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.

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.

Efficacy of Sofosbuvir/Ledipasvir in Adolescents With Chronic Hepatitis C Genotypes 1, 3, and 4: A Real-world Study.

OBJECTIVES: Sofosbuvir/Ledipasvir (SOF/LDV) has been approved by the European Medicine Agency (EMA) for the treatment of children and adolescents (at least 3 years of age) with chronic hepatitis C (CHC) genotype 1, 3, and 4 infection. The aim of this study was to evaluate the efficacy and safety of SOF/LDV in adolescents (12 to <18 years old) with CHC in the real-world setting. METHODS: Prospective, open-label, multicentre study involving 12 Italian centres. Patients received the fixed-dose combination of SOF/LDV (400/90 mg) once daily ± ribavirin as per EMA approval and recommendations. The key efficacy endpoint was sustained virological response 12 weeks after the end of treatment (SVR12) as per intention-to-treat analysis. Safety was assessed by adverse events and clinical/laboratory data. RESULTS: Seventy-eight consecutive adolescents (median age 15.2 years, range 12-17.9; girls 53.8%) were enrolled and treated between June 2018 and December 2019. Genotype distribution was as follows: genotype 1 (82.1%), 3 (2.5%), and 4 (15.4%). Seventy-six (97.4%) patients completed treatment and follow-up. Overall, SVR12 was 98.7%. One patient was lost to follow-up after 4 weeks of treatment; 1 patient completed treatment and missed the follow-up visit. No virological breakthrough or relapse were observed. No patient experienced grade 3 to 4 adverse event or serious adverse event. CONCLUSIONS: The results of this real-world study confirmed the high efficacy and the optimal safety profile of SOF/LDV for treatment of CHC in adolescents.

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.

Intrahepatic bile duct primary cilia in biliary atresia.

AIM: The etiopathogenesis of non-syndromic biliary atresia (BA) is obscure. The primary aim was to investigate intrahepatic bile duct cilia (IHBC) in BA at diagnosis and its correlation with clinical outcome. The secondary aim was to analyze IHBC in routine paraffin-embedded liver biopsies using conventional scanning electron microscopy (SEM). METHODS: Surgical liver biopsies taken at diagnosis from 22 BA infants (age range, 39-116 days) and from eight children with non-BA chronic cholestasis (age range, 162 days -16.8 years) were evaluated for IHBC by immunofluorescence (IF) and SEM. A minimum 18-month follow-up after surgery was available for all patients. RESULTS: By IF, cilia were present in 6/8 (75%) non-BA but only in 3/22 (14%) BA cases, and cilia were reduced or absent in 19/22 (86%) BA and 2/8 (25%) non-BA livers (P < 0.01). In BA, cilia presence was found to be associated with clearance of jaundice at 6-month follow-up (P < 0.05). However, high overall survival rates with native liver, >90% at 12 months, and >70% at 24 months post-surgery, were recorded regardless of cilia presence/absence at diagnosis. Electron microscopy was able to detect bile ducts and cilia in routine liver biopsies, revealing significant abnormalities in 100% BA livers. CONCLUSIONS: The presence of IHBC in BA livers at the diagnosis was associated with resolution of cholestasis, although was not predictive of short-term survival with native liver. Scanning electron microscopy represents a powerful new tool to study routine liver biopsies in biliary disorders. Cilia dysfunction in BA pathogenesis and/or disease progression warrants further investigation.

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.

The complex link between sleep-disordered breathing and asthma control in pediatric patients: a cross-sectional study.

BACKGROUND: In children, asthma and sleep-disordered breathing (SDB) may affect quality of life (QoL), and SDB may complicate asthma management. OBJECTIVE: To evaluate the prevalence of SDB, its association with asthma control, and risk factors associated with SDB in a cohort of asthmatic children. The effects of asthma control and SDB on QoL were also investigated. METHODS: We consecutively recruited asthmatic children referred to our Pulmonology Service from 1 December 2022 to 31 May 2023. Data on anthropometrics, respiratory function, and allergies were collected. The prevalence of SDB was assessed by the Pediatric Sleep Questionnaire (PSQ). Asthma control status was assessed by the Childhood Asthma Control Test (C-ACT), while QoL was evaluated by the Pediatric Quality of Life Inventory (PedsQL) questionnaire. Factors associated with SDB were analyzed. RESULTS: In total 78 asthmatic children aged 5-12 years were included. SDB was found in 37.2% of them, with a higher prevalence in children with uncontrolled versus well-controlled asthma (60.1% vs. 27.3%; p-value =0.005). The C-ACT score was significantly lower in SDB-positive versus SDB-negative group, and uncontrolled asthma (C-ACT ≤19) was associated with a 4.15-fold increased risk of SDB. The PedsQL score was significantly lower in asthmatic children with than without SDB and was associated with lower SDB risk. SDB increased the risk of uncontrolled asthma in children, and asthmatic children with SDB had lower QoL. CONCLUSION: In asthmatic children, SDB affects both asthma control and QoL. Children with uncontrolled asthma should be referred for polysomnography to identify a possible underlying SDB.

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.

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.

Metabolomics in the developing infant.

PURPOSE OF REVIEW: The aim of this review is to update readers on the most recent publications concerning clinical metabolomics in developing infants. RECENT FINDINGS: Only a limited number of neonatal and pediatric metabolomic studies have been published, in comparison to the adult. However, this number of pediatric and neonatal papers is constantly increasing. The latest papers are related to intrauterine growth restricted and small for gestational age neonates, prematurity, mode of delivery, hypoxic ischemic encephalopathy, persistent ductus arteriosus, respiratory syndrome and surfactant therapy, cytomegalovirus infection, nephrouropathy, inborn errors of metabolism, pharmametabolomics, and nutrimetabolomics (including study of maternal milk and formula). Also numerous papers have been presented in experimental neonatology. In particular, the fluids most frequently used were as follows: urine, cord blood plasma, but also milk and stools. Each condition or disease presents a specific discriminating set of metabolites, which can be considered like a 'bar code'. SUMMARY: In the near future, improved tools for metabolomic analysis (like simplified 'dipsticks' for urine) and its integration with other 'omics' will make this technology available in the clinical setting, leading to better or easier clinical decision making. Urinary metabolomics will probably be one of the most used tools in pediatrics and the metabolome will be 'our world'.

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.

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.

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.

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.

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.