Standard of care for viral haemorrhagic fevers (VHFs): a systematic review of clinical management guidelines for high-priority VHFs.

The Sudan virus disease outbreak in Uganda in 2022 showed our vulnerability to viral haemorrhagic fevers (VHFs). Although there are regular outbreaks of VHFs with high morbidity and mortality, which disproportionally affect low-income settings, our understanding of how to treat them remains inadequate. In this systematic review, we aim to explore the availability, scope, standardisation, and quality of clinical management guidelines for VHFs. We identified 32 guidelines, 25 (78%) of which were low quality and did not have supporting evidence and eight (25%) of which had been produced or updated in the past 3 years. Guidance on supportive care and therapeutics had little detail and was sometimes contradictory. Guidelines based on uncertain evidence are a risk to patients, an ethical challenge for clinicians, and a challenge to implementing trials due to heterogeneous standards of care. We recommend a standard living guideline framework to improve the quality, scope, and applicability of guidelines. Furthermore, investments into trials should aim to identify optimal treatment strategies for VHFs and prioritise affordable and scalable interventions to improve outcomes globally.

An evaluation of global Chikungunya clinical management guidelines: A systematic review.

Background: Chikungunya virus (CHIKV) has expanded its geographical reach in recent decades and is an emerging global health threat. CHIKV can cause significant morbidity and lead to chronic, debilitating arthritis/arthralgia in up to 40% of infected individuals. Prevention, early identification, and clinical management are key for improving outcomes. The aim of this review is to evaluate the quality, availability, inclusivity, and scope of evidence-based clinical management guidelines (CMG) for CHIKV globally. Methods: We conducted a systematic review. Six databases were searched from Jan 1, 1989, to 14 Oct 2021 and grey literature until Sept 16, 2021, for CHIKV guidelines providing supportive care and treatment recommendations. Quality was assessed using the appraisal of Guidelines for Research and Evaluation tool. Findings are presented in a narrative synthesis. PROSPERO registration: CRD42020167361. Findings: 28 CMGs were included; 54% (15/28) were produced more than 5 years ago, and most were of low-quality (median score 2 out of 7 (range 1-7)). There were variations in the CMGs' guidance on the management of different at-risk populations, long-term sequelae, and the prevention of disease transmission. While 54% (15/28) of CMGs recommended hospitalisation for severe cases, only 39% (11/28) provided guidance for severe disease management. Further, 46% (13/28) advocated for steroids in the chronic phase, but 18% (5/28) advised against its use. Interpretation: There was a lack of high-quality CMGs that provided supportive care and treatment guidance, which may impact patient care and outcomes. It is essential that existing guidelines are updated and adapted to provide detailed evidence-based treatment guidelines for different at-risk populations. This study also highlights a need for more research into the management of the acute and chronic phases of CHIKV infection to inform evidence-based care. Funding: The UK Foreign, Commonwealth and Development Office, Wellcome Trust [215091/Z/18/Z] and the Bill & Melinda Gates Foundation [OPP1209135].

Availability, scope and quality of monkeypox clinical management guidelines globally: a systematic review.

BACKGROUND: Monkeypox (MPX) is an important human Orthopoxvirus infection. There has been an increase in MPX cases and outbreaks in endemic and non-endemic regions in recent decades. We appraised the availability, scope, quality and inclusivity of clinical management guidelines for MPX globally. METHODS: For this systematic review, we searched six databases from inception until 14 October 2021, augmented by a grey literature search until 17 May 2022. MPX guidelines providing treatment and supportive care recommendations were included, with no exclusions for language. Two reviewers assessed the guidelines. Quality was assessed using the Appraisal of Guidelines for Research and Evaluation II tool. RESULTS: Of 2026 records screened, 14 guidelines were included. Overall, most guidelines were of low-quality with a median score of 2 out of 7 (range: 1-7), lacked detail and covered a narrow range of topics. Most guidelines focused on adults, five (36%) provided some advice for children, three (21%) for pregnant women and three (21%) for people living with HIV. Treatment guidance was mostly limited to advice on antivirals; seven guidelines advised cidofovir (four specified for severe MPX only); 29% (4/14) tecovirimat, and 7% (1/14) brincidofovir. Only one guideline provided recommendations on supportive care and treatment of complications. All guidelines recommended vaccination as post-exposure prophylaxis (PEP). Three guidelines advised on vaccinia immune globulin as PEP for severe cases in people with immunosuppression. CONCLUSION: Our results highlight a lack of evidence-based clinical management guidelines for MPX globally. There is a clear and urgent need for research into treatment and prophylaxis including for different risk populations. The current outbreak provides an opportunity to accelerate this research through coordinated high-quality studies. New evidence should be incorporated into globally accessible guidelines, to benefit patient and epidemic outcomes. A 'living guideline' framework is recommended. PROSPERO REGISTRATION NUMBER: CRD42020167361.

Empirical treatment of tuberculosis: TB or not TB?

Of the 8.6 million new cases of tuberculosis (TB) that occur globally each year, a quarter occur in India. We describe the case of a 38-year-old Indian woman who presented with symptoms of hepatitis after being treated empirically with anti-TB therapy for five months. The patient was suspected to have TB after having recurrent episodes of coughing which would improve briefly before her respiratory symptoms returned, which led to her being treated at various healthcare clinics and hospitals. We highlight the challenges the patient faced due to the lack of centralised medical records which would have prevented unnecessary investigations and treatment.

Immune checkpoint inhibitors in cancer therapy.

In recent years immune checkpoint inhibitors have garnered attention as being one of the most promising types of immunotherapy on the horizon. There has been particular focus on the immune checkpoint molecules, cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1) which have been shown to have potent immunomodulatory effects through their function as negative regulators of T cell activation. CTLA-4, through engagement with its ligands B7-1 (CD80) and B7-2 (CD86), plays a pivotal role in attenuating the activation of naïve and memory T cells. In contrast, PD-1 is primarily involved in modulating T cell activity in peripheral tissues via its interaction with PD-L1 and PD-L2. The discovery of these negative regulators of the immune response was crucial in the development of checkpoint inhibitors. This shifted the focus from developing therapies that targeted activation of the host immune system against cancer to checkpoint inhibitors, which aimed to mediate tumor cell destruction through the removal of coinhibitory signals blocking anti-tumor T cell responses.

CRISPR-Cas9 as a Powerful Tool for Efficient Creation of Oncolytic Viruses.

The development of oncolytic viruses has led to an emerging new class of cancer therapeutics. Although the safety profile has been encouraging, the transition of oncolytic viruses to the clinical setting has been a slow process due to modifications. Therefore, a new generation of more potent oncolytic viruses needs to be exploited, following our better understanding of the complex interactions between the tumor, its microenvironment, the virus, and the host immune response. The conventional method for creation of tumor-targeted oncolytic viruses is based on homologous recombination. However, the creation of new mutant oncolytic viruses with large genomes remains a challenge due to the multi-step process and low efficiency of homologous recombination. The CRISPR-associated endonuclease Cas9 has hugely advanced the potential to edit the genomes of various organisms due to the ability of Cas9 to target a specific genomic site by a single guide RNA. In this review, we discuss the CRISPR-Cas9 system as an efficient viral editing method for the creation of new oncolytic viruses, as well as its potential future applications in the development of oncolytic viruses. Further, this review discusses the potential of off-target effects as well as CRISPR-Cas9 as a tool for basic research into viral biology.