Case report: Acute liver failure in children and the human herpes virus 6-? A factor in the recent epidemic.

The 2022 worldwide epidemic of acute hepatitis and liver failure in young children has led to a focus on unusual causes for childhood acute hepatitis. In the UK epidemic, human herpes virus subtype 6B (HHV-6B) was detected along with adenovirus subtype-41F in severely affected children, especially in those requiring liver transplantation (LT). The lifting of COVID lock-down measures has coincided with the rise in these common childhood infections with a higher than expected rate of systemic complications. The sudden exposure of young children to common childhood infections from which they were protected during the pandemic may have induced an abnormal immune mediated response potentiated by multiple pathogen exposure. Primary HHV-6 infection is one such common childhood infection. Classically known as Roseola infantum due to the appearance of a widespread erythematous rash on fever subsidence (exanthema subitem), it has a peak incidence of 6-12 months of age and almost all children will have been infected by age 2. It is the virus most frequently associated with febrile convulsions but the more serious complications of hepatitis and liver failure are rare. We report on the historic cases of three female infants who had suspected primary HHV-6B infection, acute hepatitis and rapid progression to acute liver failure (ALF) requiring LT. Appearances of their native liver were identical to those described in children in the recent hepatitis epidemic. Deteriorating clinical trajectories of recurrent graft hepatitis and rejection-like episodes followed and all three succumbed to graft failure with HHV-6B detected posthumously in their liver allografts. Our case series and the serious complications observed with the recent rise in common childhood infections is a reminder that these routinely encountered pathogens can be deadly especially in the young immunologically untrained. We advocate for HHV-6 to be screened for routinely in children with acute hepatitis and the use of effective HHV-6 anti-viral prophylaxis to prevent recurrence post-transplant.

Treating children with HCV close to home through a virtual national multidisciplinary network

AimHepatitis C Virus (HCV) infection is a major global health problem. Direct Acting Anti-viral therapy (DAA) has cure rates of 99% in adults and adolescents.1 DAAs were licensed for children 3 – 12 years during the recent coronavirus pandemic. In order to ensure equitable access and a safe, effective and convenient supply of these medications during lockdown, we established a virtual national treatment pathway for children with HCV in England and evaluated its feasibility, efficacy and treatment outcomes.MethodA paediatric Multidisciplinary Team Operational Delivery Network (pMDT ODN), supported by NHS England (NHSE), was established with relevant paediatric specialists, including pharmacists, to provide a single point of contact for referrals and information. Referral, treatment protocols and family friendly patient information were developed for all HCV therapy. On referral the pMDT ODN discussed and agreed the most appropriate DAA therapy based on clinical presentation and patient preferences, including ability to swallow tablets. Treatment was then prescribed and supplied in association with the local paediatrician and pharmacist, without the need for families to travel to national centres. All children were eligible for NHS funded therapy, each referring centre was approved by the pMDT ODN, prior to approval to dispense medication and funds were reclaimed via Blueteq authorisation. Demographic, clinical and social data was collected, and treatment outcomes were recorded. Feedback on feasibility and satisfaction on the pathway and supply of medication was sought from referrers.Results34 children were referred during the first six months;median (range) age 10 (3.9 – 14.5) years;15M;19F: Majority of referrals are HCV genotype type 1 (n=17) and 2 (n=12). DAA treatments prescribed: Sofosbuvir/Ledipasvir (n=21);Sofosbuvir/Velpatisvir (n=11) Glecaprevir/Pibrentasvir (n=2).27/34 confirmed as able to swallow tablets;3/7 have received training and are now able to successfully swallow tablets;4/7 are awaiting release of granules. All children who have completed treatment to date (11/27) have cleared virus at the end of treatment. Once the network was established, referrers found the virtual process easy to access. They valued being able to discuss their patients with the MDT providing a single point of contact with national specialists to discuss therapy. Specialist pharmacists within the pMDT were able to provide pharmaceutical information and support local Trusts to ensure safe, timely and funded supply of medication to children. There were three reported dispensing errors, where adult strength tablets were dispensed in error locally, however no doses were taken as parents noticed the error prior to giving a dose. A delay in availability of the granule or pellet formulations due to manufacturing delays during COVID, has meant a delay in referring and treating those children unable to swallow tablets.ConclusionPharmacists were a valuable resource within the National HCV Paediatric MDT Operational Delivery Network. They contributed expert knowledge on formulations and doses, supporting delivery of high-quality treatment and equity of access for children and young people with HCV in England. Education and awareness of new Paediatric formulations for local Pharmacy teams may prevent future dispensing errors.ReferenceNHS News 2021. Life saving hepatitis C treatment for children on the NHS. 24th August 2021. Available at: NHS England » Lifesaving hepatitis C treatment for children on the NHS [accessed 12th June 2022].

Reduced Presentation of Biliary Atresia During the COVID-19 Lockdown: A Population Based Observational Study.

OBJECTIVE: The aim of this study was to assess whether there has been a change in presentations of biliary atresia (BA) in England and Wales during the first and second coronavirus disease 2019 (COVID-19) lockdowns (January-June 2020 and 2021). DESIGN: This population study assessed all confirmed cases of BA, from January 2020 to December 2021 across the 3 UK pediatric liver centers originating from England and Wales. Data was then compared to the incidence of confirmed BA cases from January to December 2017, 2018, and 2019. RESULTS: During January-June 2020 and 2021, there were only 8 and 12 presenting cases of BA in England and Wales, compared to 16, 13, and 18 for the same time periods in 2017, 2018, and 2019, respectively. This difference was significant in a two-sided t test for 2020 ( P = 0.035) but not for 2021 ( P = 0.385). There was no difference in the mean days to Kasai procedure in January-June 2020 and 2021 compared to 2017-2019; however average time to Kasai after the lockdown periods was significantly higher. CONCLUSIONS: There was a significant reduction in the presenting cases of BA during the first COVID-19 lockdown, with an increased time for BA referrals after the pandemic lockdowns were lifted in England and Wales.

Treating children with HCV close to home through a virtual national multidisciplinary network

Background and AimsHepatitis C virus (HCV) infection is a major global health problem in adults & children. The recent efficacy of Direct Acting Anti-viral therapy (DAA) has cure rates of 99% in adults and adolescents. These drugs were licensed for children 3–12 yrs during the recent coronavirus pandemic. To ensure equitable access, safe & convenient supply during lockdown, we established a virtual national treatment pathway for children with HCV in England & evaluated its feasibility, efficacy & treatment outcomes.MethodA paediatric Multidisciplinary Team Operational Delivery Network (pMDT ODN), supported by NHS England (NHSE), was established with relevant paediatric specialists to provide a single point of contact for referrals & information. Referral & treatment protocols were agreed for HCV therapy approved by MHRA & EMA. On referral the pMDT ODN agreed the most appropriate DAA therapy based on clinical presentation & patient preferences, including ability to swallow tablets. Treatment was prescribed in association with the local paediatrician & pharmacist, without the need for children & families to travel to national centres. All children were eligible for NHS funded therapy;referral centres were approved by the pMDT ODN to dispense medication;funding was reimbursed via a national NHSE agreement. Demographic & clinical data, treatment outcomes & SVR 12 were collected. Feedback on feasibility & satisfaction on the pathway was sought from referrers.ResultsIn the first 6 months, 34 children were referred;30- England;4 - Wales;median (range) age 10 (3.9 – 14.5) yrs;15M;19F: Most were genotype type 1 (17) & 3 (12);2 (1);4(4). Co-morbidities included: obesity (2);cardiac anomaly (1);Cystic Fibrosis (1);Juvenile Arthritis (1). No child had cirrhosis. DAA therapy prescribed: Harvoni (21);Epclusa (11);Maviret (2) .27/34 could swallow tablets;3/7 received training to swallow tablets;4/7 are awaiting release of granules.11/27 have completed treatment and cleared virus;of these 7/11 to date achieved SVR 12. 30 children requiring DAA granule formulation are awaiting referral and treatment.Referrers found the virtual process easy to access, valuing opportunity to discuss their patient’s therapy with the MDT & many found it educational. There were difficulties in providing the medication through the local pharmacy. However there are manufacturing delays in providing granule formulations because suppliers focused on treatments for COVID, leading to delays in referring and treating children unable to swallow tablets.ConclusionThe National HCV pMDT ODN delivers high quality treatment & equity of access for children & young people, 3– 18 yrs with HCV in England, ensuring they receive care close to home with 100% cure rates.

Depression, anxiety, substance misuse and self-harm in children and young people with rare chronic liver disease.

The burden of mental illness in young people with chronic liver disease is not known. In this population cohort study in England, we identified 358 individuals (aged ≤25 years) diagnosed with autoimmune hepatitis or liver disease related to cystic fibrosis and 1541 propensity-score-matched controls. By the first year of follow-up, the cumulative burden of psychiatric events in participants with liver disease was high compared with controls: anxiety disorder (6.87 per 100 individuals [95% CI 4.00-9.73] v. 2.22 [95% CI 1.37-3.07]), depression (5.10 [95% CI 2.83-7.37] v. 0.86 [95% CI 0.53-1.19]), substance misuse (10.61 [95% CI 9.50-11.73] v. 1.23 [95% CI 0.71-1.75]) and self-harm (3.09 [95% CI 1.12-5.05] v. 0.20 [95% CI 0.07-0.33]). Participants with liver disease had a 2-fold increase (OR = 1.94, 95% CI 1.45-2.58), a 2.5-fold increase (OR = 2.59, 95% CI 1.91-3.50) and 4.4-fold increase (OR = 4.44; 95% CI 3.46-5.71) in the risk of anxiety, depression and substance misuse, respectively. These findings highlight the need for effective intervention in psychiatric disorders in young people with rare liver disease.

Reduced presentation of biliary atresia during the COVID-19 lockdown – a population based observational study

BackgroundBiliary Atresia (BA) is the commonest surgical cause of cholestasis in infancy, affecting 1 in 1700 live births in England and Wales. Previous reports have demonstrated an average of 50 BA cases every year across the three UK centres, however observations from clinicians across these three centers have suggested a reduction in the number of presenting cases during the COVID-19 lockdown.ObjectivesThe aim of this study was to assess whether there has been a change in presentations of Biliary Atresia (BA) in England and Wales during the first COVID-19 lockdown (January – July 2020).MethodsThis population study assessed all confirmed cases of BA, from January 2020 to July 2020, across the 3 UK paediatric liver centers originating from England and Wales. Data was then compared to the incidence of confirmed BA cases from January - July 2017, 2018 and 2019, as documented within the Biliary Atresia National Registry.ResultsFrom January – July 2020, there were only 8 presenting cases of BA in England and Wales, compared to 24, 17 and 20 for the same time periods in 2017, 2018 and 2019 respectively. This difference was significant in a two-sided t-test (p = 0.0150). While the mean days to Kasai procedure was longer in 2020 compared to 2016–2019 (64.6 vs. 56.6), this difference was not observed to be significant (p=0.551).ConclusionsThere was a significant reduction in the presenting cases of BA during the first COVID-19 lockdown. This could either be due to a reduction in referrals or from a reduction in incidence of the condition, potentially due to an infectious cause being less prevalent during the national lockdown. If the former is correct there is potential for a significant number of BA babies with cholestatic jaundice remaining within the community. General practitioners and community paediatricians should be alert for these patients.

Paediatric Liver Transplantation During COVID-19 Pandemic: Lessons Learned and Unanswered Questions.

COVID-19 pandemic has imposed many challenges on paediatric liver transplantation (PLT) services and has necessitated several adaptations in different stages of the process to ensure transplant centres can still deliver the proposed services in addition to protecting patients and staff against infection. This review article digs through the current literature to clarify the challenges imposed by SARS-CoV2 on PLT centres globally. It provides an overview of current practice as well as suggestions from experts in the field to overcome multiple obstacles. In paediatrics, the reaction to SARS-CoV2 may be less severe than that seen in the adult population, but this can change in view of newly discovered virus strains. Response of transplant centres to the current pandemic was variable depending on the anticipated risk and available resources. Telemedicine has helped PLT programmes to continue their activities while protecting patients, as well as staff against the risk of SARS-CoV2 virus. Further studies are needed to guide immunosuppression management in post-transplant infected candidates; answering this critical question will help PLT centres solve this dilemma.

Understanding COVID-19: are children the key?

The devastating impact of the COVID-19 pandemic on global health and economic stability is immeasurable. The situation is dynamic and fast-evolving, with the world facing new variants of concern which may have immune escape potential. With threatened treatment and preventative strategies at stake, and the prospect of reinfection prolonging the pandemic, it is more crucial than ever to understand the pathogenesis of SARS-CoV-2 infection, which intriguingly disproportionately affects adults and the elderly. Children infected with SARS-CoV-2 remain largely asymptomatic or undergo a transient mild illness. Understanding why children have a milder phenotype and a significant survival advantage may help identify modifiable risk factors in adults. Current evidence suggests adults with COVID-19 show variability in innate and adaptive immune responses, which result in uncontrolled proinflammatory cytokine production in some patients, leading to severe disease and mortality. Children with acute COVID-19 infection seldom progress to acute respiratory distress syndrome and are less likely to exhibit the cytokine storm which is so prominent in adults. Even with the Kawasaki-like illness, a hyperinflammation syndrome also known as paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2, mortality is low. The key to successfully combating SARS-CoV-2 and future zoonotic pandemics may lie in understanding these critical differences and merits focused consideration and research. The impact of community transmission among asymptomatic children is unknown; sustained global decline in infection rates and control of the COVID-19 pandemic may not be achieved until vaccination of children occurs. In this review, we discuss the fundamental differences in the immune response between children and adults in the fight against SARS-CoV-2.

COVID-19 in Children With Liver Disease.

Background: The global pandemic caused by novel Coronavirus SARS-CoV-2 disease (COVID-19) is a major threat to the general population and for patients with pre-existing chronic conditions. We report data concerning SARS-CoV-2 infection in children with chronic liver disease (CLD). Methods: A literature review using the online database PubMed was performed to summarize available findings on the association between pre-existing liver disease and COVID-19 infection in children. Results: Children with COVID-19 have preserved effector and immunosuppressive components resulting in a milder disease compared to adults. The most common hepatic manifestation is an elevation of hepatic transaminases. Liver damage may be directly caused by viral infection of liver cells, by medications or by the chronic hypoxia seen in COVID-19 patients. A multicenter study reported that the majority of children with a CLD remained healthy during the outbreak. Similarly, studies reported that children on immunosuppressive treatment, including patients with autoimmune liver disease (AILD) and liver transplantation (LT), maintained good health during the outbreak without experiencing major complications even if infected with COVID-19. Conclusion: COVID-19-related liver injury presents with a mild elevation of transaminases, although its clinical significance is unclear. Children with CLD, including those with AILD and post-LT, do not have an increased risk for severe disease course of SARS-CoV-2 infection with little or no liver dysfunction. These data highlight the necessity to ensure normal standards of care while adhering to national Covid-19 guidelines, and particularly to maintain immunosuppressive medication to prevent relapse or rejection. Further research is required to evaluate the differences in clinical course between immunosuppressed adults and children and in particular whether asymptomatic infection is a concern.

New dimensions for hospital services and early detection of disease: a Review from the Lancet Commission into liver disease in the UK.

This Review, in addressing the unacceptably high mortality of patients with liver disease admitted to acute hospitals, reinforces the need for integrated clinical services. The masterplan described is based on regional, geographically sited liver centres, each linked to four to six surrounding district general hospitals-a pattern of care similar to that successfully introduced for stroke services. The plan includes the establishment of a lead and deputy lead clinician in each acute hospital, preferably a hepatologist or gastroenterologist with a special interest in liver disease, who will have prime responsibility for organising the care of admitted patients with liver disease on a 24/7 basis. Essential for the plan is greater access to intensive care units and high-dependency units, in line with the reconfiguration of emergency care due to the COVID-19 pandemic. This Review strongly recommends full implementation of alcohol care teams in hospitals and improved working links with acute medical services. We also endorse recommendations from paediatric liver services to improve overall survival figures by diagnosing biliary atresia earlier based on stool colour charts and better caring for patients with impaired cognitive ability and developmental mental health problems. Pilot studies of earlier diagnosis have shown encouraging progress, with 5-6% of previously undiagnosed cases of severe fibrosis or cirrhosis identified through use of a portable FibroScan in primary care. Similar approaches to the detection of early asymptomatic disease are described in accounts from the devolved nations, and the potential of digital technology in improving the value of clinical consultation and screening programmes in primary care is highlighted. The striking contribution of comorbidities, particularly obesity and diabetes (with excess alcohol consumption known to be a major factor in obesity), to mortality in COVID-19 reinforces the need for fiscal and other long delayed regulatory measures to reduce the prevalence of obesity. These measures include the food sugar levy and the introduction of the minimum unit price policy to reduce alcohol consumption. Improving public health, this Review emphasises, will not only mitigate the severity of further waves of COVID-19, but is crucial to reducing the unacceptable burden from liver disease in the UK.