Genomic Investigations of Acute Hepatitis of Unknown Aetiology in Children (preprint)

Since the first reports of hepatitis of unknown aetiology occurring in UK children, over 1000 cases have been reported worldwide, including 268 cases in the UK, with the majority younger than 6 years old. Using genomic, proteomic and immunohistochemical methods, we undertook extensive investigation of 28 cases and 136 control subjects. In five cases who underwent liver transplantation, we detected high levels of adeno-associated virus 2 (AAV2) in the explanted livers. AAV2 was also detected at high levels in blood from 10/11 non-transplanted cases. Low levels of Adenovirus (HAdV) and Human Herpesvirus 6B (HHV-6B), both of which enable AAV2 lytic replication, were also found in the five explanted livers and blood from 15/17 and 6/9 respectively, of the 23 non-transplant cases tested. In contrast, AAV2 was detected at low titre in 6/100 whole bloods from child controls from cohorts with presence or absence of hepatitis and/or adenovirus infection. Our data show an association of AAV2 at high titre in blood or liver tissue, with unexplained hepatitis in children infected in the recent HAdV-F41 outbreak. We were unable to find evidence by electron microscopy, immunohistochemistry or proteomics of HAdV or AAV2 viral particles or proteins in explanted livers, suggesting that hepatic pathology is not due to direct lytic infection by either virus. The potential that AAV2, although not previously associated with disease, may, together with HAdV-F41 and/or HHV-6, be causally implicated in the outbreak of unexplained hepatitis, requires further investigation.

A comparison of two frameworks for multi-state modelling, applied to outcomes after hospital admissions with COVID-19 (preprint)

We compare two multi-state modelling frameworks that can be used to represent dates of events following hospital admission for people infected during an epidemic. The methods are applied to data from people admitted to hospital with COVID-19, to estimate the probability of admission to ICU, the probability of death in hospital for patients before and after ICU admission, the lengths of stay in hospital, and how all these vary with age and gender. One modelling framework is based on defining transition-specific hazard functions for competing risks. A less commonly used framework defines partially-latent subpopulations who will experience each subsequent event, and uses a mixture model to estimate the probability that an individual will experience each event, and the distribution of the time to the event given that it occurs. We compare the advantages and disadvantages of these two frameworks, in the context of the COVID-19 example. The issues include the interpretation of the model parameters, the computational efficiency of estimating the quantities of interest, implementation in software and assessing goodness of fit. In the example, we find that some groups appear to be at very low risk of some events, in particular ICU admission, and these are best represented by using "cure-rate" models to define transition-specific hazards. We provide general-purpose software to implement all the models we describe in the "flexsurv" R package, which allows arbitrarily-flexible distributions to be used to represent the cause-specific hazards or times to events.

Trends in COVID-19 hospital outcomes in England before and after vaccine introduction, a cohort study (preprint)

Widespread vaccination campaigns have changed the landscape for COVID-19, vastly altering symptoms and reducing morbidity and mortality. We estimate trends in mortality by month of admission and vaccination status among those hospitalised with COVID-19 in England between March 2020 to September 2021, controlling for demographic factors and hospital load. Among 259,727 hospitalised COVID-19 cases, 51,948 (20.0%) experienced mortality in hospital. Hospitalised fatality risk ranged from 40.3% (95% confidence interval 39.4-41.3%) in March 2020 to 8.1% (7.2-9.0%) in June 2021. Older individuals and those with multiple co-morbidities were more likely to die or else experienced longer stays prior to discharge. Compared to unvaccinated people, the hazard of hospitalised mortality was 0.71 (0.67-0.77) with a first vaccine dose, and 0.56 (0.52-0.61) with a second vaccine dose. Compared to hospital load at 0-20% of the busiest week, the hazard of hospitalised mortality during periods of peak load (90-100%), was 1.23 (1.12-1.34). The prognosis for people hospitalised with COVID-19 in England has varied substantially throughout the pandemic and according to case-mix, vaccination, and hospital load. Our estimates provide an indication for demands on hospital resources, and the relationship between hospital burden and outcomes.

Trends in risks of severe events and lengths of stay for COVID-19 hospitalisations in England over the pre-vaccination era: results from the Public Health England SARI-Watch surveillance scheme (preprint)

Background: Trends in hospitalised case-fatality risk (HFR), risk of intensive care unit (ICU) admission and lengths of stay for patients hospitalised for COVID-19 in England over the pre-vaccination era are unknown. Methods: Data on hospital and ICU admissions with COVID-19 at 31 NHS trusts in England were collected by Public Health England's Severe Acute Respiratory Infections surveillance system and linked to death information. We applied parametric multi-state mixture models, accounting for censored outcomes and regressing risks and times between events on month of admission, geography, and baseline characteristics. Findings: 20,785 adults were admitted with COVID-19 in 2020. Between March and June/July/August estimated HFR reduced from 31.9% (95% confidence interval 30.3-33.5%) to 10.9% (9.4-12.7%), then rose steadily from 21.6% (18.4-25.5%) in September to 25.7% (23.0-29.2%) in December, with steeper increases among older patients, those with multi-morbidity and outside London/South of England. ICU admission risk reduced from 13.9% (12.8-15.2%) in March to 6.2% (5.3-7.1%) in May, rising to a high of 14.2% (11.1-17.2%) in September. Median length of stay in non-critical care increased during 2020, from 6.6 to 12.3 days for those dying, and from 6.1 to 9.3 days for those discharged. Interpretation: Initial improvements in patient outcomes, corresponding to developments in clinical practice, were not sustained throughout 2020, with HFR in December approaching the levels seen at the start of the pandemic, whilst median hospital stays have lengthened. The role of increased transmission, new variants, case-mix and hospital pressures in increasing COVID-19 severity requires urgent further investigation.

Rapid Evidence Review of Harm Reduction Interventions and Messaging for People Who Inject Drugs During Pandemic Events: Implications for the On-Going COVID-19 Response (preprint)

Background: People who inject drugs (PWID) are at increased health risk in a pandemic due to their greater susceptibility to severe disease and as a consequence of the restrictions put in place to halt the spread of infection. Harm reduction (HR) services, which aim to reduce the negative effects of drug use on health, are likely to be diminished in a pandemic. However, innovative HR interventions and messaging may also develop in response to such a crisis. It is vital to understand the most effective ways to deliver HR in pandemic situations so that guidance can be provided for current and future disruptions to service provision. Methods: A rapid evidence review was conducted with the aim of exploring what HR interventions and messaging are most effective during a pandemic type situation. Ten health databases were systematically searched using terms relevant to the research aim. A search was also made of grey literature, including a targeted search of HR messaging from key national and service provider websites. Results: In the initial search, 121 pieces of evidence were identified which, after screening and de-duplication, resulted in 60 for inclusion. The included evidence consists mainly of non-peer reviewed, pre-publication or expert opinion pieces. The rapid findings suggest that HR services should be deemed essential during a pandemic, with staff supported to work safely and social distancing adaptations implemented. Services should be encouraged to operate more flexibly; for instance, in deciding the amounts of take-home supplies of injecting equipment and medications. The evidence on HR communication was very limited but key messages on infection control, uncertain drug supply and accessing services were identified. Conclusions: This rapid evidence review identifies implications for national policy makers, commissioners and HR service providers. A person-centred rather than disease-centred approach to HR delivered by collaborating partners, as well as prioritizing tailored HR messaging, is recommended. Further research evaluating the delivery of HR services and messaging, particularly focusing on health inequalities, is urgently needed.