Severe acute hepatitis of unknown aetiology in children-what is known?

The ongoing investigations into clusters of children affected by severe acute hepatitis of unknown aetiology have put our global capacity for a coordinated, effective response to the test. The global health community have rapidly convened to share data and inform the response. In the UK, where most cases were initially identified, a coordinated public health and clinical research response was rapidly initiated. Since then, cases have been reported from other countries, predominantly from higher-income countries. While agencies are keeping an open mind to the cause, the working hypothesis and case notifications raise important questions about our capacity to detect emerging cases in lower-resourced settings with a recognised lack of access to diagnostics even for commonly circulating viruses such as hepatitis A. The limited capability to generate integrated global pathogen surveillance data is a challenge for the outbreak investigations, highlighting an urgent need to strengthen access to diagnostics, with a focus on lower-resourced settings, to improve the capacity to detect emerging diseases to inform care and to improve outcomes and outbreak control.

Preparing for pandemics: a systematic review of pandemic influenza clinical management guidelines.

BACKGROUND: The COVID-19 pandemic has highlighted the importance of evidence-based clinical decision-making. Clinical management guidelines (CMGs) may help reduce morbidity and mortality by improving the quality of clinical decisions. This systematic review aims to evaluate the availability, inclusivity, and quality of pandemic influenza CMGs, to identify gaps that can be addressed to strengthen pandemic preparedness in this area. METHODS: Ovid Medline, Ovid Embase, TRIP (Turning Research Into Practice), and Guideline Central were searched systematically from January 2008 to 23rd June 2022, complemented by a grey literature search till 16th June 2022. Pandemic influenza CMGs including supportive care or empirical treatment recommendations were included. Two reviewers independently extracted data from the included studies and assessed their quality using AGREE II (Appraisal of Guidelines for Research & Evaluation). The findings are presented narratively. RESULTS: Forty-eight CMGs were included. They were produced in high- (42%, 20/48), upper-middle- (40%, 19/48), and lower-middle (8%, 4/48) income countries, or by international organisations (10%, 5/48). Most CMGs (81%, 39/48) were over 5 years old. Guidelines included treatment recommendations for children (75%, 36/48), pregnant women (54%, 26/48), people with immunosuppression (33%, 16/48), and older adults (29%, 14/48). Many CMGs were of low quality (median overall score: 3 out of 7 (range 1-7). All recommended oseltamivir; recommendations for other neuraminidase inhibitors and supportive care were limited and at times contradictory. Only 56% (27/48) and 27% (13/48) addressed oxygen and fluid therapy, respectively. CONCLUSIONS: Our data highlights the limited availability of up-to-date pandemic influenza CMGs globally. Of those identified, many were limited in scope and quality and several lacked recommendations for specific at-risk populations. Recommendations on supportive care, the mainstay of treatment, were limited and heterogeneous. The most recent guideline highlighted that the evidence-base to support antiviral treatment recommendations is still limited. There is an urgent need for trials into treatment and supportive care strategies including for different risk populations. New evidence should be incorporated into globally accessible guidelines, to benefit patient outcomes. A 'living guideline' framework is recommended and further research into guideline implementation in different resourced settings, particularly low- and middle-income countries.

Characteristics and outcomes of COVID-19 patients admitted to hospital with and without respiratory symptoms.

Background: COVID-19 is primarily known as a respiratory illness; however, many patients present to hospital without respiratory symptoms. The association between non-respiratory presentations of COVID-19 and outcomes remains unclear. We investigated risk factors and clinical outcomes in patients with no respiratory symptoms (NRS) and respiratory symptoms (RS) at hospital admission. Methods: This study describes clinical features, physiological parameters, and outcomes of hospitalised COVID-19 patients, stratified by the presence or absence of respiratory symptoms at hospital admission. RS patients had one or more of: cough, shortness of breath, sore throat, runny nose or wheezing; while NRS patients did not. Results: Of 178,640 patients in the study, 86.4 % presented with RS, while 13.6 % had NRS. NRS patients were older (median age: NRS: 74 vs RS: 65) and less likely to be admitted to the ICU (NRS: 36.7 % vs RS: 37.5 %). NRS patients had a higher crude in-hospital case-fatality ratio (NRS 41.1 % vs. RS 32.0 %), but a lower risk of death after adjusting for confounders (HR 0.88 [0.83-0.93]). Conclusion: Approximately one in seven COVID-19 patients presented at hospital admission without respiratory symptoms. These patients were older, had lower ICU admission rates, and had a lower risk of in-hospital mortality after adjusting for confounders.

The diagnostic accuracy of rapid diagnostic tests for Ebola virus disease: a systematic review.

BACKGROUND: Ebola virus disease (EVD) is a dangerous condition that can cause an epidemic. Several rapid diagnostic tests (RDTs) have been developed to diagnose EVD. These RDTs promise to be quicker and easier to use than the current reference standard diagnostic test, PCR. OBJECTIVES: To assess the diagnostic accuracy of RDTs for EVD. METHODS: A systematic review of diagnostic accuracy studies. DATA SOURCES: The following bibliographic databases were searched from inception to present: MEDLINE (Ovid), Embase, Global Health, Cochrane Central Register of Controlled Trials, WHO Global Index Medicus database, Web of Science, PROSPERO register of Systematic Reviews, and Clinical Trials.Gov. STUDY ELIGIBILITY CRITERIA: Diagnostic accuracy studies. PARTICIPANTS: Patients presenting to the Ebola treatment units with symptoms of EVD. INTERVENTIONS: RDTs; reference standard, RT-PCR. ASSESSMENT OF RISK OF BIAS: Quality Assessment of Diagnostic Accuracy Studies-2 tool. METHODS OF DATA SYNTHESIS: Summary estimates of diagnostic accuracy study were produced for each device type. Subgroup analyses were performed for RDT type and specimen material. A sensitivity analysis was performed to assess the effect of trial design and bias. RESULTS: We included 15 diagnostic accuracy studies. The summary estimate of sensitivity for lateral flow assays was 86.1% (95% CI, 86-86.2%), with specificity of 97% (95% CI, 96.1-97.9%). The summary estimate for rapid PCR devices was sensitivity of 96.2% (95% CI, 95.3-97.9%), with a specificity of 96.8% (95% CI, 95.3-97.9%). Pre-specified subgroup analyses demonstrated that RDTs were effective on a range of specimen material. Overall, the risk of bias throughout the included studies was low, but it was high in patient selection and uncertain in the flow and timing domains. CONCLUSIONS: RDTs possess both high sensitivity and specificity compared with RT-PCR among symptomatic patients presenting to the Ebola treatment units. Our findings support the use of RDTs as a 'rule in' test to expedite treatment and vaccination.

Trans-Atlantic aeromedical repatriation of multiple COVID-19 patients: a hybrid military-civilian model.

Here, we report the first known transcontinental aeromedical evacuation of a large number (55) of patients with known and suspected positive COVID-19. These patients were evacuated from Havana, Cuba, to the UK through MOD Boscombe Down as part of Operation BROADSHARE, the British military's overseas response to COVID-19. We describe the safe transfer of patients with COVID-19 using a combined military-civilian model. In our view, we have demonstrated that patients with COVID-19 can be aeromedically transferred while ensuring the safety of patients and crew using a hybrid military-civilian model; this report contains lessons for future aeromedical evacuation of patients with COVID-19.

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.

Characteristics and outcomes of an international cohort of 600 000 hospitalized patients with COVID-19.

BACKGROUND: We describe demographic features, treatments and clinical outcomes in the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) COVID-19 cohort, one of the world's largest international, standardized data sets concerning hospitalized patients. METHODS: The data set analysed includes COVID-19 patients hospitalized between January 2020 and January 2022 in 52 countries. We investigated how symptoms on admission, co-morbidities, risk factors and treatments varied by age, sex and other characteristics. We used Cox regression models to investigate associations between demographics, symptoms, co-morbidities and other factors with risk of death, admission to an intensive care unit (ICU) and invasive mechanical ventilation (IMV). RESULTS: Data were available for 689 572 patients with laboratory-confirmed (91.1%) or clinically diagnosed (8.9%) SARS-CoV-2 infection from 52 countries. Age [adjusted hazard ratio per 10 years 1.49 (95% CI 1.48, 1.49)] and male sex [1.23 (1.21, 1.24)] were associated with a higher risk of death. Rates of admission to an ICU and use of IMV increased with age up to age 60 years then dropped. Symptoms, co-morbidities and treatments varied by age and had varied associations with clinical outcomes. The case-fatality ratio varied by country partly due to differences in the clinical characteristics of recruited patients and was on average 21.5%. CONCLUSIONS: Age was the strongest determinant of risk of death, with a ∼30-fold difference between the oldest and youngest groups; each of the co-morbidities included was associated with up to an almost 2-fold increase in risk. Smoking and obesity were also associated with a higher risk of death. The size of our international database and the standardized data collection method make this study a comprehensive international description of COVID-19 clinical features. Our findings may inform strategies that involve prioritization of patients hospitalized with COVID-19 who have a higher risk of death.

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.

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].

ISARIC-COVID-19 dataset: A Prospective, Standardized, Global Dataset of Patients Hospitalized with COVID-19.

The International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) COVID-19 dataset is one of the largest international databases of prospectively collected clinical data on people hospitalized with COVID-19. This dataset was compiled during the COVID-19 pandemic by a network of hospitals that collect data using the ISARIC-World Health Organization Clinical Characterization Protocol and data tools. The database includes data from more than 705,000 patients, collected in more than 60 countries and 1,500 centres worldwide. Patient data are available from acute hospital admissions with COVID-19 and outpatient follow-ups. The data include signs and symptoms, pre-existing comorbidities, vital signs, chronic and acute treatments, complications, dates of hospitalization and discharge, mortality, viral strains, vaccination status, and other data. Here, we present the dataset characteristics, explain its architecture and how to gain access, and provide tools to facilitate its use.

Characterising long COVID: a living systematic review.

BACKGROUND: While it is now apparent clinical sequelae (long COVID) may persist after acute COVID-19, their nature, frequency and aetiology are poorly characterised. This study aims to regularly synthesise evidence on long COVID characteristics, to help inform clinical management, rehabilitation strategies and interventional studies to improve long-term outcomes. METHODS: A living systematic review. Medline, CINAHL (EBSCO), Global Health (Ovid), WHO Global Research on COVID-19 database, LitCovid and Google Scholar were searched till 17 March 2021. Studies including at least 100 people with confirmed or clinically suspected COVID-19 at 12 weeks or more post onset were included. Risk of bias was assessed using the tool produced by Hoy et al. Results were analysed using descriptive statistics and meta-analyses to estimate prevalence. RESULTS: A total of 39 studies were included: 32 cohort, 6 cross-sectional and 1 case-control. Most showed high or moderate risk of bias. None were set in low-income countries and few included children. Studies reported on 10 951 people (48% female) in 12 countries. Most included previously hospitalised people (78%, 8520/10 951). The longest mean follow-up time was 221.7 (SD: 10.9) days post COVID-19 onset. Over 60 physical and psychological signs and symptoms with wide prevalence were reported, most commonly weakness (41%; 95% CI 25% to 59%), general malaise (33%; 95% CI 15% to 57%), fatigue (31%; 95% CI 24% to 39%), concentration impairment (26%; 95% CI 21% to 32%) and breathlessness (25%; 95% CI 18% to 34%). 37% (95% CI 18% to 60%) of patients reported reduced quality of life; 26% (10/39) of studies presented evidence of reduced pulmonary function. CONCLUSION: Long COVID is a complex condition with prolonged heterogeneous symptoms. The nature of studies precludes a precise case definition or risk evaluation. There is an urgent need for prospective, robust, standardised, controlled studies into aetiology, risk factors and biomarkers to characterise long COVID in different at-risk populations and settings. PROSPERO REGISTRATION NUMBER: CRD42020211131.

Ten months of temporal variation in the clinical journey of hospitalised patients with COVID-19: An observational cohort.

Background: There is potentially considerable variation in the nature and duration of the care provided to hospitalised patients during an infectious disease epidemic or pandemic. Improvements in care and clinician confidence may shorten the time spent as an inpatient, or the need for admission to an intensive care unit (ICU) or high dependency unit (HDU). On the other hand, limited resources at times of high demand may lead to rationing. Nevertheless, these variables may be used as static proxies for disease severity, as outcome measures for trials, and to inform planning and logistics. Methods: We investigate these time trends in an extremely large international cohort of 142,540 patients hospitalised with COVID-19. Investigated are: time from symptom onset to hospital admission, probability of ICU/HDU admission, time from hospital admission to ICU/HDU admission, hospital case fatality ratio (hCFR) and total length of hospital stay. Results: Time from onset to admission showed a rapid decline during the first months of the pandemic followed by peaks during August/September and December 2020. ICU/HDU admission was more frequent from June to August. The hCFR was lowest from June to August. Raw numbers for overall hospital stay showed little variation, but there is clear decline in time to discharge for ICU/HDU survivors. Conclusions: Our results establish that variables of these kinds have limitations when used as outcome measures in a rapidly evolving situation. Funding: This work was supported by the UK Foreign, Commonwealth and Development Office and Wellcome [215091/Z/18/Z] and the Bill & Melinda Gates Foundation [OPP1209135]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Scope, quality, and inclusivity of clinical guidelines produced early in the covid-19 pandemic: rapid review.

OBJECTIVE: To appraise the availability, quality, and inclusivity of clinical guidelines produced in the early stage of the coronavirus disease 2019 (covid-19) pandemic. DESIGN: Rapid review. DATA SOURCES: Ovid Medline, Ovid Embase, Ovid Global Health, Scopus, Web of Science Core Collection, and WHO Global Index Medicus, searched from inception to 14 Mar 2020. Search strategies applied the CADTH database guidelines search filter, with no limits applied to search results. Further studies were identified through searches of grey literature using the ISARIC network. INCLUSION CRITERIA: Clinical guidelines for the management of covid-19, Middle East respiratory syndrome (MERS), and severe acute respiratory syndrome (SARS) produced by international and national scientific organisations and government and non-governmental organisations relating to global health were included, with no exclusions for language. Regional/hospital guidelines were excluded. Only the earliest version of any guideline was included. QUALITY ASSESSMENT: Quality was assessed using the Appraisal of Guidelines for Research and Evaluation (AGREE) II tool. The quality and contents of early covid-19 guidelines were also compared with recent clinical guidelines for MERS and SARS. RESULTS: 2836 studies were identified, of which 2794 were excluded after screening. Forty two guidelines were considered eligible for inclusion, with 18 being specific to covid-19. Overall, the clinical guidelines lacked detail and covered a narrow range of topics. Recommendations varied in relation to, for example, the use of antiviral drugs. The overall quality was poor, particularly in the domains of stakeholder involvement, applicability, and editorial independence. Links between evidence and recommendations were limited. Minimal provision was made for vulnerable groups such as pregnant women, children, and older people. CONCLUSIONS: Guidelines available early in the covid-19 pandemic had methodological weaknesses and neglected vulnerable groups such as older people. A framework for development of clinical guidelines during public health emergencies is needed to ensure rigorous methods and the inclusion of vulnerable populations. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020167361.

Comparison of BOLD and direct-MR neuronal detection (DND) in the human visual cortex at 3T.

Direct-MR neuronal detection (DND) of transient magnetic fields has recently been investigated as a novel imaging alternative to the conventional BOLD functional MRI (fMRI) technique. However, there remain controversial issues and debate surrounding this methodology, and this study attempts clarification by comparing BOLD responses in the human visual system with those of DND. BOLD relies on indirectly measuring blood oxygenation and flow changes as a result of neuronal activity, whereas the putative DND method is based on the hypothesis that the components of the in vivo neuronal magnetic fields, which lie parallel to the B(0) field, can potentially modulate the MR signal, thus providing a means of direct detection of nerve impulses. Block paradigms of checkerboard patterns were used for visual stimulation in both DND and BOLD experiments, allowing detection based on different frequency responses. This study shows colocalization of some voxels with slow BOLD responses and putative fast DND responses using General Linear Model (GLM) analysis. Frequency spectra for the activated voxel cluster are also shown for both stimulated and control data. The mean percentage signal change for the DND responses is 0.2%, corresponding to a predicted neuronal field of 0.14 nT.

Acute intermittent porphyria leading to posterior reversible encephalopathy syndrome (PRES): a rare cause of abdominal pain and seizures.

Acute intermittent porphyria (AIP) is an inherited deficiency in the haem biosynthesis pathway. AIP is rare, affecting around 1 in 75 000 people. Acute attacks are characterised by abdominal pain associated with autonomic, neurological and psychiatric symptoms. AIP is rarely associated with posterior reversible encephalopathy syndrome (PRES). PRES is a clinicoradiological condition caused by the failure of the posterior circulation to autoregulate, resulting in cerebral oedema, headaches, nausea and seizures. This association is important because drugs used in the management of seizures may worsen an attack of AIP. This article describes a case of AIP and PRES in a young woman.

Laparoscopic management of a delayed traumatic diaphragmatic rupture complicated by bowel strangulation.

Traumatic rupture of the diaphragm (TDR) presents diagnostic difficulty, with basic radiological investigations discovering less than half of all cases. As a consequence, complications of diaphragmatic rupture may present long after the initial injury has occurred-the time delay obscuring diagnosis. Once discovered repair is necessary with previous reports advocating open repair. Here, we report a case of traumatic diaphragmatic rupture causing small bowel obstruction 20 years after initial injury. The patient, a young woman, underwent successful laparoscopic assisted diaphragmatic repair with small bowel resection. TDR is an unusual but important differential diagnosis of an acute abdomen. A high index of suspicion is required to avoid delayed diagnosis and increased mortality.