Chloroquine or hydroxychloroquine for prevention and treatment of COVID-19.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has resulted in substantial mortality. Some specialists proposed chloroquine (CQ) and hydroxychloroquine (HCQ) for treating or preventing the disease. The efficacy and safety of these drugs have been assessed in randomized controlled trials. OBJECTIVES: To evaluate the effects of chloroquine (CQ) or hydroxychloroquine (HCQ) for 1) treating people with COVID-19 on death and time to clearance of the virus; 2) preventing infection in people at risk of SARS-CoV-2 exposure; 3) preventing infection in people exposed to SARS-CoV-2. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Current Controlled Trials (www.controlled-trials.com), and the COVID-19-specific resources www.covid-nma.com and covid-19.cochrane.org, for studies of any publication status and in any language. We performed all searches up to 15 September 2020. We contacted researchers to identify unpublished and ongoing studies. SELECTION CRITERIA: We included randomized controlled trials (RCTs) testing chloroquine or hydroxychloroquine in people with COVID-19, people at risk of COVID-19 exposure, and people exposed to COVID-19. Adverse events (any, serious, and QT-interval prolongation on electrocardiogram) were also extracted. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed eligibility of search results, extracted data from the included studies, and assessed risk of bias using the Cochrane 'Risk of bias' tool. We contacted study authors for clarification and additional data for some studies. We used risk ratios (RR) for dichotomous outcomes and mean differences (MD) for continuous outcomes, with 95% confidence intervals (CIs). We performed meta-analysis using a random-effects model for outcomes where pooling of effect estimates was appropriate. MAIN RESULTS: 1. Treatment of COVID-19 disease We included 12 trials involving 8569 participants, all of whom were adults. Studies were from China (4); Brazil, Egypt, Iran, Spain, Taiwan, the UK, and North America (each 1 study); and a global study in 30 countries (1 study). Nine were in hospitalized patients, and three from ambulatory care. Disease severity, prevalence of comorbidities, and use of co-interventions varied substantially between trials. We found potential risks of bias across all domains for several trials. Nine trials compared HCQ with standard care (7779 participants), and one compared HCQ with placebo (491 participants); dosing schedules varied. HCQ makes little or no difference to death due to any cause (RR 1.09, 95% CI 0.99 to 1.19; 8208 participants; 9 trials; high-certainty evidence). A sensitivity analysis using modified intention-to-treat results from three trials did not influence the pooled effect estimate.  HCQ may make little or no difference to the proportion of people having negative PCR for SARS-CoV-2 on respiratory samples at day 14 from enrolment (RR 1.00, 95% CI 0.91 to 1.10; 213 participants; 3 trials; low-certainty evidence). HCQ probably results in little to no difference in progression to mechanical ventilation (RR 1.11, 95% CI 0.91 to 1.37; 4521 participants; 3 trials; moderate-certainty evidence). HCQ probably results in an almost three-fold increased risk of adverse events (RR 2.90, 95% CI 1.49 to 5.64; 1394 participants; 6 trials; moderate-certainty evidence), but may make little or no difference to the risk of serious adverse events (RR 0.82, 95% CI 0.37 to 1.79; 1004 participants; 6 trials; low-certainty evidence). We are very uncertain about the effect of HCQ on time to clinical improvement or risk of prolongation of QT-interval on electrocardiogram (very low-certainty evidence). One trial (22 participants) randomized patients to CQ versus lopinavir/ritonavir, a drug with unknown efficacy against SARS-CoV-2, and did not report any difference for clinical recovery or adverse events. One trial compared HCQ combined with azithromycin against standard care (444 participants). This trial did not detect a difference in death, requirement for mechanical ventilation, length of hospital admission, or serious adverse events. A higher risk of adverse events was reported in the HCQ-and-azithromycin arm; this included QT-interval prolongation, when measured. One trial compared HCQ with febuxostat, another drug with unknown efficacy against SARS-CoV-2 (60 participants). There was no difference detected in risk of hospitalization or change in computed tomography (CT) scan appearance of the lungs; no deaths were reported. 2. Preventing COVID-19 disease in people at risk of exposure to SARS-CoV-2 Ongoing trials are yet to report results for this objective. 3. Preventing COVID-19 disease in people who have been exposed to SARS-CoV-2 One trial (821 participants) compared HCQ with placebo as a prophylactic agent in the USA (around 90% of participants) and Canada. Asymptomatic adults (66% healthcare workers; mean age 40 years; 73% without comorbidity) with a history of exposure to people with confirmed COVID-19 were recruited. We are very uncertain about the effect of HCQ on the primary outcomes, for which few events were reported: 20/821 (2.4%) developed confirmed COVID-19 at 14 days from enrolment, and 2/821 (0.2%) were hospitalized due to COVID-19 (very low-certainty evidence). HCQ probably increases the risk of adverse events compared with placebo (RR 2.39, 95% CI 1.83 to 3.11; 700 participants; 1 trial; moderate-certainty evidence). HCQ may result in little or no difference in serious adverse events (no RR: no participants experienced serious adverse events; low-certainty evidence). One cluster-randomized trial (2525 participants) compared HCQ with standard care for the prevention of COVID-19 in people with a history of exposure to SARS-CoV-2 in Spain. Most participants were working or residing in nursing homes; mean age was 49 years. There was no difference in the risk of symptomatic confirmed COVID-19 or production of antibodies to SARS-CoV-2 between the two study arms. AUTHORS' CONCLUSIONS: HCQ for people infected with COVID-19 has little or no effect on the risk of death and probably no effect on progression to mechanical ventilation. Adverse events are tripled compared to placebo, but very few serious adverse events were found. No further trials of hydroxychloroquine or chloroquine for treatment should be carried out. These results make it less likely that the drug is effective in protecting people from infection, although this is not excluded entirely. It is probably sensible to complete trials examining prevention of infection, and ensure these are carried out to a high standard to provide unambiguous results.

Use and reliability of multiplex bead-based assays (Luminex) at Containment Level 4.

In the UK, research on hazard group 4 (HG4) pathogens requires specialised Containment Level 4 (CL4) facilities. These differ from Biosafety Level 4 (BSL4) conditions in that work is conducted in class III microbiological safety cabinets for primary containment instead of using positive pressure suits. This presents unique challenges associated with the physical restrictions of working in a limited space, and prohibits the use of many techniques and specialist equipment. In consequence, detailed studies on the biology of HG4 pathogens and in particular their immunological relationships with the host are understudied in the UK; for example, the majority of immunological assays with which the immune system is interrogated require specialist equipment that is unsuitable for CL4. Multiplexing to simultaneously measure multiple analytes is increasingly being used in immunological studies. This assay is attractive for CL4 work because it reduces the time spent in the laboratory whilst maximising the use of valuable sample volume. The Luminex microsphere approach allows for the determination of many cytokines and chemokines, however, the detection system uses fixed aligned lasers and integrated computer systems which are unsuitable for use at CL4. Therefore, we have developed an approach in which the Luminex assay is conducted within the CL4 laboratory and a formalin-fixation stage is introduced to allow for analysis to be undertaken outside of containment. Quality control preparations allow the assay characteristics to be monitored and analysis of assay performance to be evaluated. Our data demonstrate that Luminex is an applicable tool for use at CL4 and that assays can be run reliably to generate reproducible standardised data across different plates and individual experiments.

Disability Among Ebola Survivors and Their Close Contacts in Sierra Leone: A Retrospective Case-Controlled Cohort Study.

Ebola survivors (21/27 [77.8%]) suffered more disability than their close contacts (6/54 [11.1%]) (adjusted odds ratio, 23.5 [95% confidence interval, 6.5-85.7]; P < .001) when measured by the Washington Group Disability Extended Questionnaire. Major limitations in vision, mobility, cognition, and affect were observed in survivors 1 year following the 2014-2016 Ebola outbreak, highlighting the need for long-term rehabilitation.

Clinical presentation of patients with Ebola virus disease in Conakry, Guinea.

BACKGROUND: In March 2014, the World Health Organization was notified of an outbreak of Zaire ebolavirus in a remote area of Guinea. The outbreak then spread to the capital, Conakry, and to neighboring countries and has subsequently become the largest epidemic of Ebola virus disease (EVD) to date. METHODS: From March 25 to April 26, 2014, we performed a study of all patients with laboratory-confirmed EVD in Conakry. Mortality was the primary outcome. Secondary outcomes included patient characteristics, complications, treatments, and comparisons between survivors and nonsurvivors. RESULTS: Of 80 patients who presented with symptoms, 37 had laboratory-confirmed EVD. Among confirmed cases, the median age was 38 years (interquartile range, 28 to 46), 24 patients (65%) were men, and 14 (38%) were health care workers; among the health care workers, nosocomial transmission was implicated in 12 patients (32%). Patients with confirmed EVD presented to the hospital a median of 5 days (interquartile range, 3 to 7) after the onset of symptoms, most commonly with fever (in 84% of the patients; mean temperature, 38.6°C), fatigue (in 65%), diarrhea (in 62%), and tachycardia (mean heart rate, >93 beats per minute). Of these patients, 28 (76%) were treated with intravenous fluids and 37 (100%) with antibiotics. Sixteen patients (43%) died, with a median time from symptom onset to death of 8 days (interquartile range, 7 to 11). Patients who were 40 years of age or older, as compared with those under the age of 40 years, had a relative risk of death of 3.49 (95% confidence interval, 1.42 to 8.59; P=0.007). CONCLUSIONS: Patients with EVD presented with evidence of dehydration associated with vomiting and severe diarrhea. Despite attempts at volume repletion, antimicrobial therapy, and limited laboratory services, the rate of death was 43%.

Optimal Polygon Decomposition for UAV Survey Coverage Path Planning in Wind.

In this paper, a new method for planning coverage paths for fixed-wing Unmanned Aerial Vehicle (UAV) aerial surveys is proposed. Instead of the more generic coverage path planning techniques presented in previous literature, this method specifically concentrates on decreasing flight time of fixed-wing aircraft surveys. This is achieved threefold: by the addition of wind to the survey flight time model, accounting for the fact fixed-wing aircraft are not constrained to flight within the polygon of the region of interest, and an intelligent method for decomposing the region into convex polygons conducive to quick flight times. It is shown that wind can make a huge difference to survey time, and that flying perpendicular can confer a flight time advantage. Small UAVs, which have very slow airspeeds, can very easily be flying in wind, which is 50% of their airspeed. This is why the technique is shown to be so effective, due to the fact that ignoring wind for small, slow, fixed-wing aircraft is a considerable oversight. Comparing this method to previous techniques using a Monte Carlo simulation on randomised polygons shows a significant reduction in flight time.

Recovery of complete genome sequences of Crimean-Congo haemorrhagic fever virus (CCHFV) directly from clinical samples: A comparative study between targeted enrichment and metagenomic approaches.

Crimean-Congo haemorrhagic fever (CCHF) is the most prevalent human tick-borne viral disease, endemic to the Balkans, Africa, Middle East and Asia. There are currently no licensed vaccines or effective antivirals against CCHF. CCHF virus (CCHFV) has a negative sense segmented tripartite RNA genome consisting of the small (S), medium (M) and large (L) segments. Depending on the segment utilised for genetic affiliation, there are up to 7 circulating lineages of CCHFV. The current lack of geographical representation of CCHFV sequences in various repositories highlights a requirement for increased CCHFV sequencing capabilities in endemic regions. We have optimised and established a multiplex PCR tiling methodology for the targeted enrichment of complete genomes of Europe 1 CCHFV lineage directly from clinical samples and compared its performance to a non-targeted enrichment approach on both short-read and long-read sequencing platforms. We have found a statistically significant increase in mapped viral sequencing reads produced with our targeted enrichment approach. This has allowed us to recover near complete S segment sequences and above 90% of the M and L segment sequences for samples with Ct values as high as 31.3. This study demonstrates the superiority of a targeted enrichment approach for recovery of CCHFV genomic sequences from samples with low virus titre. CCHFV is an important vector-borne human pathogen with wide geographical distribution. The validated methodology reported here adds value to front-line public health laboratories employing genomic sequencing for CCHFV Europe 1 lineage surveillance, particularly in the Balkan and Middle Eastern territories currently monitoring the spread of the pathogen. Tracking the genomic evolution of the virus across regions improves risk assessment and directly informs the development of diagnostics, therapeutics, and vaccines.

A novel LC-MS/MS method for the determination of favipiravir ribofuranosyl-5'-triphosphate (T-705-RTP) in human peripheral mononuclear cells.

Favipiravir is a broad-spectrum antiviral that is metabolised intracellularly into the active form, favipiravir ribofuranosyl-5'-triphosphate (F-RTP). Measurement of the intracellular concentration of F-RTP in mononuclear cells is a crucial step to characterising the pharmacokinetics of F-RTP and to enable more appropriate dose selection for the treatment of COVID-19 and emerging infectious diseases. The described method was validated over the range 24 - 2280 pmol/sample. Peripheral blood mononuclear cells (PBMCs) were isolated from whole blood and lysed using methanol-water (70:30, v/v) before cellular components were precipitated with acetonitrile and the supernatant further cleaned by weak anion exchange solid phase extraction. The method was found to be both precise and accurate and was successfully utilised to analyse F-RTP concentrations in patient samples collected as part of the AGILE CST-6 clinical trial.

Malaria.

Malaria is a life-threatening disease, with its largest impact being due to Plasmodium falciparum infection in Africa. Military populations continue to be at a high risk of malaria and reported case series have frequently revealed poor compliance with preventative measures. The symptoms of malaria are non-specific and its management depends on awareness of the diagnosis and early recognition and treatment. This is aided by new and simple rapid diagnostic tests, but these should not replace the examination of blood films if these are available. Artemisinin combination therapy provides a more rapid and dependable cure of uncomplicated P falciparum infection, with artesunate now being the drug of choice in severe infection.

Deployed antimicrobial stewardship: an audit of antimicrobial use at Role 3.

INTRODUCTION: Infections due to multidrug-resistant organisms are increasingly prevalent, and antimicrobial stewardship has become a priority for many healthcare organisations, including the Defence Medical Services. In military environments, infectious diseases remain a significant burden, and infections complicating the care of modern complex combat injuries are well recognised. A focus on infection prevention and control in the deployed environment is essential, and an important element of this is an antimicrobial formulary and stewardship programme. This audit analyses antimicrobial prescribing practices by military clinicians in patients admitted to UK/US Role 3 medical treatment facility in Camp Bastion, Afghanistan, relative to the UK published guidance. METHODS: Retrospective case note review of all in-patient admissions during two time periods (October 2011 and October 2012). Notes were independently reviewed by an infection specialist not involved in the management of the patients. RESULTS: 475 case notes were reviewed, of which 250 received antimicrobials. Coalition forces represented the most common patient group (131/250), with battle injury the most frequent indication (139/250) for antimicrobial prescription, followed by disease (100/250). A total of 302 antimicrobials were prescribed, with co-amoxiclav being the most frequently used antibiotic in 74% (185/250) of patients. 84.8% (212/250) were prescribed antimicrobials in line with the antimicrobial formulary. In battle injury, 93.5% (130/139) of antimicrobial prescriptions were in line with the formulary compared with 73.9% (82/111) in disease and non-battle injury patients. CONCLUSIONS: Maintaining a strong infection control effort in the deployed setting, even in a stabilised operational environment, is difficult, but our data show good compliance to the antimicrobial formulary superior to that reported in civilian hospitals. To improve this, further innovative strategies are required, combined with a continued focus on infection control basics across the full spectrum of care.

Development and validation of an LC-MS/MS method for quantification of favipiravir in human plasma.

Favipiravir (FVP) is a broad-spectrum antiviral that selectively inhibits viral RNA-dependent RNA polymerase, first trialled for the treatment of influenza infection. It has been shown to be effective against a number of RNA virus families including arenaviruses, flaviviruses and enteroviruses. Most recently, FVP has been investigated as a potential therapeutic for severe acute respiratory syndrome coronavirus 2 infection. A liquid chromatography tandem mass spectrometry method for the quantification of FVP in human plasma has been developed and validated for use in clinical trials investigating favipiravir as treatment for coronavirus disease-2019. Samples were extracted by protein precipitation using acetonitrile, using 13C, 15N- Favipiravir as internal standard. Elution was performed on a Synergi Polar-RP 150 × 2.1 mm 4 µm column using a gradient mobile phase programme consisting of 0.2% formic acid in water and 0.2% formic acid in methanol. The assay was validated over the range 500-50,000 ng/mL; this method was found to be precise and accurate and recovery of FVP from the matrix was high. Stability experiments confirmed and expanded on the known stability of FVP, including under heat treatment and for a period of 10 months at - 80 °C.

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.

Increasing anti-S antibody testing: a quality improvement initiative with evolving COVID-19 guidelines.

BACKGROUND: COVID-19 management guidelines are constantly evolving, making them difficult to implement practically. Ronapreve was a neutralising monoclonal antibody introduced into UK COVID-19 guidelines in 2021. It reduces mortality in seronegative patients infected with non-omicron variants. Antibody testing on admission is therefore vital in ensuring patients could be considered for Ronapreve as inpatients. LOCAL PROBLEM: We found that on our COVID-19 ward, 31.4% of patients were not having anti-S tests despite fulfilling the other criteria to be eligible for Ronapreve. This was identified as an important target to improve; by not requesting anti-S tests, we were forgoing the opportunity to use an intervention that could improve outcomes. METHODS: We analysed patient records for patients with COVID-19 admitted to our ward over 4 months to observe if awareness of the need to request anti-S increased through conducting plan-do-study-act (PDSA) cycles. INTERVENTIONS: Our first intervention was an multidisciplinary team (MDT) discussion at our departmental audit meeting highlighting our baseline findings and the importance of anti-S requesting. Our second intervention was to hang printed posters in both the doctors' room and the ward as a visual reminder to staff. Our final intervention was trust-wide communications of updated local COVID-19 guidance that included instructions for anti-S requesting on admission. RESULTS: Our baseline data showed that only 68.6% of patients with symptomatic COVID-19 were having anti-S antibody tests requested. This increased to 95.0% following our three interventions. There was also a reduction in the amount of anti-S requests being 'added on', from 57.1% to 15.8%. CONCLUSIONS: COVID-19 guidelines are constantly evolving and require interventions that can be quickly and easily implemented to improve adherence. Sustained reminders through different approaches allowed a continued increase in requesting. This agrees with research that suggests a mixture of educational sessions and visual reminders of guidelines increase their application in clinical practice.

Air and surface sampling for monkeypox virus in a UK hospital: an observational study.

BACKGROUND: An outbreak of monkeypox virus infections in non-endemic countries was recognised on May 12, 2022. As of September 29, more than 67 000 infections have been reported globally, with more than 3400 confirmed cases in the UK by September 26. Monkeypox virus is believed to be predominantly transmitted through direct contact with lesions or infected body fluids, with possible involvement of fomites and large respiratory droplets. A case of monkeypox in a health-care worker in the UK in 2018 was suspected to be due to virus exposure while changing bedding. We aimed to measure the extent of environmental contamination in the isolation rooms of patients with symptomatic monkeypox. METHODS: We investigated environmental contamination with monkeypox virus from infected patients admitted to isolation rooms at the Royal Free Hospital (London, UK) between May 24 and June 17, 2022. Surface swabs of high-touch areas in five isolation rooms, of the personal protective equipment (PPE) of health-care workers in doffing areas in three rooms, and from air samples collected before and during bedding changes in five rooms were analysed using quantitative PCR to assess monkeypox virus contamination levels. Virus isolation was performed to confirm presence of infectious virus in selected positive samples. FINDINGS: We identified widespread surface contamination (56 [93%] of 60 samples were positive) in occupied patient rooms (monkeypox DNA cycle threshold [Ct] values 24·7-37·4), on health-care worker PPE after use (Ct 26·1-35·6), and in PPE doffing areas (Ct 26·3-36·8). Of 20 air samples taken, five (25%) were positive. Three (75%) of four air samples collected before and during a bedding change in one patient's room were positive (Ct 32·7-36·2). Replication-competent virus was identified in two (50%) of four samples selected for viral isolation, including from air samples collected during bedding change. INTERPRETATION: These data show contamination in isolation facilities and potential for suspension of monkeypox virus into the air during specific activities. PPE contamination was observed after clinical contact and changing of bedding. Contamination of hard surfaces in doffing areas supports the importance of cleaning protocols, PPE use, and doffing procedures. FUNDING: None.

Implementation study of SARS-CoV-2 antigen lateral flow tests in men's professional (Premiership) rugby union sports squads in England during the COVID-19 pandemic.

This study evaluated the validity and utility of antigen-detection rapid diagnostic tests (Ag-RDTs) for SARS-CoV-2 in elite sports. The data on utility, ease of use and application for Ag-RDTs as a new testing format were positive from players and staff. This evaluation was limited by the low prevalence of SARS-CoV-2 circulating within the three squads. This study highlights the need for continued service evaluations for SARS-CoV-2 Ag-RDTs in elite sport settings.

SARS-CoV-2 viability on sports equipment is limited, and dependent on material composition.

The control of the COVID-19 pandemic in the UK has necessitated restrictions on amateur and professional sports due to the perceived infection risk to competitors, via direct person to person transmission, or possibly via the surfaces of sports equipment. The sharing of sports equipment such as tennis balls was therefore banned by some sport's governing bodies. We sought to investigate the potential of sporting equipment as transmission vectors of SARS-CoV-2. Ten different types of sporting equipment, including balls from common sports, were inoculated with 40 µl droplets containing clinically relevant concentrations of live SARS-CoV-2 virus. Materials were then swabbed at time points relevant to sports (1, 5, 15, 30, 90 min). The amount of live SARS-CoV-2 recovered at each time point was enumerated using viral plaque assays, and viral decay and half-life was estimated through fitting linear models to log transformed data from each material. At one minute, SARS-CoV-2 virus was recovered in only seven of the ten types of equipment with the low dose inoculum, one at five minutes and none at 15 min. Retrievable virus dropped significantly for all materials tested using the high dose inoculum with mean recovery of virus falling to 0.74% at 1 min, 0.39% at 15 min and 0.003% at 90 min. Viral recovery, predicted decay, and half-life varied between materials with porous surfaces limiting virus transmission. This study shows that there is an exponential reduction in SARS-CoV-2 recoverable from a range of sports equipment after a short time period, and virus is less transferrable from materials such as a tennis ball, red cricket ball and cricket glove. Given this rapid loss of viral load and the fact that transmission requires a significant inoculum to be transferred from equipment to the mucous membranes of another individual it seems unlikely that sports equipment is a major cause for transmission of SARS-CoV-2. These findings have important policy implications in the context of the pandemic and may promote other infection control measures in sports to reduce the risk of SARS-CoV-2 transmission and urge sports equipment manufacturers to identify surfaces that may or may not be likely to retain transferable virus.

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.