Safety and efficacy of elexacaftor/tezacaftor/ivacaftor in people with Cystic Fibrosis following liver transplantation: A systematic review.

BACKGROUND & AIMS: Cystic Fibrosis (CF) liver disease progresses to liver failure requiring transplantation in about 3 % of patients, 0.7 % of CF patients are post liver transplant. The prognosis of CF has improved with the introduction of elexacaftor/tezacaftor/ivacaftor (ETI). Due to the paucity of data and concerns regarding interactions with immunosuppressive drug regimens, there is no general consensus on use of ETI post liver transplantation. The aim of this review is to report the safety and efficacy of ETI in CF patients who underwent liver transplantation. METHODS: A systematic review was conducted through MEDLINE/Pubmed and EMBASE databases. English-written articles reporting clinical data on liver transplanted CF patients treated with ETI were included. Article quality was evaluated using the Critical Appraisal Checklist for Case Reports. RESULTS: Twenty cases were retrieved from 6 reports. Temporary discontinuation and/or dose reduction due to elevated transaminases was required in 5 cases. ETI restarted on a reduced dose was tolerated in 3 out of 5 patients, 1 patient tolerated full dose. Tacrolimus dose change was required in 14 cases, in 1 case ETI was discontinued due to tacrolimus toxicity. Improvement in percentage predicted FEV1 was noted in 15/19 patients (median +17 %, range 8 %-38 %). CONCLUSIONS: In the majority of liver transplanted patients ETI is well tolerated, although adverse events and liver function abnormalities may occur. Close monitoring of liver function and tacrolimus level is warranted. Significant improvement in lung function after ETI initiation is confirmed, highlighting the importance of accessing this medication for this group of patients.

Corrigendum: HLH as an additional warning sign of inborn errors of immunity beyond familial-HLH in children: a systematic review.

[This corrects the article DOI: 10.3389/fimmu.2024.1282804.].

Efficacy and safety of odevixibat in patients with Alagille syndrome (ASSERT): a phase 3, double-blind, randomised, placebo-controlled trial.

BACKGROUND: In patients with Alagille syndrome, cholestasis-associated clinical features can include high serum bile acids and severe pruritus that can necessitate liver transplantation. We aimed to evaluate the efficacy and safety of the ileal bile acid transporter inhibitor odevixibat versus placebo in patients with Alagille syndrome. METHODS: The ASSERT study was a phase 3, double-blind, randomised, placebo-controlled trial that enrolled patients at 21 medical centres or hospitals in ten countries (Belgium, France, Germany, Italy, Malaysia, the Netherlands, Poland, Türkiye, the UK, and the USA). Eligible patients had a genetically confirmed diagnosis of Alagille syndrome, a history of significant pruritus, and elevated serum bile acids. Patients were randomly assigned (2:1) to receive oral odevixibat 120 µg/kg per day or placebo for 24 weeks (in a block size of six and stratified by age: <10 years and ≥10 years to <18 years) via a web-based system. Patients, clinicians, study staff, and people analysing the data were masked to treatment allocation. The primary efficacy endpoint was change in caregiver-reported scratching score (on the PRUCISION instrument; range 0-4) from baseline to weeks 21-24. The prespecified key secondary efficacy endpoint was change in serum bile acid concentration from baseline to the average of weeks 20 and 24. Outcomes were analysed in patients who received at least one dose of study drug (the full analysis set for efficacy outcomes and the safety analysis set for safety outcomes). This trial is registered on ClinicalTrials.gov (NCT04674761) and EudraCT (2020-004011-28), and is completed. FINDINGS: Between Feb 26, 2021, and Sept 9, 2022, 52 patients were randomly assigned to receive odevixibat (n=35) or placebo (n=17), all of whom were included in the analysis sets. The median age was 5·5 years (IQR 3·2 to 8·9). 27 (52%) of 52 patients were male and 25 (48%) were female. The mean scratching score was elevated at baseline in both groups (2·8 [SD 0·5] for odevixibat vs 3·0 [0·6] for placebo). Mean scratching scores at weeks 21-24 were 1·1 (0·9) for odevixibat and 2·2 (1·0) for placebo, representing a least-squares (LS) mean change of -1·7 (95% CI -2·0 to -1·3) for odevixibat and -0·8 (-1·3 to -0·3) for placebo, which was significantly greater for odevixibat than for placebo (difference in LS mean change from baseline -0·9 [95% CI -1·4 to -0·3]; p=0·0024). Odevixibat also resulted in significantly greater reductions in mean serum bile acids from baseline versus placebo (237 µmol/L [SD 115] with odevixibat vs 246 µmol/L [121] with placebo) to the average of weeks 20 and 24 (149 µmol/L [102] vs 271 µmol/L [167]; LS mean change -90 µmol/L [95% CI -133 to -48] with odevixibat vs 22 µmol/L [-35 to 80] with placebo; difference in LS mean change -113 µmol/L [95% CI -179 to -47]; p=0·0012). The most common treatment-emergent adverse events were diarrhoea (ten [29%] of 35 patients in the odevixibat group vs one [6%] of 17 in the placebo group) and pyrexia (eight [23%] vs four [24%]). Seven patients had serious treatment-emergent adverse events during the treatment period: five (14%) in the odevixibat group and two (12%) in the placebo group. No patients discontinued treatment and there were no deaths. INTERPRETATION: Odevixibat could be an efficacious non-surgical intervention to improve pruritus, reduce serum bile acids, and enhance the standard of care in patients with Alagille syndrome. Longer-term safety and efficacy data of odevixibat in this population are awaited from the ongoing, open-label ASSERT-EXT study. FUNDING: Albireo Pharma, an Ipsen company.

Convergence and divergence in Kawasaki disease and multisystem inflammatory syndrome in children: results from the COVASAKI survey.

OBJECTIVES: To compare Kawasaki disease (KD) and multisystem inflammatory syndrome (MIS-C) in children. METHODS: Prospective collection of demographics, clinical and treatment data. Assessment of type 1 interferon (IFN) score, CXCL9, CXCL10, Interleukin (IL)18, IFNγ, IL6, IL1b at disease onset and at recovery. RESULTS: 87 patients (43 KD, 44 MIS-C) were included. Age was higher in MIS-C compared to KD group (mean 31±23 vs. 94±50 months, p<0.001). Extremities abnormalities (p=0.027), mucosal involvement (p<0.001), irritability (p<0.001), gallbladder hydrops (p=0.01) and lymphadenopathy (p=0.07) were more often recorded in KD. Neurological findings (p=0.002), gastrointestinal symptoms (p=0.013), respiratory involvement (p=0.019) and splenomegaly (p=0.026) were more frequently observed in MIS-C. Cardiac manifestations were higher in MIS-C (p<0.001), although coronary aneurisms were more frequent in KD (p=0.012). In the MIS-C group, the multiple linear regression analysis revealed that a higher IFN score at onset was related to myocardial disfunction (p<0.001), lymphadenopathy (p=<0.001) and need of ventilation (p=0.024). Both CXCL9 and CXCL10 were related to myocardial disfunction (p<0.001 and p=0.029). IL18 was positively associated to PICU admission (0.030) and ventilation (p=004) and negatively associated to lymphadenopathy (0.004). IFNγ values were related to neurological involvement and lymphadenopathy (p<0.001), IL1b to hearth involvement (0.006). A negative correlation has been observed between IL6 values, heart involvement (p=0.013) and PICU admission (p<0.001). CONCLUSIONS: The demographic and clinical differences between KD e MIS-C cohorts confirm previous reported data. The assessment of biomarkers levels at MIS-C onset could be useful to predict a more severe disease course and the development of cardiac complications.

Severe A(H1N1)pdm09 influenza acute encephalopathy outbreak in children in Tuscany, Italy, December 2023 to January 2024.

A severe outbreak of influenza A(H1N1pdm09) infection in seven children (median age: 52 months) occurred between December 2023 and January 2024 in Tuscany, Italy. Clinical presentation ranged from milder encephalopathy to acute necrotizing encephalopathy (ANE) with coma and multiorgan failure; one child died. This report raises awareness for clinicians to identify and treat early acute encephalopathy caused by H1N1 influenza and serves as a reminder of severe presentations of influenza in young children and the importance of vaccination.

Corrigendum: The new Italian registry of infantile thrombosis (RITI): a reflection on its journey, challenges and pitfalls.

[This corrects the article DOI: 10.3389/fped.2023.1094246.].

Corrigendum: Choosing wisely in pediatric healthcare: a narrative review.

[This corrects the article DOI: 10.3389/fped.2022.1071088.].

ESPGHAN recommendations on treatment of chronic hepatitis C virus infection in adolescents and children including those living in resource-limited settings.

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease worldwide, with more than three million viraemic adolescents and children. Treatment of adults with HCV infection and HCV-related liver disease has advanced considerably thanks to development and improvements in therapy. Direct-acting antiviral regimens are safe and effective. Three regimens with pangenotypic activity (glecaprevir/pibrentasvir, sofosbuvir/velpatasvir and sofosbuvir/velpatasvir/voxilaprevir) and three regimens with genotype-specific activity (sofosbuvir/ribavirin, sofosbuvir/ledipasvir and elbasvir/grazoprevir) have been approved with age-specific limitation for treatment of children with chronic hepatitis C by the European Medicines Agency and the United States Food and Drug Administration. The World Health Organization has set the ambitious target to eliminate hepatitis C as a major public health threat by 2030 and based its actions against HCV on the large use of direct acting antivirals. These updated European Society for Pediatric Gastroenterology, Hepatology and Nutrition recommendations on treatment of hepatitis C describe the optimal therapeutic management of adolescents and children with HCV infection including specific indications for those living in resource-limited settings.

Disrupted Seasonality of Respiratory Viruses: Retrospective Analysis of Pediatric Hospitalizations in Italy from 2019 to 2023.

This multicenter study in Italian hospitals highlights the epidemiologic disruptions in the circulation of the 5 main respiratory viruses from 2019 to 2023. Our data reveal a resurgence of respiratory syncytial virus and influenza during the 2022-2023 winter season, with an earlier peak in cases for both viruses, emphasizing the importance of timely monitoring.

HLH as an additional warning sign of inborn errors of immunity beyond familial-HLH in children: a systematic review.

Background: Hemophagocytic Lymphohistiocytosis (HLH) is a rare and life-threatening condition characterized by a severe impairment of the immune homeostasis. While Familial-HLH (FHL) is a known cause, the involvement of other Inborn Errors of Immunity (IEI) in pediatric-HLH remains understudied. Objective: This systematic review aimed to assess the clinical features, triggers, laboratory data, treatment, and outcomes of pediatric HLH patients with IEI other than FHL (IEInotFHL), emphasizing the importance of accurate identification and management. Methods: A systematic search for studies meeting inclusion criteria was conducted in PubMed, EMBASE, MEDLINE, and Cochrane Central. Quality assessment was performed through JBI criteria. Results: A comprehensive search yielded 108 records meeting inclusion criteria, involving 178 patients. We identified 46 different IEI according to IUIS 2022 Classification. Combined immunodeficiencies, immune dysregulation disorders, and phagocyte defects were the IEI most frequently associated with HLH. In 75% of cases, HLH preceded the IEI diagnosis, often with an unrecognized history of severe infections. Triggers reflected the specific infection susceptibilities within IEI groups. Liver and central nervous system involvement were less common than in FHL cases. Treatment approaches and outcomes varied, with limited long-term follow-up data, limiting the assessment of therapeutic efficacy across IEI groups. Conclusion: A comprehensive evaluation encompassing immunological, infectious, and genetic aspects is essential in pediatric-HLH. Relying solely on FHL or EBV susceptibility disorders tests is insufficient, as diverse other IEI can contribute to HLH. Early recognition of HLH as a potential warning sign can guide timely diagnostic investigations and facilitate tailored therapeutic interventions for improved outcomes. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=371425, PROSPERO, CRD42022371425.

Knowledge, attitudes and behaviours of a sample of Italian paediatricians towards RSV and its preventive strategies: a cross-sectional study.

BACKGROUND: Respiratory Syncytial Virus (RSV) infection mainly affects newborns, infants and young children aged < 2 years. Since an RSV vaccine is in the European Medicines Agency's waitlist validation, nowadays the prevention only includes passive immunization with monoclonal antibodies (mAb). In the present study we aimed at investigating Italian paediatricians' knowledge, attitudes and behaviours towards RSV and its prevention. METHODS: From February to May 2023, an anonymous online questionnaire, with answers based on the Likert scale, was administered to a sample of Italian paediatricians' members of the Italian Society of Paediatrics. Descriptive and inferential statistical analyses were performed using STATA 17. RESULTS: The paediatricians who answered the questionnaire were 507, mostly women (70.6%), aged 30-45 (33.1%), employed in hospitals in 66.6% of cases. The 10.8% of respondents reported that RSV is transmitted only among children younger than 2 years of age and 80.33% of participants that school-age children are not at risk of developing severe forms of RSV disease. The 25% of participants thought that active immunization is currently available to prevent RSV infection and 35.7% that does not exist passive immunization to prevent RSV for infants and newborns aged < 2 years. The 97.5% of physicians managed bronchiolitis cases and 65.6% of participants did not prescribe the administration of mAb. Higher age, seniority and RSV knowledge score were found to be associated with having a higher mAb knowledge score (p < 0.001) and having a higher RSV knowledge was associated with a higher mAb knowledge score (p < 0.001). The logistic regression model found that the odds of a positive attitude towards mAB knowledge score increased by over 3 times (OR 3.23, 95% CI [1.41, 7.40], p = 0.006) for being female and the odds of a positive attitude towards mAB knowledge score increased by almost 10 times (OR 9.73, 95% CI [3.06, 30.89], p < 0.001) for a one-unit increase in RSV knowledge score. CONCLUSIONS: Paediatricians' limited knowledge or awareness could represent a barrier to the implementation of preventive strategies against RSV infection. Strategies to improve paediatricians' education on RSV prevention are, therefore, crucial.

Opinion paper on the diagnosis and treatment of progressive familial intrahepatic cholestasis.

Background & Aims: Progressive familial intrahepatic cholestasis (PFIC) relates to a group of rare, debilitating, liver disorders which typically present in early childhood, but have also been reported in adults. Without early detection and effective treatment, PFIC can result in end-stage liver disease. The aim of the paper was to put forward recommendations that promote standardisation of the management of PFIC in clinical practice. Methods: A committee of six specialists came together to discuss the challenges faced by physicians in the management of PFIC. The committee agreed on two key areas where expert guidance is required to optimise care: (1) how to diagnose and treat patients with a clinical presentation of PFIC in the absence of clear genetic test results/whilst awaiting results, and (2) how to monitor disease progression and response to treatment. A systematic literature review was undertaken to contextualise and inform the recommendations. Results: An algorithm was developed for the diagnosis and treatment of children with suspected PFIC. The algorithm recommends the use of licensed inhibitors of ileal bile acid transporters as the first-line treatment for patients with PFIC and suggests that genetic testing be used to confirm genotype whilst treatment is initiated in patients in whom PFIC is suspected. The authors recommend referring patients to an experienced centre, and ensuring that monitoring includes measurements of pruritus, serum bile acid levels, growth, and quality of life following diagnosis and during treatment. Conclusions: The algorithm presented within this paper offers guidance to optimise the management of paediatric PFIC. The authors hope that these recommendations will help to standardise the management of PFIC in the absence of clear clinical guidelines. Impact and implications: This opinion paper outlines a consistent approach to the contemporaneous diagnosis, monitoring, referral and management of children with progressive familial intrahepatic cholestasis. This should assist physicians given the recent developments in genetic diagnosis and the availability of effective drug therapy. This manuscript will also help to raise awareness of current developments and educate health planners on the place for new drug therapies in progressive familial intrahepatic cholestasis.

Efficacy and safety of DAA in children and adolescents with chronic HCV infection: A systematic review and meta-analysis.

BACKGROUND AND AIMS: We evaluated the effectiveness and safety of pan-genotypic regimens, glecaprevir/pibrentasvir (GLE/PIB), sofosbuvir/velpatasvir (SOF/VEL), and sofosbuvir/daclatasvir (SOF/DCV) and other direct-acting antivirals (DAA) regimens for the treatment of hepatitis C virus (HCV)-infected adolescents (12-18 years), older children (6-11 years), and young children (3-5 years). The purpose of this systematic review and meta-analysis was to inform the World Health Organization (WHO) guidelines. METHODS: We included clinical trials and observational studies published up to August 11, 2021, that evaluated DAA regimens in HCV-infected adolescents, older children, and young children. We searched MEDLINE, EMBASE, and CENTRAL databases and key conference abstracts. Sustained virological response 12 weeks after the end of treatment (SVR12), adverse events (AEs), and treatment discontinuation were the outcomes evaluated. Risk of bias was assessed using a modified version of the ROBINS-I tool. Data were pooled using random-effects models, and certainty of the evidence was assessed using the GRADE approach. RESULTS: A total of 49 studies including 1882 adolescents, 436 older children, and 166 young children were considered. The SVR12 was 100% (95% Confidence Interval: 96-100), 96% (90-100), and 96% (83-100) for GLE/PIB in adolescents, older, and young children, respectively; 95% (90-99), 93% (86-98), and 83% (70-93), for SOF/VEL, respectively; and 100% (97-100) and 100% (94-100) for SOF/DCV in adolescent and older children, respectively. There was a clear trend towards a higher rate of any reported AE from adolescents (50%), older children (53%), to young children (72%). Serious AEs and treatment discontinuations were uncommon in adolescents and older children (<1%) but slightly higher in young children (3%). CONCLUSIONS: All three pan-genotypic DAA regimens were highly effective and well-tolerated and are now recommended by the WHO for use in adults, adolescents, and children down to 3 years, which will simplify procurement and supply chain management. The evidence was based largely on single-arm non-randomized controlled studies. Moreover, there were also missing data regarding key variables such as route of HCV acquisition, presence or absence of cirrhosis, or HIV co-infection that precluded evaluation of the impact of these factors on outcomes. PROSPERO RECORD: CRD42020146752.

Health-related quality of life in patients aged 6-18 years with chronic hepatitis C treated with sofosbuvir/velpatasvir.

BACKGROUND & AIMS: The aim of this study was to assess the effect of treatment with sofosbuvir/velpatasvir (SOF/VEL) on the health-related quality of life (HRQL) of children with chronic hepatitis C. METHODS: In the non-commercial, non-randomized, open-label PANDAA-PED study, 50 children aged 6-18 years with chronic hepatitis C were treated with a fixed dose of SOF/VEL. All patients achieved sustained virologic response 12 weeks after the end of treatment (SVR12). Evaluation of HRQL was performed twice: at baseline (before the treatment) and during the SVR12 analysis using the KIDSCREEN-27 questionnaires, which included 5 dimensions of HRQL, for child self-reporting and parent proxy reporting. The normal range for the population was set to T values of 50 ± 10 points. Child-parent agreement was analysed using the intra-class correlation coefficient (ICC) and Bland-Altman test. RESULTS: Mean T values were within the normal range for all dimensions, both before and after treatment. There was a significant improvement in physical well-being based on the children's self-assessment (from 48.53 to 51.21, p = .03). In addition, a trend towards better scores in the 'social support & peers' part of the parent proxy evaluation (from 45.98 to 48.66, p = .06) was noticed. After the treatment, the proportion of children self-assessing their physical well-being as below normal significantly decreased from 17% to 5% (p = .007). HRQL scores were not associated with patients' sex, but in most cases, younger age correlated with better HRQL. Evaluation of the ICC for child self-reports versus parent proxy reports revealed poor to moderate agreement for most single measures. Bland-Altman analysis showed that in all dimensions, both before and after treatment, the limits of agreement (LoAs) exceeded ±5 points (half of the SD and considered a maximum allowed difference). CONCLUSIONS: A significant proportion of children with chronic hepatitis C have decreased HRQL in all dimensions, but effective treatment with SOF/VEL leads to an improvement in some areas of well-being. As the effect of HCV on HRQL is more pronounced in older patients, treatment of younger children should be indicated to prevent them from experiencing decreased HRQL due to ongoing HCV infection in the future.