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Abstract 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.

ABSTRACT Metagenomic sequencing is a promising new method for pathogen detection. We aimed to detect pathogens from archived plasma using metagenomic sequencing in a previously well-characterized cohort of 254 predominantly HIV-infected patients with sepsis in Uganda. We used Illumina sequencing and the Chan Zuckerberg ID metagenomics platform to sequence and identify pathogens. On average, each plasma sample yielded 3,404,737 ± 2,201,997 reads (mean ± standard deviation), of which 220,032 ± 416,691 (6.3% ± 8.6%) were identified as nonhuman reads. Using a background model filter, 414 genus-specific pathogen identifications were found in the 254 samples. Nineteen pathogens were previously detected positive by quantitative PCR (qPCR), compared to sequencing, which demonstrated 30.2% sensitivity and 99.5% specificity. Sensitivity was higher for viral pathogens than nonviral pathogens (37% versus 5%). For example, HIV viremia was detected in 69% of samples using qPCR, and sequencing revealed 70% sensitivity and 92% specificity. There were 75 genus-specific potential pathogens identified by sequencing in this cohort, including hepatitis B and Epstein-Barr virus (EBV), among several others. qPCR showed a prevalence of hepatitis B and EBV viremia of 17% and 45%, respectively. In-hospital mortality was associated with a lower qPCR threshold cycle value for EBV (adjusted odds ratio, 0.85; P

BackgroundMore than 50 countries, mainly in Sub-Saharan Africa and South Asia, are not on course to meet the neonatal and under-five mortality target set by the Sustainable Development Goals (SDGs) for the year 2030. One important, yet neglected, aspect of child mortality rates is deaths occurring during the post-discharge period. For children living in resource-poor countries, the rate of post-discharge mortality within the first several months after discharge is often as high as the rates observed during the initial admission period. This has generally been observed within the context of acute illness and has been closely linked to underlying conditions such as malnutrition, HIV, and anemia. These post-discharge mortality rates tend to be underreported and present a major oversight in the efforts to reduce overall child mortality. This review will explore recurrent illness following discharge through determination of rates of, and risk factors for, pediatric post-discharge mortality in resource-poor settings.MethodsEligible studies will be retrieved using MEDLINE, EMBASE, and CINAHL databases. Only studies with a post-discharge observation period of more than 7 days following discharge will be eligible for inclusion. Secondary outcomes will include post-discharge mortality relative to in-hospital mortality, overall readmission rates, pooled estimates of risk factors (e.g. admission details vs discharge factors, clinical vs social factors), pooled post-discharge mortality Kaplan-Meier survival curves, and outcomes by disease subgroups (e.g. malnutrition, anemia, general admissions). A narrative description of the included studies will be synthesized to categorize commonly affected patient population categories and a random-effects meta-analysis will be conducted to quantify overall post-discharge mortality rates at the 6-month time point.DiscussionPost-discharge mortality contributes to global child mortality rates with a greater burden of deaths occurring in resource-poor settings. Literature concentrated on child mortality published over the last decade has expanded to focus on the fatal outcomes of children post-discharge and associated risk factors. The results from this systematic review will inform current policy and interventions on the epidemiological burden of post-discharge mortality and morbidity following acute illness among children living in resource-poor settings.Systematic review registrationPROSPERO Registration ID: CRD42022350975.

Abstract Background There is an urgent unmet clinical need for the identification of novel therapeutics for the treatment of COVID-19. A number of COVID-19 late phase trial platforms have been developed to investigate (often repurposed) drugs both in the UK and globally (e.g. RECOVERY led by the University of Oxford and SOLIDARITY led by WHO). There is a pressing need to investigate novel candidates within early phase trial platforms, from which promising candidates can feed into established later phase platforms. AGILE grew from a UK-wide collaboration to undertake early stage clinical evaluation of candidates for SARS-CoV-2 infection to accelerate national and global healthcare interventions. Methods/design AGILE is a seamless phase I/IIa platform study to establish the optimum dose, determine the activity and safety of each candidate and recommend whether it should be evaluated further. Each candidate is evaluated in its own trial, either as an open label single arm healthy volunteer study or in patients, randomising between candidate and control usually in a 2:1 allocation in favour of the candidate. Each dose is assessed sequentially for safety usually in cohorts of 6 patients. Once a phase II dose has been identified, efficacy is assessed by seamlessly expanding into a larger cohort. AGILE is completely flexible in that the core design in the master protocol can be adapted for each candidate based on prior knowledge of the candidate (i.e. population, primary endpoint and sample size can be amended). This information is detailed in each candidate specific trial protocol of the master protocol. Discussion Few approved treatments for COVID-19 are available such as dexamethasone, remdesivir and tocilizumab in hospitalised patients. The AGILE platform aims to rapidly identify new efficacious and safe treatments to help end the current global COVID-19 pandemic. We currently have three candidate specific trials within this platform study that are open to recruitment. Trial registration EudraCT Number: 2020-001860-27 14 March 2020 ClinicalTrials.gov Identifier: NCT04746183 19 February 2021 ISRCTN reference: 27106947

Abstract Background Sepsis guidelines are widely used in high-income countries and intravenous fluids are an important supportive treatment modality. However, fluids have been harmful in intervention trials in low-income countries, most notably in sub-Saharan Africa. We assessed the relevance, quality and applicability of available guidelines for the fluid management of adult patients with sepsis in this region. Methods We identified sepsis guidelines by systematic review with broad search terms, duplicate screening and data extraction. We included peer-reviewed publications with explicit relevance to sepsis and fluid therapy. We excluded those designed exclusively for specific aetiologies of sepsis, for limited geographic locations, or for non-adult populations. We used the AGREE II tool to assess the quality of guideline development, performed a narrative synthesis and used theoretical case scenarios to assess practical applicability to everyday clinical practice in resource-constrained settings. Results Published sepsis guidelines are heterogeneous in sepsis definition and in quality: 8/10 guidelines had significant deficits in applicability, particularly with reference to resource considerations in low-income settings. Indications for intravenous fluid were hypotension (8/10), clinical markers of hypoperfusion (6/10) and lactataemia (3/10). Crystalloids were overwhelmingly recommended (9/10). Suggested volumes varied; 5/10 explicitly recommended “fluid challenges” with reassessment, totalling between 1 L and 4 L during initial resuscitation. Fluid balance, including later de-escalation of therapy, was not specifically described in any. Norepinephrine was the preferred initial vasopressor (5/10), specifically targeted to MAP > 65 mmHg (3/10), with higher values suggested in pre-existing hypertension (1/10). Recommendations for guidelines were almost universally derived from evidence in high-income countries. None of the guidelines suggested any refinement for patients with malnutrition. Conclusions Widely used international guidelines contain disparate recommendations on intravenous fluid use, lack specificity and are largely unattainable in low-income countries given available resources. A relative lack of high-quality evidence from sub-Saharan Africa increases reliance on recommendations which may not be relevant or implementable.