Acute severe hepatitis outbreak in children: a perfect storm. What do we know, and what questions remain?

During the first half of 2022, the World Health Organization reported an outbreak of acute severe hepatitis of unknown aetiology (AS-Hep-UA) in children, following initial alerts from the United Kingdom (UK) where a cluster of cases was first observed in previously well children aged <6 years. Sporadic cases were then reported across Europe and worldwide, although in most countries incidence did not increase above the expected baseline. There were no consistent epidemiological links between cases, and microbiological investigations ruled out known infectious causes of hepatitis. In this review, we explore the evidence for the role of viral infection, superimposed on a specific host genetic background, as a trigger for liver pathology. This hypothesis is based on a high prevalence of Human Adenovirus (HAdV) 41F in affected children, together with metagenomic evidence of adeno-associated virus (Adeno-associated viruses)-2, which is a putative trigger for an immune-mediated liver injury. Roles for superantigen-mediated pathology have also been explored, with a focus on the potential contribution of SARS-CoV-2 infection. Affected children also had a high frequency of the MHC allele HLA-DRB1*04:01, supporting an immunological predisposition, and may have been vulnerable to viral coinfections due to disruption in normal patterns of exposure and immunity as a result of population lockdowns during the COVID-19 pandemic. We discuss areas of ongoing uncertainty, and highlight the need for ongoing scrutiny to inform clinical and public health interventions for this outbreak and for others that may evolve in future

HIV & Comorbidity in the era of modern antiretroviral therapy: Heritages of the past & challenges for the future

The introduction of combination antiretroviral therapy (cART) has led to a dramatic increase in life expectancy for people living with HIV (PLWH). As a result, the long-term effects of HIV and cART on different organ systems are the main topics of interest in current HIV management. In this thesis, the focus is on comorbidity in three of these organ systems. The first part encompasses the spectrum of liver disease in PLWH, the most important organ-specific cause of death in this population. We describe how the risk for mortality in people living with both HIV and Hepatitis B virus infection has declined over the years, coinciding with the introduction of the antiretroviral drug tenofovir. Furthermore, this part includes a narrative review on fatty liver disease, which is becoming the most prevalent liver disease among PLWH. In part two, the focus is on bone-related disease in PLWH. In one of the chapters, data are presented suggesting that cART-related loss of bone mineral density is due to dysregulation of the parathyroid glands and calcium homeostasis. In the last part of the thesis, two aspects of Pneumocystis jirovecii pneumonia (PJP) in PLWH are described. PJP is a pneumonia which occurs when patients have a severe impaired immune system and is the most common AIDS-defining condition in PLWH. Over the years, the treatment has improved significantly, but little is known on the long-term effects of PJP. In this part, the immunological recovery and the prevalence of persistent lung function abnormalities after PJP are described