Current Uses of Bromelain in Children: A Narrative Review.

Bromelain is a complex natural mixture of sulfhydryl-containing proteolytic enzymes that can be extracted from the stem or fruit of the pineapple. This compound is considered a safe nutraceutical, has been used to treat various health problems, and is also popular as a health-promoting dietary supplement. There is continued interest in bromelain due to its remarkable therapeutic properties. The mechanism of action of bromelain appears to extend beyond its proteolytic activity as a digestive enzyme, encompassing a range of effects (mucolytic, anti-inflammatory, anticoagulant, and antiedematous effects). Little is known about the clinical use of bromelain in pediatrics, as most of the available data come from in vitro and animal studies, as well as a few RCTs in adults. This narrative review was aimed at highlighting the main aspects of the use of bromelain in children, which still appears to be limited compared to its potential. Relevant articles were identified through searches in MEDLINE, PubMed, and EMBASE. There is no conclusive evidence to support the use of bromelain in children, but the limited literature data suggest that its addition to standard therapy may be beneficial in treating conditions such as upper respiratory tract infections, specific dental conditions, and burns. Further studies, including RCTs in pediatric settings, are needed to better elucidate the mechanism of action and properties of bromelain in various therapeutic areas.

Vitamin D Status in an Italian Pediatric Cohort: Is There a Role for Tobacco Smoking Exposure?

Introduction: Vitamin D deficiency is a common public health issue worldwide. The purpose of this study was to investigate the vitamin D status and its potential determinants in children residing in Sardinia (40°N), Italy. Methods: A total of 182 children (males: 51.7%; median age: 9 years) were enrolled over a 12-month period. Serum 25(OH)D was measured by an immune-chemiluminescence assay. A questionnaire was used to gather information on other variables, including passive smoke exposure. Results: Mean (SD) serum 25(OH)D was 25.2 (8.3) ng/mL for the whole group. The majority (n=123, 67.6%) of children had vitamin D sufficient values >20 ng/mL, while about 1/3 had vitamin D insufficient/deficient values (≤20 ng/mL (n=59, 32.4%). Among the variables investigated, passive smoke exposure was significantly associated with insufficient 25(OH)D levels (p<0.0001). Conclusion: Our results further prove that hypovitaminosis D is common in the Italian children and documented that passive smoke exposure is a significant risk factor for hypovitaminosis D.

Electrocardiography in Children Hospitalized for COVID-19 and Not Suffering from Multisystem Inflammatory Syndrome in Children (MIS-C): An Observational Study.

The risk of cardiac involvement with electrophysiological abnormalities during COVID-19 infection has been reported in adults but remains poorly studied in children. Our aim was to determine the frequency of cardiac involvement and the necessity of routine cardiac evaluation in children hospitalized for COVID-19. This observational study included 127 children, with a median (IQR) age of 2 (0.83-6.0) years, who were hospitalized for COVID-19 between 1 January 2021 and 31 August 2022, 62 (48.8%) of whom were males. Each patient underwent an ECG on admission and discharge as well as a laboratory assessment. A comparison between patients with COVID-19 and healthy controls showed significantly higher HR (p < 0.0001) and lower PR values (p = 0.02) in the first group. No arrhythmias or other electrocardiographic abnormalities were detected during hospitalization. The median levels of troponin, NT-proBNP, ferritin, and D-dimer were significantly higher in children aged <2 years, but they fell within the normal range for their age. Our results indicate that a detectable cardiac involvement is very rare in children hospitalized for COVID-19 and not suffering from Multisystem Inflammatory Syndrome in Children (MIS-C) and suggest that routine electrocardiographic assessment is not mandatory in these patients in the absence of cardiac symptoms/signs.

Impact of COVID-19 on patients with beta-thalassemia major: an observational study.

INTRODUCTION:  The prevalence of COVID-19 is slightly lower, and its mortality is higher in beta-thalassemia patients than in the general population. We evaluated the impact of COVID-19 in terms of incidence, clinical course, management, and specific antibody response to vaccination in a cohort of patients with beta-thalassemia major. METHODS:  We retrospectively enrolled all transfusion-dependent beta-thalassemia major patients attending the Thalassemia Day Care Center of the University Hospital of Sassari, Italy, from March 1, 2020, to May 31, 2021. For each patient, demographic, clinical, laboratory, instrumental, and therapy data were collected. Patients aged ≥16 years received two doses of mRNA COVID-19 vaccine. Anti-SARS-CoV-2 serum antibodies were tested before and after the first vaccine dose. RESULTS:  A total of 68 patients (median age: 36.5 years; IQR: 13-42 years) were included. Nasopharyngeal swab (NPS) for SARS-CoV-2 detection by RT-PCR was positive in 5 (7.35%) of 68 patients (4 symptomatic). No COVID-19-related complications, hospitalizations, or deaths were observed. The transfusion regimen and iron chelation therapy were not significantly changed. Prior to COVID-19 vaccination, anti-SARS-CoV-2 antibodies were tested in 61 patients, 51 negative and 10 positive; five of the latter were also positive for SARS-CoV-2 on NPS. The 46 vaccinated subjects had an antibody response, with higher levels in subjects previously infected with SARS-CoV-2. CONCLUSION:   Our findings suggest that patients with beta-thalassemia major are not at a higher risk of contracting SARS-CoV-2 infection and developing a severe form of COVID-19 despite being considered more vulnerable than the general population.

Adenotonsillectomy in Children with Obstructive Sleep Apnea Syndrome: Clinical and Functional Outcomes.

Adenotonsillectomy (AT) is the first-line treatment for pediatric obstructive sleep apnea syndrome (OSAS). Relatively few studies have evaluated the clinical and functional outcomes of AT in children with OSAS, but these studies show that surgery improves behavior and quality of life (QOL). However, residual OSAS after AT is reported in severe cases. This study aimed to retrospectively evaluate the clinical and functional outcomes of AT in a cohort of children with OSAS. We consecutively enrolled children with OSAS who underwent AT and were admitted to our clinic from 1 July 2020 to 31 December 2022. For each participant, medical history and physical examinations were performed. Before and after surgery, all patients underwent a standard polygraphic evaluation, and caregivers completed the OSA-18 questionnaire. A total of 65 children with OSAS, aged 2-9 years, were included. After AT, 64 (98.4%) children showed a reduction in AHI, with median (IQR) values decreasing from 13.4/h (8.3-18.5/h) to 2.4/h (1.8-3.1/h) (p-value < 0.0001). Conversely, median (IQR) SpO2 nadir increased after surgery from 89% (84-92%) to 94% (93-95%) (p-value < 0.0001). Moreover, 27 children (18%) showed residual OSAS. The OSA-18 score decreased after AT from median (IQR) values of 84 (76-91) to values of 33 (26-44) (p-value < 0.0001). A positive significant correlation was found between OSA-18 post-operative scores and AHI post-operative scores (rho 0.31; p-value = 0.01). Our findings indicate that, in children with OSAS, AT is associated with significant improvements in behavior, QOL, and polygraphic parameters. However, long-term post-surgical follow-up to monitor for residual OSAS is highly recommended, especially in more severe cases.

GAU-PED study for early diagnosis of Gaucher disease in children with splenomegaly and cytopenia.

BACKGROUND: Gaucher disease (GD) diagnosis can be delayed due to non-specific symptoms and lack of awareness, leading to unnecessary procedures and irreversible complications. GAU-PED study aims to assess GD prevalence in a high-risk pediatric population and the presence, if any, of novel clinical or biochemical markers associated with GD. MATERIALS AND METHODS: DBS samples were collected and tested for ß-glucocerebrosidase enzyme activity for 154 patients selected through the algorithm proposed by Di Rocco et al. Patients showing ß-glucocerebrosidase activity below normal values were recalled to confirm the enzyme deficiency with the gold standard essay on cellular homogenate. Patients tested positive at the gold standard analysis were evaluated through GBA1 gene sequencing. RESULTS: 14 out of 154 patients were diagnosed with GD, with a prevalence of 9.09% (5.06-14.78%, CI 95%). Hepatomegaly, thrombocytopenia, anemia, growth delay/deceleration, elevated serum ferritin, elevated Lyso-Gb1 and chitotriosidase were significantly associated with GD. CONCLUSIONS: GD prevalence in a pediatric population at high-risk appeared to be higher compared to high-risk adults. Lyso-Gb1 was associated with GD diagnosis. The algorithm proposed by Di Rocco et al. can potentially improve the diagnostic accuracy of pediatric GD, allowing the prompt start of therapy, aiming to reduce irreversible complications.

Clinical use of gastric antisecretory drugs in pediatric patients with gastroesophageal reflux disease: a narrative review.

Background and Objective: Gastroesophageal reflux (GER) is a common condition in infants. Usually, it resolves spontaneously in 95% of cases within 12-14 months of age, but gastroesophageal reflux disease (GERD) may develop in some children. Most authors do not recommend pharmacological treatment of GER, while the management of GERD is debated. The aim of this narrative review is to analyze and summarize the available literature on the clinical use of gastric antisecretory drugs in pediatric patients with GERD. Methods: References were identified through MEDLINE, PubMed, and EMBASE search engines. Only articles in English were considered. The following keywords were used: "gastric antisecretory drugs", "H2RA", "PPI", "ranitidine", "GERD", "infant", "child". Key Content and Findings: Increasing evidence of poor efficacy and potential risks of proton pump inhibitors (PPIs) is emerging in neonates and infants. Histamine-2 receptor antagonists (H2RAs), including ranitidine, have been used successfully in older children, although less effective than PPIs at relieving symptoms and healing GERD. However, in April 2020, both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) requested manufacturers of ranitidine to remove all ranitidine products from the market due to the risk of carcinogenicity. Pediatric studies comparing effectiveness and safety of different acid-suppressing treatments for GERD are generally inconclusive. Conclusions: A proper differential diagnosis between GER and GERD is crucial to avoid the overuse of acid-suppressing medications in children. Further research should be directed towards the development of novel antisecretory drugs, with proven efficacy and good safety profile, for treating pediatric GERD, particularly in newborns and infants.

Relationships between 25-Hydroxyvitamin D Levels and Obstructive Sleep Apnea Severity in Children: An Observational Study.

The prevalence of hypovitaminosis D is increasing worldwide. Vitamin D deficiency is supposed to play a role in sleep disturbances, but the complex relationships between hypovitaminosis D and pediatric obstructive sleep apnea syndrome (OSAS) are still incompletely understood. This study was aimed to retrospectively investigate the vitamin D status and significant clinical, laboratory, and instrumental variables in a cohort of pediatric patients with OSAS and to assess the possible relationship between serum vitamin D levels and OSAS severity. We consecutively enrolled all children aged 2-14 years admitted to our Pediatric Clinic from 1 July 2018 to 30 November 2020 for sleep-disordered breathing. Each patient underwent standard overnight in-hospital polygraphic evaluation, measurement of serum 25-hydroxyvitamin D (25(OH)D) levels, and clinical and laboratory investigation. A total of 127 children with OSAS were included. The 25(OH)D levels and BMI of OSAS patients were compared with those of an age-matched control group: the serum 25(OH)D levels were significantly lower in OSAS patients than in controls (22.4 vs. 25.5 ng/mL; p-value = 0.009), whereas no differences in the BMI percentile were found between the two groups. The mean value of 25(OH)D was not significantly lower (20.9 ng/mL) in the severe OSAS group compared with the mild (23.0 ng/mL) and moderate (23.3 ng/mL) OSAS groups (p-value = 0.28). Our findings indicate a relationship between vitamin D status and OSAS in children and suggest that severe cases of OSAS have lower vitamin D levels. Future, more extensive prospective studies are needed to confirm such preliminary findings.

Clinical Use of Gastric Antisecretory Drugs in Hospitalized Pediatric Patients.

Antisecretory drugs are frequently used in the treatment of pediatric gastrointestinal disorders. This study was aimed to assess the prescribing patterns and the safety of ranitidine and proton pump inhibitors (PPIs) in a cohort of Italian pediatric patients. Children aged >1 month to <16 years that were admitted to our Pediatric Clinic between 2016 and 2018 were enrolled in this retrospective observational study. All data were obtained from medical records and a parent telephone questionnaire. The exclusion criteria included the use of antisecretory therapy at hospital admission, failure to collect the relevant clinical data, and failure to administer the questionnaire. This study included 461 subjects, who were divided into four age groups: <2 years, 2−5 years, 6−11 years, and ≥12 years. Ranitidine was prescribed in 396 (85.9%) patients, mainly for the acute treatment of gastrointestinal symptoms, and a PPI was given to 65 (14.1%) children to treat gastroesophageal reflux disease, gastritis/ulcer, or for gastroprotection. During the study period, the percentage of patients treated with ranitidine progressively increased, except in the 2−5-year age group. We observed eighty-seven adverse drug reactions (ADRs), 61 of which occurred in the ranitidine group and 26 in the PPI group. The most common ADR was constipation (n = 35), which occurred more frequently in children treated with PPIs and in the 6−11-year age group. Ranitidine was the most used antisecretory drug in all the age groups, especially for acute treatment. Conversely, PPIs were the drugs of choice for prolonged treatments. Further research should be focused on developing an effective and safer alternative to ranitidine.

Impact of COVID-19 Pandemic and Associated Restrictions on Vitamin D Status in a Large Cohort of Italian Children and Adolescents.

Background and Objectives: Vitamin D is synthesized in the skin upon sunlight exposure, showing variations with season and latitude. We aimed to investigate the influence of age, sex, and season on vitamin D status in a large pediatric cohort during the COVID-19 pandemic period and the corresponding pre-pandemic period. Materials and Methods: Retrospective data concerning subjects aged < 18 years were extracted anonymously from the large database of a reference laboratory hospital (Sassari, Northern Sardinia, Italy). Serum 25-hydroxyvitamin D [25(OH)D] levels measured during the pre-pandemic period (1 March 2018 to 30 September 2019) were compared with those detected during the pandemic period (1 March 2020 to 30 September 2021). Results: A total of 2317 samples from subjects aged < 18 years were included in the analysis, 1303 (47.9% females) of which were collected in the pre-pandemic period and 1014 (51.3% females) in the pandemic period. No significant differences in 25(OH)D levels were found between the two periods, whereas, in children aged < 2 years, levels were higher than those in children aged 11-16 years (p < 0.05). Monthly levels of 25(OH)D between pre-pandemic and pandemic periods did not differ, although significant differences were detected across months (p < 0.0001). Similarly, 25(OH)D values did not differ significantly between males and females in both periods. Marked seasonal variations were observed in males and females across all age groups. Conclusions: Serum vitamin D levels and their season-related variations were not significantly affected by the COVID-19 pandemic and associated restrictions in a large cohort of Italian children and adolescents.

Use of Azithromycin in Pregnancy: More Doubts than Certainties.

Macrolides such as azithromycin are commonly prescribed antibiotics during pregnancy. The good oral bioavailability and transplacental transfer of azithromycin make this drug suitable for the treatment of sexually transmitted diseases, toxoplasmosis, and malaria. Moreover, azithromycin is useful both in the management of preterm pre-labor rupture of membranes and in the adjunctive prophylaxis for cesarean delivery. The aim of this comprehensive narrative review is to critically analyze and summarize the available literature on the main aspects of azithromycin use in pregnant women, with a special focus on adverse offspring outcomes associated with prenatal exposure to the drug. References for this review were identified through searches of MEDLINE, PubMed, and EMBASE. Fetal and neonatal outcomes following prenatal azithromycin exposure have been investigated in several studies, yielding conflicting results. Increased risks of spontaneous miscarriage, major congenital malformations, cardiovascular malformations, digestive system malformations, preterm birth, and low birth weight have been reported in some studies but not in others. Currently, there is no conclusive evidence to support that azithromycin use by pregnant women causes adverse outcomes in their offspring. Therefore, this agent should only be used during pregnancy when clinically indicated, if the benefits of treatment are expected to outweigh the potential risks.

Fetal Growth and Neonatal Outcomes in Pregestational Diabetes Mellitus in a Population with a High Prevalence of Diabetes.

The aim of this retrospective study, conducted in an Italian tertiary care hospital, was to evaluate maternal-fetal and neonatal clinical outcomes in a group of patients with pregestational diabetes mellitus (PGDM), such as diabetes mellitus type 1 (DM1), diabetes mellitus type 2 (DM2), and maturity onset diabetes of the young (MODY). Overall, 174 pregnant women, nulliparous and multiparous, with a single pregnancy were enrolled. Data on pregnancy, childbirth, and newborns were collected from medical records. The selected patients were divided into two groups: the PGDM group (42 with DM1, 14 with DM2, and 2 with MODY), and the control group (116 patients with a negative pathological history of diabetes mellitus). We reported an incidence of preterm delivery of 55.2% in the PGDM group, including 59.5% of those with DM1 and 42.9% of those with DM2, vs. 6% in the controls. Fetal growth disorders, such as intrauterine growth retardation, small for gestational age, and fetal macrosomia were found in 19% and 3.6% in the case and control groups, respectively. A relationship between DM2 and gestational hypertension was found.

Antihuman Endogenous Retrovirus Immune Response and Adaptive Dysfunction in Autism.

ASD is a neurodevelopmental disorder of unknown aetiology but with a known contribution of pathogenic immune-mediated mechanisms. HERVs are associated with several neuropsychiatric diseases, including ASD. We studied anti-HERV-W, -K and -H-env immune profiles in ASD children to analyse differences between their respective mothers and child/mother control pairs and possible correlations to ASD severity and loss of adaptive abilities. Of the 84 studied individuals, 42 children (23 ASD and 19 neurotypical) and their paired mothers underwent clinical and neuropsychological evaluations. ASD severity was analysed with standardised tests. Adaptive functioning was studied with ABAS-II and GAC index. Plasma anti-env responses of HERV-K, -H and -W were tested with indirect ELISA. ASD and neurotypical children did not differ in age, gender, comorbidities and anti-HERV responses. In children with ASD, anti-HERV levels were not correlated to ASD severity, while a significant inverse correlation was found between anti-HERV-W-248-262 levels and adaptive/social abilities. Upregulation of anti-HERV-W response correlates to dysfunctional social and adaptive competences in ASD but not in controls, suggesting anti-HERV response plays a role in the appearance of peculiar ASD symptoms.

Impact of the SARS-CoV-2 pandemic and associated restrictions on Pediatric Emergency Department utilization in Sardinia: a retrospective bicentric observational study.

BACKGROUND: The COVID-19 pandemic and associated public health measures have had a profound impact on health systems worldwide. The aim of this study was to assess quantitative and qualitative changes in Pediatric Emergency Department (PED) visits in Sardinia, Italy, during the early period of the COVID-19 pandemic. METHODS: We retrospectively investigated the number and characteristics of visits to two major Sardinian PEDs, in the periods January-June 2020 and January-June 2019. RESULTS: From January to June 2020, 8399 PED visits with 1160 hospital admissions (13.8% of PED visits) were registered, compared with 15,692 PED visits (Δ = -46.5%) and 1819 hospital admissions (11.6% of PED visits) occurring from January to June 2019. Comparing January-June 2020 with January-June 2019, we found differences in the percentage of visits for age groups, and significant changes in the proportion of triage codes, with a decrease in green codes (72.1% vs 74.2%, respectively) and an increase in white codes (19.0% vs 16.5%, respectively). Moreover, in the period January-June 2020, the frequency of skin disorders and acute respiratory disease significantly decreased, while the frequency of trauma, acute surgical disease, intoxication, and neuropsychiatric disease significantly increased. CONCLUSIONS: After the beginning of the Italian lockdown, we observed a marked drop in the number of PED visits, an increase in hospital admission rate, and radical changes in the reason for visit.

Infant botulism: an underestimated threat.

Infant botulism (IB) is defined as a potentially life-threatening neuroparalytic disorder affecting children younger than 12 months. It is caused by ingestion of food or dust contaminated by Clostridium botulinum spores, which germinate in the infant's large bowel and produce botulinum neurotoxin. Although the real impact of IB is likely underestimated worldwide, the USA has the highest number of cases. The limited reporting of IB in many countries is probably due to diagnostic difficulties and nonspecific presentation. The onset is usually heralded by constipation, followed by bulbar palsy, and then by a descending bilateral symmetric paralysis; ultimately, palsy can involve respiratory and diaphragmatic muscles, leading to respiratory failure. The treatment is based on supportive care and specific therapy with Human Botulism Immune Globulin Intravenous (BIG-IV), and should be started as early as possible. The search for new human-like antibody preparations that are both highly effective and well tolerated has led to the creation of a mixture of oligoclonal antibodies that are highly protective and can be produced in large quantities without the use of animals. Ongoing research for future treatment of IB involves the search for new molecular targets to produce a new generation of laboratory-produced antitoxins, and the development of new vaccines with safety and efficacy profiles that can be scaled up for clinical use. This narrative literature review aims to provide a readable synthesis of the best current literature on microbiological, epidemiological and clinical features of IB, and a practical guide for its treatment.

Paracetamol overdose in the newborn and infant: a life-threatening event.

PURPOSE: Paracetamol is the only drug recommended to treat fever in neonates. At recommended doses, paracetamol has not been associated with liver injury in neonates, while hepatotoxicity may occur after intake of a single high dose or multiple excessive doses. The aim of this narrative review is to critically analyze and summarize the available literature on newborns and infants exposed to supratherapeutic doses of paracetamol, with special focus on their clinical features, outcome, and management. METHODS: The PubMed, SCOPUS, and Google Scholar search engines were used to collect data, without time limitation. The following keywords were used: paracetamol/acetaminophen, overdose, hepatotoxicity, N-acetylcysteine, newborn, infant. RESULTS: The literature search identified a total of 27 case reports, a number of review articles, and few other relevant publications. Neonatal poisoning from paracetamol resulted from transplacental drug transfer after maternal overdose in some published cases, while it was the consequence of medication errors in other cases. Newborns and infants who have received a single overdose and have paracetamol concentrations below the Rumack-Matthew nomogram limits are at low risk of serious hepatic damage, while those who have recently ingested more than one supratherapeutic dose of paracetamol should be managed with caution. The treatment of choice for paracetamol poisoning is N-acetylcysteine, a specific antidote which reduces paracetamol hepatotoxic effects. N-Acetylcysteine should be given according to specific regimens through weight-based dosing tables. CONCLUSIONS: Caution should be used when paracetamol is administered to the newborn. In the event of an overdose, careful patient monitoring and personalization of post-overdose procedures are recommended.

Ceftriaxone-associated biliary pseudolithiasis in children: do we know enough?

Ceftriaxone is an antibiotic agent frequently used in paediatric hospital practice for the treatment of severe bacterial infections. The use of this agent can result in cholelithiasis and/or biliary sludge, more commonly in children than in adults. This systematic review was aimed at analysing available literature concerning ceftriaxone-associated biliary pseudolithiasis in paediatric patients, with a special emphasis on the clinical aspects. A literature analysis was performed using Medline and Embase electronic databases (articles published in English up to December 2019), with the search terms and combinations as follows:'ceftriaxone', 'cholelithiasis', 'biliary sludge' 'gallstones' 'neonates' 'children' 'clinical aspects' 'management'. Several case reports, case series and prospective/retrospective studies have documented a relationship between ceftriaxone treatment and biliary pseudolithiasis in the paediatric population, even though literature data regarding neonates and infants are scarce. Ceftriaxone-associated biliary pseudolithiasis is dose-dependent and usually asymptomatic but, sometimes, it may present with abdominal pain, nausea and emesis. Abdominal ultrasonography should be performed when this complication is suspected. Generally, ceftriaxone-associated cholelithiasis resolves over a variable period of time (days to months) after cessation of therapy. Therefore, a conservative approach to this condition is advocated, but a prolonged follow-up may be necessary. A personalized assessment of factors predisposing to ceftriaxone-associated biliary pseudolithiasis before prescribing the drug can allow to minimize the risk of developing it, with significant advantages in terms of human and economic costs.