Bubonic plague: can the size of buboes be accurately and consistently measured with a digital calliper?

INTRODUCTION: Conducting clinical research on treatments for emerging infectious diseases is often complicated by methodological challenges, such as the identification of appropriate outcome measures to assess treatment response and the lack of validated instruments available to measure patient outcomes. In bubonic plague, some studies have assessed bubo size as an indicator of treatment success, a measure widely assumed to be indicative of recovery. Evaluating this outcome however is challenging as there is no validated method for measuring bubo size. The aim of this study is to assess the accuracy and inter- and intra-rater agreement of artificial bubo measurements using a digital calliper to understand whether a calliper is an appropriate measurement instrument to assess this outcome. METHODS: Study technicians measured 14 artificial buboes made from silicone overlaid with artificial silicone skin sheets over the course of two training sessions. Each artificial bubo was measured by each study technician once per training session, following a Standard Operating Procedure. The objectives of this study are to (i) evaluate the accuracy of individual measurements against the true size of the artificial bubo when using a digital calliper, (ii) understand whether the characteristics of the artificial bubo influence measurement accuracy and (iii) evaluate inter- and intra-rater measurement agreement. RESULTS: In total, 14 artificial buboes ranging from 52.7 to 121.6 mm in size were measured by 57 raters, generating 698 measurements recorded across two training sessions. Raters generally over-estimated the size of the artificial bubo. The median percentage difference between the measured and actual bubo size was 13%. Measurement accuracy and intra-rater agreement decreased as the size of the bubo decreased. Three quarters of all measurements had a maximum of 25% difference from another measurement of the same artificial bubo. Inter-rater agreement did not vary with density, size or presence of oedema of the artificial bubo. CONCLUSIONS: The results of this study demonstrate the challenges for both individual and multiple raters to repeatedly generate consistent and accurate measurements of the same artificial buboes with a digital calliper.

A systematic review of the clinical profile of patients with bubonic plague and the outcome measures used in research settings.

BACKGROUND: Plague is a zoonotic disease that, despite affecting humans for more than 5000 years, has historically been the subject of limited drug development activity. Drugs that are currently recommended in treatment guidelines have been approved based on animal studies alone-no pivotal clinical trials in humans have yet been completed. As a result of the sparse clinical research attention received, there are a number of methodological challenges that need to be addressed in order to facilitate the collection of clinical trial data that can meaningfully inform clinicians and policy-makers. One such challenge is the identification of clinically-relevant endpoints, which are informed by understanding the clinical characterisation of the disease-how it presents and evolves over time, and important patient outcomes, and how these can be modified by treatment. METHODOLOGY/PRINCIPAL FINDINGS: This systematic review aims to summarise the clinical profile of 1343 patients with bubonic plague described in 87 publications, identified by searching bibliographic databases for studies that meet pre-defined eligibility criteria. The majority of studies were individual case reports. A diverse group of signs and symptoms were reported at baseline and post-baseline timepoints-the most common of which was presence of a bubo, for which limited descriptive and longitudinal information was available. Death occurred in 15% of patients; although this varied from an average 10% in high-income countries to an average 17% in low- and middle-income countries. The median time to death was 1 day, ranging from 0 to 16 days. CONCLUSIONS/SIGNIFICANCE: This systematic review elucidates the restrictions that limited disease characterisation places on clinical trials for infectious diseases such as plague, which not only impacts the definition of trial endpoints but has the knock-on effect of challenging the interpretation of a trial's results. For this reason and despite interventional trials for plague having taken place, questions around optimal treatment for plague persist.

Infectious Proctitis due to Human Mpox.

We describe 2 cases of infectious proctitis secondary to human monkeypox in patients presenting with rectal pain. These cases highlight the importance of multidisciplinary management of monkeypox and in expanding case definitions and enabling clinical recognition in patients presenting without skin rash.

Lack of Evidence for Ribavirin Treatment of Lassa Fever in Systematic Review of Published and Unpublished Studies1.

Ribavirin has been used widely to treat Lassa fever in West Africa since the 1980s. However, few studies have systematically appraised the evidence for its use. We conducted a systematic review of published and unpublished literature retrieved from electronic databases and gray literature from inception to March 8, 2022. We identified 13 studies of the comparative effectiveness of ribavirin versus no ribavirin treatment on mortality outcomes, including unpublished data from a study in Sierra Leone provided through a US Freedom of Information Act request. Although ribavirin was associated with decreased mortality rates, results of these studies were at critical or serious risk for bias when appraised using the ROBINS-I tool. Important risks for bias related to lack of control for confounders, immortal time bias, and missing outcome data. Robust evidence supporting the use of ribavirin in Lassa fever is lacking. Well-conducted clinical trials to elucidate the effectiveness of ribavirin for Lassa fever are needed.

Ribavirin for treating Lassa fever: A systematic review of pre-clinical studies and implications for human dosing.

Ribavirin is currently the standard of care for treating Lassa fever. However, the human clinical trial data supporting its use suffer from several serious flaws that render the results and conclusions unreliable. We performed a systematic review of available pre-clinical data and human pharmacokinetic data on ribavirin in Lassa. In in-vitro studies, the EC50 of ribavirin ranged from 0.6 µg/ml to 21.72 µg/ml and the EC90 ranged from 1.5 µg/ml to 29 µg/ml. The mean EC50 was 7 µg/ml and the mean EC90 was 15 µg/ml. Human PK data in patients with Lassa fever was sparse and did not allow for estimation of concentration profiles or pharmacokinetic parameters. Pharmacokinetic modelling based on healthy human data suggests that the concentration profiles of current ribavirin regimes only exceed the mean EC50 for less than 20% of the time and the mean EC90 for less than 10% of the time, raising the possibility that the current ribavirin regimens in clinical use are unlikely to reliably achieve serum concentrations required to inhibit Lassa virus replication. The results of this review highlight serious issues with the evidence, which, by today standards, would be unlikely to support the transition of ribavirin from pre-clinical studies to human clinical trials. Additional pre-clinical studies are needed before embarking on expensive and challenging clinical trials of ribavirin in Lassa fever.

A standardised Phase III clinical trial framework to assess therapeutic interventions for Lassa fever.

BACKGROUND: Only one recommendation currently exists for the treatment of Lassa fever (LF), which is ribavirin administered in conjunction with supportive care. This recommendation is primarily based on evidence generated from a single clinical trial that was conducted more than 30 years ago-the methodology and results of which have recently come under scrutiny. The requirement for novel therapeutics and reassessment of ribavirin is therefore urgent. However, a significant amount of work now needs to be undertaken to ensure that future trials for LF can be conducted consistently and reliably to facilitate the efficient generation of evidence. METHODOLOGY: We convened a consultation group to establish the position of clinicians and researchers on the core components of future trials. A Core Eligibility Criteria (CEC), Core Case Definition (CCD), Core Outcome Set (COS) and Core Data Variables (CDV) were developed through the process of a multi-stakeholder consultation that took place using a modified-Delphi methodology. RESULTS: A consensus position was achieved for each aspect of the framework, which accounts for the inclusion of pregnant women and children in future LF clinical trials. The framework consists of 8 core criteria, as well as additional considerations for trial protocols. CONCLUSIONS: This project represents the first step towards delineating the clinical development pathway for new Lassa fever therapeutics, following a period of 40 years without advancement. Future planned projects will bolster the work initiated here to continue the advancement of LF clinical research through a regionally-centred, collaborative methodology, with the aim of delineating a clear pathway through which LF clinical trials can progress efficiently and ensure sustainable investments are made in research capacity at a regional level.

The impact of COVID-19 on clinical research for Neglected Tropical Diseases (NTDs): A case study of bubonic plague.

BACKGROUND: Among the many collaterals of the COVID-19 pandemic is the disruption of health services and vital clinical research. COVID-19 has magnified the challenges faced in research and threatens to slow research for urgently needed therapeutics for Neglected Tropical Diseases (NTDs) and diseases affecting the most vulnerable populations. Here we explore the impact of the pandemic on a clinical trial for plague therapeutics and strategies that have been considered to ensure research efforts continue. METHODS: To understand the impact of the COVID-19 pandemic on the trial accrual rate, we documented changes in patterns of all-cause consultations that took place before and during the pandemic at health centres in two districts of the Amoron'I Mania region of Madagascar where the trial is underway. We also considered trends in plague reporting and other external factors that may have contributed to slow recruitment. RESULTS: During the pandemic, we found a 27% decrease in consultations at the referral hospital, compared to an 11% increase at peripheral health centres, as well as an overall drop during the months of lockdown. We also found a nation-wide trend towards reduced number of reported plague cases. DISCUSSION: COVID-19 outbreaks are unlikely to dissipate in the near future. Declining NTD case numbers recorded during the pandemic period should not be viewed in isolation or taken as a marker of things to come. It is vitally important that researchers are prepared for a rebound in cases and, most importantly, that research continues to avoid NTDs becoming even more neglected.

Clinical characterization of Lassa fever: A systematic review of clinical reports and research to inform clinical trial design.

BACKGROUND: Research is urgently needed to reduce the morbidity and mortality of Lassa fever (LF), including clinical trials to test new therapies and to verify the efficacy and safety of the only current treatment recommendation, ribavirin, which has a weak clinical evidence base. To help establish a basis for the development of an adaptable, standardised clinical trial methodology, we conducted a systematic review to identify the clinical characteristics and outcomes of LF and describe how LF has historically been defined and assessed in the scientific literature. METHODOLOGY: Primary clinical studies and reports of patients with suspected and confirmed diagnosis of LF published in the peer-reviewed literature before 15 April 2021 were included. Publications were selected following a two-stage screening of abstracts, then full-texts, by two independent reviewers at each stage. Data were extracted, verified, and summarised using descriptive statistics. RESULTS: 147 publications were included, primarily case reports (36%), case series (28%), and cohort studies (20%); only 2 quasi-randomised studies (1%) were found. Data are mostly from Nigeria (52% of individuals, 41% of publications) and Sierra Leone (42% of individuals, 31% of publications). The results corroborate the World Health Organisation characterisation of LF presentation. However, a broader spectrum of presenting symptoms is evident, such as gastrointestinal illness and other nervous system and musculoskeletal disorders that are not commonly included as indicators of LF. The overall case fatality ratio was 30% in laboratory-confirmed cases (1896/6373 reported in 109 publications). CONCLUSION: Systematic review is an important tool in the clinical characterisation of diseases with limited publications. The results herein provide a more complete understanding of the spectrum of disease which is relevant to clinical trial design. This review demonstrates the need for coordination across the LF research community to generate harmonised research methods that can contribute to building a strong evidence base for new treatments and foster confidence in their integration into clinical care.

Time to reconsider the role of ribavirin in Lassa fever.

Ribavirin is the only available Lassa fever treatment. The rationale for using ribavirin is based on one clinical study conducted in the early 1980s. However, reanalysis of previous unpublished data reveals that ribavirin may actually be harmful in some Lassa fever patients. An urgent reevaluation of ribavirin is therefore needed.

Lassa fever outcomes and prognostic factors in Nigeria (LASCOPE): a prospective cohort study.

BACKGROUND: Lassa fever is a viral haemorrhagic fever endemic in parts of west Africa. New treatments are needed to decrease mortality, but pretrial reference data on the disease characteristics are scarce. We aimed to document baseline characteristics and outcomes for patients hospitalised with Lassa fever in Nigeria. METHODS: We did a prospective cohort study (LASCOPE) at the Federal Medical Centre in Owo, Nigeria. All patients admitted with confirmed Lassa fever were invited to participate and asked to give informed consent. Patients of all ages, including newborn infants, were eligible for inclusion, as were pregnant women. All participants received standard supportive care and intravenous ribavirin according to Nigeria Centre for Disease Control guidelines and underwent systematic biological monitoring for 30 days. Patients' characteristics, care received, mortality, and associated factors were recorded using standard WHO forms. We used univariable and multivariable logistic regression models to investigate an association between baseline characteristics and mortality at day 30. FINDINGS: Between April 5, 2018, and March 15, 2020, 534 patients with confirmed Lassa fever were admitted to hospital, of whom 510 (96%) gave consent and were included in the analysis. The cohort included 258 (51%) male patients, 252 (49%) female patients, 426 (84%) adults, and 84 (16%) children (younger than 18 years). The median time between first symptoms and hospital admission was 8 days (IQR 7-13). At baseline, 176 (38%) of 466 patients had a Lassa fever RT-PCR cycle threshold (Ct) lower than 30. From admission to end of follow-up, 120 (25%) of 484 reached a National Early Warning Score (second version; NEWS2) of 7 or higher, 67 (14%) of 495 reached a Kidney Disease-Improving Global Outcome (KDIGO) stage of 2 or higher, and 41 (8%) of 510 underwent dialysis. All patients received ribavirin for a median of 10 days (IQR 9-13). 62 (12%) patients died (57 [13%] adults and five [6%] children). The median time to death was 3 days (1-6). The baseline factors independently associated with mortality were the following: age 45 years or older (adjusted odds ratio 16·30, 95% CI 5·31-50·30), NEWS2 of 7 or higher (4·79, 1·75-13·10), KDIGO grade 2 or higher (7·52, 2·66-21·20), plasma alanine aminotransferase 3 or more times the upper limit of normal (4·96, 1·69-14·60), and Lassa fever RT-PCR Ct value lower than 30 (4·65, 1·50-14·50). INTERPRETATION: Our findings comprehensively document clinical and biological characteristics of patients with Lassa fever and their relationship with mortality, providing prospective estimates that could be useful for designing future therapeutic trials. Such trials comparing new Lassa fever treatments to a standard of care should take no more than 15% as the reference mortality rate and consider adopting a combination of mortality and need for dialysis as the primary endpoint. FUNDING: Institut National de la Santé et de la Recherche Médicale, University of Oxford, EU, UK Department for International Development, Wellcome Trust, French Ministry of Foreign Affairs, Agence Nationale de Recherches sur le SIDA et les hépatites virales, French National Research Institute for Sustainable Development.

Remote-Controlled and Pulse Pressure-Guided Fluid Treatment for Adult Patients with Viral Hemorrhagic Fevers.

Circulatory shock, caused by severe intravascular volume depletion resulting from gastrointestinal losses and profound capillary leak, is a common clinical feature of viral hemorrhagic fevers, including Ebola virus disease, Marburg hemorrhagic fever, and Lassa fever. These conditions are associated with high case fatality rates, and they carry a significant risk of infection for treating personnel. Optimized fluid therapy is the cornerstone of management of these diseases, but there are few data on the extent of fluid losses and the severity of the capillary leak in patients with VHFs, and no specific guidelines for fluid resuscitation and hemodynamic monitoring exist. We propose an innovative approach for monitoring VHF patients, in particular suited for low-resource settings, facilitating optimizing fluid therapy through remote-controlled and pulse pressure-guided fluid resuscitation. This strategy would increase the capacity for adequate supportive care, while decreasing the risk for virus transmission to health personnel.

Phase 2a, open-label, dose-escalating, multi-center pharmacokinetic study of favipiravir (T-705) in combination with oseltamivir in patients with severe influenza.

BACKGROUND: The pharmacokinetics and appropriate dose regimens of favipiravir are unknown in hospitalized influenza patients; such data are also needed to determine dosage selection for favipiravir trials in COVID-19. METHODS: In this dose-escalating study, favipiravir pharmacokinetics and tolerability were assessed in critically ill influenza patients. Participants received one of two dosing regimens; Japan licensed dose (1600 mg BID on day 1 and 600 mg BID on the following days) and the higher dose (1800 mg/800 mg BID) trialed in uncomplicated influenza. The primary pharmacokinetic endpoint was the proportion of patients with a minimum observed plasma trough concentration (Ctrough) ≥20 mg/L at all measured time points after the second dose. RESULTS: Sixteen patients were enrolled into the low dose group and 19 patients into the high dose group of the study. Favipiravir Ctrough decreased significantly over time in both groups (p <0.01). Relative to day 2 (48 hrs), concentrations were 91.7% and 90.3% lower in the 1600/600 mg group and 79.3% and 89.5% lower in the 1800/800 mg group at day 7 and 10, respectively. In contrast, oseltamivir concentrations did not change significantly over time. A 2-compartment disposition model with first-order absorption and elimination described the observed favipiravir concentration-time data well. Modeling demonstrated that less than 50% of patients achieved Ctrough ≥20 mg/L for >80% of the duration of treatment of the two dose regimens evaluated (18.8% and 42.1% of patients for low and high dose regimen, respectively). Increasing the favipravir dosage predicted a higher proportion of patients reaching this threshold of 20 mg/L, suggesting that dosing regimens of ≥3600/2600 mg might be required for adequate concentrations. The two dosing regimens were well-tolerated in critical ill patients with influenza. CONCLUSION: The two dosing regimens proposed for uncomplicated influenza did not achieve our pre-defined treatment threshold.

An open-label, randomized, non-inferiority trial of the efficacy and safety of ciprofloxacin versus streptomycin + ciprofloxacin in the treatment of bubonic plague (IMASOY): study protocol for a randomized control trial.

BACKGROUND: Bubonic plague is the primary manifestation of infection with Yersinia pestis, accounting for 90% of all plague cases and with 75% of global cases reported in Madagascar. All drugs in use for treating plague are registered based on experimental data and anecdotal evidence, and no regimen currently recommended is supported by a randomized clinical trial. The IMASOY trial intends to fill this knowledge gap by comparing two 10-day regimens included in the national guidelines in Madagascar. The primary objective of the trial is to test the hypothesis that ciprofloxacin monotherapy is non-inferior to streptomycin followed by ciprofloxacin for the treatment of bubonic plague, thus avoiding the need for injectable, potentially toxic, aminoglycosides. METHODS: A two-arm parallel-group randomized control trial will be conducted across peripheral health centres in Madagascar in five districts. Males and non-pregnant females of all ages with suspected bubonic or pneumonic plague will be recruited over the course of three plague 'seasons'. The primary endpoint of the trial is to assess the proportion of patients with bubonic plague who have a therapeutic response to treatment (defined as alive, resolution of fever, 25% reduction in the size of measurable buboes, has not received an alternative treatment and no clinical decision to continue antibiotics) as assessed on day 11. DISCUSSION: If successful, the trial has the potential to inform the standard of care guidelines not just in Madagascar but in other countries afflicted by plague. The trial is currently ongoing and expected to complete recruitment in 2022. TRIAL REGISTRATION: ClinicalTrials.gov NCT04110340 . Registered on 1 October 2019.

Factors Influencing Atypical Clinical Presentations during the 2017 Madagascar Pneumonic Plague Outbreak: A Prospective Cohort Study.

In late 2017, Madagascar experienced a large urban outbreak of pneumonic plague, the largest outbreak to date this century. During the outbreak, there were widespread reports of plague patients presenting with atypical symptoms, such as prolonged duration of illness and upper respiratory tract symptoms. Reported mortality among plague cases was also substantially lower than that reported in the literature (25% versus 50% in treated patients). A prospective multicenter observational study was carried out to investigate potential reasons for these atypical presentations. Few subjects among our cohort had confirmed or probable plague, suggesting that, in part, there was overdiagnosis of plague cases by clinicians. However, 35% subjects reported using an antibiotic with anti-plague activity before hospital admission, whereas 55% had antibiotics with anti-plague activity detected in their serum at admission. Although there may have been overdiagnosis of plague by clinicians during the outbreak, the high frequency of community antibiotic may partly explain the relatively few culture-positive sputum samples during the outbreak. Community antibiotic use may have also altered the clinical presentation of plague patients. These issues make accurate detection of patients and the development of clinical case definitions and triage algorithms in urban pneumonic plague outbreaks difficult.

Lassa fever clinical course and setting a standard of care for future randomized trials: A protocol for a cohort study of Lassa-infected patients in Nigeria (LASCOPE).

BACKGROUND: Lassa Fever (LF), is a severe viral disease prevalent in Western Africa. It is classified as a priority disease by the World Health Organization (WHO). Ribavirin is the recommended therapy despite weak evidence of its efficacy. Promising therapeutic agents are becoming available for evaluation in human. Before launching therapeutic trials, we need data on the evolution of the disease under the best possible conditions of care. METHODS: We have initiated a prospective study in Nigeria to better understand the clinical course and prognostic factors of LF while implementing high quality standardized care. Inclusion criteria are: suspected or confirmed LF and informed consent. Participants are followed 60 days from admission and receive free of charge standardized supportive care and biological monitoring, as well as intravenous ribavirin for those with confirmed LF. Data are collected using standardized case report forms (CRF). Primary and secondary outcomes are fatality and severe morbidity, with special focus on acute kidney dysfunction and pregnancy complications. Factors associated with outcomes will be investigated. RESULTS: The cohort is planned for 3 years. Inclusions started in April 2018 at the Federal Medical Center Owo in Ondo State. A second site will open in Nigeria in 2020 and discussions are underway to open a site in Benin. 150 to 200 new participants are expected per year. CONCLUSIONS: This cohort will: provide evidence to standardize LF case management; provide key inputs to design future clinical trials of novel therapeutics; and establish clinical research teams capable of conducting such trials in LF-endemic areas. STUDY REGISTRATION: The LASCOPE study was registered on ClinicalTrial.gov (NCT03655561).

Comparative Effectiveness of Combined Favipiravir and Oseltamivir Therapy Versus Oseltamivir Monotherapy in Critically Ill Patients With Influenza Virus Infection.

BACKGROUND: A synergistic effect of combination therapy with favipiravir and oseltamivir has been reported in preclinical models of influenza. However, no data are available on the clinical effectiveness of combination therapy in severe influenza. METHODS: Data from 2 separate prospective studies of influenza adults were used to compare outcomes between combination and oseltamivir monotherapy. Outcomes included rate of clinical improvement (defined as a decrease of 2 categories on a 7-category ordinal scale) and viral RNA detectability over time. Subhazard ratios (sHRs) were estimated by the Fine and Gray model for competing risks. RESULTS: In total, 40 patients were treated with combination therapy and 128 with oseltamivir alone. Clinical improvement on day 14 in the combination group was higher than in the monotherapy group (62.5% vs 42.2%; P = .0247). The adjusted sHR for combination therapy was 2.06 (95% confidence interval, 1.30-3.26). The proportion of undetectable viral RNA at day 10 was higher in the combination group than the oseltamivir group (67.5% vs 21.9%; P < .01). No significant differences were observed in mortality or other outcomes. CONCLUSIONS: Favipiravir and oseltamivir combination therapy may accelerate clinical recovery compared to oseltamivir monotherapy in severe influenza, and this strategy should be formally evaluated in a randomized controlled trial.

Clinical REsearch During Outbreaks (CREDO) Training for Low- and Middle-Income Countries.

We describe a pilot of the Clinical REsearch During Outbreaks (CREDO) initiative, a training curriculum for researchers in epidemic-prone low- and middle-income countries who may respond to disease outbreaks. Participants reported improved confidence in their ability to conduct such research and overall satisfaction with the course structure, content, and training.

A systematic review of clinical guidelines on the management of acute, community-acquired CNS infections.

BACKGROUND: The epidemiology of CNS infections in Europe is dynamic, requiring that clinicians have access to up-to-date clinical management guidelines (CMGs) to aid identification of emerging infections and for improving quality and a degree of standardisation in diagnostic and clinical management practices. This paper presents a systematic review of CMGs for community-acquired CNS infections in Europe. METHODS: A systematic review. Databases were searched from October 2004 to January 2019, supplemented by an electronic survey distributed to 115 clinicians in 33 European countries through the CLIN-Net clinical network of the COMBACTE-Net Innovative Medicines Initiative. Two reviewers screened records for inclusion, extracted data and assessed the quality using the AGREE II tool. RESULTS: Twenty-six CMGs were identified, 14 addressing bacterial, ten viral and two both bacterial and viral CNS infections. Ten CMGs were rated high quality, 12 medium and four low. Variations were identified in the definition of clinical case definitions, risk groups, recommendations for differential diagnostics and antimicrobial therapy, particularly for paediatric and elderly populations. CONCLUSION: We identified variations in the quality and recommendations of CMGs for community-acquired CNS infections in use across Europe. A harmonised European "framework-CMG" with adaptation to local epidemiology and risks may improve access to up-to-date CMGs and the early identification and management of (re-)emerging CNS infections with epidemic potential.

A rapid research needs appraisal methodology to identify evidence gaps to inform clinical research priorities in response to outbreaks-results from the Lassa fever pilot.

BACKGROUND: Infectious disease epidemics are a constant threat, and while we can strengthen preparedness in advance, inevitably, we will sometimes be caught unaware by novel outbreaks. To address the challenge of rapidly identifying clinical research priorities in those circumstances, we developed and piloted a protocol for carrying out a systematic, rapid research needs appraisal (RRNA) of existing evidence within 5 days in response to outbreaks globally, with the aim to inform clinical research prioritization. METHODS: The protocol was derived from rapid review methodologies and optimized through effective use of pre-defined templates and global time zones. It was piloted using a Lassa fever (LF) outbreak scenario. Databases were searched from 1969 to July 2017. Systematic reviewers based in Canada, the UK, and the Philippines screened and extracted data using a systematic review software. The pilot was evaluated through internal analysis and by comparing the research priorities identified from the data, with those identified by an external LF expert panel. RESULTS: The RRNA pilot was completed within 5 days. To accommodate the high number of articles identified, data extraction was prioritized by study design and year, and the clinical research prioritization done post-day 5. Of 118 potentially eligible articles, 52 met the data extraction criteria, of which 46 were extracted within the 5-day time frame. The RRNA team identified 19 clinical research priorities; the expert panel independently identified 21, of which 11 priorities overlapped. Each method identified a unique set of priorities, showing that combining both methods for clinical research prioritization is more robust than using either method alone. CONCLUSIONS: This pilot study shows that it is feasible to carry out a systematic RRNA within 5 days in response to a (re-) emerging outbreak to identify gaps in existing evidence, as long as sufficient resources are identified, and reviewers are experienced and trained in advance. Use of an online systematic review software and global time zones effectively optimized resources. Another 3 to 5 days are recommended for review of the extracted data and to formulate clinical research priorities. The RRNA can be used for a "Disease X" scenario and should optimally be combined with an expert panel to ensure breadth and depth of coverage of clinical research priorities.