centre for paediatric infectious diseases in Italy. RESULTS: Forty-nine Italian and 30 foreign-origin children were included. Children from foreign families had more complicated diseases (20 % vs 0 %; P = 0.002), harbored more drug resistant strains (20 % vs 2 %; P = 0.011), showed longer hospital stay (12 ± 13.1 vs 5.1 ± 6.5 days; P = 0.012) and higher proportion of missed medical visits (15.7 ± 16 vs 8.6 ± 9.6; P ≤ 0.042) than those from Italian families. Harboring drug resistant strains was an independent risk factor for complicated disease course (OR: 72.98; 95 %CI: 1.54-3468.58; P = 0.029), and this risk is higher in children from Eastern Europe (OR: 10.16; 95 %CI: 1.7-61.9; P = 0.012). CONCLUSIONS: Children from immigrant families showed an increased risk of complicated course of tuberculosis due to a higher rate of resistant strains and raise problems in clinical management. Specific protocols are needed to support these populations ensuring easy access to health services and monitoring.

Pediatric Tuberculosis in Italian Children: Epidemiological and Clinical Data from the Italian Register of Pediatric Tuberculosis.

Tuberculosis (TB) is one of the leading causes of death worldwide. Over the last decades, TB has also emerged in the pediatric population. Epidemiologic data of childhood TB are still limited and there is an urgent need of more data on very large cohorts. A multicenter study was conducted in 27 pediatric hospitals, pediatric wards, and public health centers in Italy using a standardized form, covering the period of time between 1 January 2010 and 31 December 2012. Children with active TB, latent TB, and those recently exposed to TB or recently adopted/immigrated from a high TB incidence country were enrolled. Overall, 4234 children were included; 554 (13.1%) children had active TB, 594 (14.0%) latent TB and 3086 (72.9%) were uninfected. Among children with active TB, 481 (86.8%) patients had pulmonary TB. The treatment of active TB cases was known for 96.4% (n = 534) of the cases. Overall, 210 (39.3%) out of these 534 children were treated with three and 216 (40.4%) with four first-line drugs. Second-line drugs where used in 87 (16.3%) children with active TB. Drug-resistant strains of Mycobacterium tuberculosis were reported in 39 (7%) children. Improving the surveillance of childhood TB is important for public health care workers and pediatricians. A non-negligible proportion of children had drug-resistant TB and was treated with second-line drugs, most of which are off-label in the pediatric age. Future efforts should concentrate on improving active surveillance, diagnostic tools, and the availability of antitubercular pediatric formulations, also in low-endemic countries.

Rational use of antibiotics for the management of children's respiratory tract infections in the ambulatory setting: an evidence-based consensus by the Italian Society of Preventive and Social Pediatrics.

BACKGROUND: Several guidelines for the management of respiratory tract infections in children are available in Italy, as well as in other European countries and the United States of America. However, poor adherence to guidelines and the sustained inappropriate use of antibiotics have been reported. In the outpatient setting, almost half of antibiotics are prescribed for the treatment of common respiratory tract infections. In Italy the antibiotic prescription rate is significantly higher than in other European countries, such as Denmark or the Netherlands, and also the levels of antibiotic resistance for a large variety of bacteria are higher. Therefore, the Italian Society of Preventive and Social Paediatrics organised a consensus conference for the treatment of respiratory tract infections in children to produce a brief, easily readable, evidence-based document. METHODS: The conference method was used, according to the National Institute of Health and the National Plan Guidelines. A literature search was performed focusing on the current guidelines for the treatment of airway infections in children aged 1 month-18 years in the ambulatory setting. RESULTS: Recommendations for the treatment of acute pharyngitis, acute otitis media, sinusitis, and pneumonia have been summarized. Conditions for which antibiotic treatment should not be routinely prescribed have been highlighted. CONCLUSION: This evidence-based document is intended to accessible to primary care pediatricians and general practice physicians in order to make clinical practice uniform, in accordance with the recommendations of the current guidelines.

Dalbavancin for Acute Bacterial Skin and Skin Structure Infections in Pediatrics: Insights from Continuation Therapy Experience.

Acute Bacterial Skin and Skin Structure Infections (ABSSSI) are marked by substantial morbidity, frequent need for hospitalization, and long courses of intravenous antibiotic therapy. Herein, we report four cases of pediatric patients admitted for ABSSSI and managed with a combination antibiotic regimen incorporating dalbavancin: a second-generation lipoglycopeptide active against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus. In our experience, particularly in a setting with a high methicillin-resistance rate, dalbavancin demonstrated safety and efficacy, simplifying ABSSSI management in childhood. Its prolonged half-life enables a single-dose administration regimen, offering potential solutions to numerous challenges encountered in pediatric care, such as extended hospital stays, difficulties in securing and maintaining vascular access, lack of pediatric-specific drug indications, and limited availability of suitable oral formulations.

Hospital management of children with acute gastroenteritis.

PURPOSE OF REVIEW: Acute gastroenteritis (AGE) is a major cause of ED visits, hospitalizations, and prescription of investigations, drugs, and changes in diet. Several guidelines on management have been produced. RECENT FINDINGS: There is new information on different rehydration protocols, use of antiemetics, and antidiarrheal drugs that could reduce the burden of AGE. The need of intravenous (i.v.) rehydration is the main cause of hospital admission yet a standardized rehydration scheme is not available. Rehydration therapy through nasogastric tube is better than i.v. rehydration, in children with moderate-severe dehydration. Ultrarapid rehydration has been proposed by enteric or i.v. route to reduce the time in hospital and costs. However, reduced rehydration times are associated with high readmission rates and side effects. Antiemetics may reduce the need of i.v. rehydration because of vomiting and the number of hospital admissions. However, the main antiemetic, ondansetron, has been loaded with a warning for potentially severe side effects. Selected antidiarrheal drugs could reduce the length of stay, but data on their use in inpatients are still not conclusive. SUMMARY: Inappropriate medical interventions are still common in the hospital setting and have a high impact on costs. A validated management is still needed in inpatients.

Definitions and outcomes of nutritional interventions in children with respiratory infections: the approach of the COMMENT initiative.

BACKGROUND/AIMS: This study is aimed at assessing definitions and outcomes used to measure the effects of nutrition in the prevention and treatment of respiratory tract infections in childhood. METHODS: We reviewed clinical trials studying the impact of nutritional interventions on upper and lower respiratory tract infections (URTI and LRTI), focusing on definitions and key outcomes. RESULTS: Fifty trials were included (46 on prevention and 4 on treatment). The definitions of respiratory infections were highly heterogeneous. In 15 of the trials, URTI or LRTI were diagnosed by a pediatrician. In 30 trials, definitions were based on symptoms reported by family members or field-workers only. Five trials did not provide any specific definition. Incidence was the most common outcome measure reported in the trials on prevention, and duration and illness severity were the most common in the treatment trials. CONCLUSIONS: The results showed a major heterogeneity with the use of a wide array of different definitions and clinical end points. To overcome these limitations, outcome measures might be differentiated into two categories: 'direct outcomes' in which respiratory infections are diagnosed and monitored by physicians according to rigorous definitions and 'indirect outcomes' (e.g. chest X-ray, antibiotic prescription and hospitalizations) to assess the burden of respiratory illnesses. Agreement on standard definitions and end points is needed to drive future trials.

Clinical Presentation and Severity of SARS-CoV-2 Infection Compared to Respiratory Syncytial Virus and Other Viral Respiratory Infections in Children Less than Two Years of Age.

The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the implementation of restrictive measures led to a dramatic reduction in respiratory syncytial virus (RSV) occurrence together with rare and mild bronchiolitis induced by SARS-CoV-2. We described the respiratory picture of SARS-CoV-2 infection and evaluated the frequency and the severity of SARS-CoV-2 bronchiolitis comparing it with other respiratory viral infections in children less than two years of age. The severity of respiratory involvement was evaluated based on the need for oxygen therapy, intravenous hydration, and the length of hospital stay. A total of 138 children hospitalized for respiratory symptoms were enrolled: 60 with SARS-CoV-2 and 78 with RSV. In the group of SARS-CoV-2-infected children, 13/60 (21%) received a diagnosis of co-infection. Among the enrolled children, 87/138 (63%) received a diagnosis of bronchiolitis. The comparative evaluation showed a higher risk of the need for oxygen therapy and intravenous hydration in children with RSV infection and co-infection compared to children with SARS-CoV-2 infection. In the children with a diagnosis of bronchiolitis, no differences in the main outcomes among the groups were observed. Although children with SARS-CoV-2 infection have less severe respiratory effects than adults, the pediatrician should pay attention to bronchiolitis due to SARS-CoV-2, which could have a severe clinical course in younger children.

Postbiotic Preparation of Lacticaseibacillus rhamnosus GG against Diarrhea and Oxidative Stress Induced by Spike Protein of SARS-CoV-2 in Human Enterocytes.

The Spike protein of SARS-CoV-2 acts as an enterotoxin able to induce chloride secretion and production of reactive oxygen species (ROS), involved in diarrhea pathogenesis. L. rhamnosus GG (LGG) is recommended in pediatric acute gastroenteritis guidelines as a therapy independent of infectious etiology. We tested a postbiotic preparation of LGG (mLGG) in an in vitro model of COVID-associated diarrhea. Caco-2 cell monolayers mounted in Ussing chambers were exposed to Spike protein, and electrical parameters of secretory effect (Isc and TEER) were recorded in the Ussing chambers system. Oxidative stress was analyzed by measuring ROS production (DCFH-DA), GSH levels (DNTB), and lipid peroxidation (TBARS). Experiments were repeated after mLGG pretreatment of cells. The Isc increase induced by Spike was consistent with the secretory diarrhea pattern, which was dependent on oxidative stress defined by a 2-fold increase in ROS production and lipid peroxidation and variation in glutathione levels. mLGG pretreatment significantly reduced the secretory effect (p = 0.002) and oxidative stress, namely ROS (p < 0.001), lipid peroxidation (p < 0.001), and glutathione level changes (p < 0.001). LGG counteracts Spike-induced diarrhea by inhibiting the enterotoxic effect and oxidative stress. The LGG efficacy in the form of a postbiotic depends on metabolites secreted in the medium with antioxidant properties similar to NAC. Because SARS-CoV-2 is an enteric pathogen, the efficacy of LGG independent of etiology in the treatment of acute gastroenteritis is confirmed by our data.

Pharmacological interventions for pediatric irritable bowel syndrome.

INTRODUCTION: Irritable bowel syndrome is a common functional gastrointestinal disorder in children, characterized by recurrent abdominal pain associated with altered bowel habits in terms of both frequency and consistency. According to change in stool consistency it is categorized into 4 subtypes. From the etiological perspective, it is a combination of factors takes part in symptoms' generation, the overall treatment response rate is often unsatisfactory if a multidisciplinary is not pursued. AREAS COVERED: The aim of this manuscript is to summarize the current pharmacotherapy in pediatric irritable bowel syndrome in order to aid clinicians in treating this challenging disorder. EXPERT OPINION: Most evidence involving pediatric populations rely on open label or retrospective studies and/or are not specifically designed for irritable bowel syndrome but tend to generalize their results to mixed populations of children with functional gastrointestinal disorders. A high placebo response rate combined with poor patients' selection could account for the overall weak evidence supporting the use of pharmacological agents in pediatric irritable bowel syndrome. Given the multifaceted nature of the disorder, multidisciplinary approaches combining pharmacotherapy with alternative treatments is highly recommendable.

SARS-CoV-2 causes secretory diarrhea with an enterotoxin-like mechanism, which is reduced by diosmectite.

Background and aims: The pathophysiology of SARS-CoV-2-associated diarrhea is unknown. Using an experimental model validated for rotavirus-induced diarrhea, we investigated the effects of SARS-CoV-2 on transepithelial ion fluxes and epithelial integrity of human intestinal cells. The effect of the antidiarrheal agent diosmectite on secretion was also evaluated following its inclusion in COVID-19 management protocols. Methods: We evaluated electrical parameters (intensity of short-circuit current [Isc] and transepithelial electrical resistance [TEER]) in polarized Caco-2 cells and in colonic specimens mounted in Ussing chambers after exposure to heat-inactivated (hi) SARS-CoV-2 and spike protein. Spectrofluorometry was used to measure reactive oxygen species (ROS), a marker of oxidative stress. Experiments were repeated after pretreatment with diosmectite, an antidiarrheal drug used in COVID-19 patients. Results: hiSARS-CoV-2 induced an increase in Isc when added to the mucosal (but not serosal) side of Caco-2 cells. The effect was inhibited in the absence of chloride and calcium and by the mucosal addition of the Ca2+-activated Cl- channel inhibitor A01, suggesting calcium-dependent chloride secretion. Spike protein had a lower, but similar, effect on Isc. The findings were consistent when repeated in human colonic mucosa specimens. Neither hiSARS-CoV-2 nor spike protein affected TEER, indicating epithelial integrity; both increased ROS production. Pretreatment with diosmectite inhibited the secretory effect and significantly reduced ROS of both hiSARS-CoV-2 and spike protein. Conclusions: SARS-CoV-2 induces calcium-dependent chloride secretion and oxidative stress without damaging intestinal epithelial structure. The effects are largely induced by the spike protein and are significantly reduced by diosmectite. SARS-CoV-2 should be added to the list of human enteric pathogens.

Diarrhea Is a Hallmark of Inflammation in Pediatric COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a pathogen with enteric tropism. We compared the clinical, biochemical and radiological features of children hospitalized for acute SARS-CoV-2 infection, classified in two groups based on the presence of diarrhea. Logistic regression analyses were used to investigate the variables associated with diarrhea. Overall, 407 children were included in the study (226 males, 55.5%, mean age 3.9 ± 5.0 years), of whom 77 (18.9%) presented with diarrhea, which was mild in most cases. Diarrhea prevalence was higher during the Alpha (23.6%) and Delta waves (21.9%), and in children aged 5-11 y (23.8%). Other gastrointestinal symptoms were most commonly reported in children with diarrhea (p < 0.05). Children with diarrhea showed an increased systemic inflammatory state (higher C-reactive protein, procalcitonin and ferritin levels, p < 0.005), higher local inflammation as judged by mesenteric fat hyperechogenicity (adjusted Odds Ratio 3.31, 95%CI 1.13-9.70) and a lower chance of previous immunosuppressive state (adjusted Odds Ratio 0.19, 95%CI 0.05-0.70). Diarrhea is a frequent feature of pediatric COVID-19 and is associated with increased systemic inflammation, which is related to the local mesenteric fat inflammatory response, confirming the implication of the gut not only in multisystem inflammatory syndrome but also in the acute phase of the infection.

COVID-19 in Infants Less than 3 Months: Severe or Not Severe Disease?

Compared to adults, severe or fatal COVID-19 disease is much less common in children. However, a higher risk for progression has been reported in infants. Different pediatric COVID-19 severity scores are reported in the literature. Methods: Subjects under 90 days of age admitted to 35 Italian institutions for COVID-19 were included. The severity of COVID-19 was scored as mild/moderate or severe/critical following the classification reported in the literature by Venturini, Dong, Kanburoglu, and Gale. To assess the diagnostic accuracy of each classification system, we stratified all enrolled patients developing a posteriori severity score based on clinical presentation and outcomes and then compared all different scores analyzed. Results: We included 216 infants below 90 days of age. The most common symptom was fever, followed by coryza, poor feeding, cough, and gastrointestinal manifestations. According to Venturini, Dong, Kanburoglu, and Gale's severity scores, 18%, 6%, 4.2%, and 29.6% of infants presented with severe/critical disease, respectively. A correlation analysis between these four scores and the a posteriori severity score assigned to all enrolled subjects was performed, and a crescent strength of correlation from Gale (R = 0.355, p < 0.001) to Venturini (R = 0.425, p < 0.001), Dong (R = 0.734, p < 0.001), and Kanburoglu (R = 0.859, p < 0.001) was observed. Conclusions: The percentage of infants with severe COVID-19 varies widely according to the score systems. A unique clinical score should be designed for neonates and infants with COVID-19.