- Research article
- Open Access
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
BMC Medicine volume 17, Article number: 107 (2019)
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.
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.
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.
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.
The need and ability to conduct clinical research during infectious disease outbreaks to inform current and future responses is gaining acceptance as a core pillar of outbreak response . However, the unpredictable nature of outbreaks makes outbreak research challenging [2, 3]. Since time is of the essence, researchers, policy makers, and funders need to rapidly identify key gaps in evidence at the earliest stages of an outbreak, so that they can prioritize research to address those gaps and ensure that any research that is undertaken has maximal value . Traditional approaches to evidence assimilation, such as systematic reviews, require time and resources that are unlikely to be available during an outbreak, with traditional systematic reviews generally taking at least 12 months . Rapid reviews are a variation of a systematic review that balances time constraints with considerations in bias , designed to inform healthcare policies and guidelines . Even rapid reviews and scoping reviews might require 1 to 6 months or longer to complete [5, 6, 8, 9]. Furthermore, there is no gold standard approach for rapid or scoping reviews, with methods varying greatly [5,6,7,8,9,10,11]. This highlights a need for a robust methodology to rapidly and systematically identify key gaps in knowledge and evidence to inform research prioritization early in outbreaks. To address this, we developed and piloted a transparent and replicable protocol for carrying out a rapid research needs appraisal (RRNA), within 5 days in response to (re-) emerging outbreaks globally. The aim is not to identify and fully appraise all the available evidence, since this is not feasible within 5 days. Rather, the aim is to identify important gaps in evidence and knowledge in a robust, systematic, and replicable manner to rapidly inform clinical research prioritization.
The RRNA was piloted in 2017 using a fictitious Lassa fever (LF) outbreak scenario. LF is an acute, viral illness first recognized in Nigeria in 1969 . The causative pathogen, Lassa virus (LASV), is a zoonotic, single-stranded RNA arenavirus that is endemic in Guinea, Liberia, Sierra Leone, and Nigeria, with seasonal peaks in incidence. A limited number of cases have also been reported from Benin, Burkina Faso, Côte d’ Ivoire, Ghana, and Togo . LASV has been prioritized by the World Health Organization (WHO) as a high threat pathogen for which there is a need for accelerated research and development . In the beginning of 2018, Nigeria experienced a large outbreak of LF, with 1999 suspected cases reported by the Nigeria Centre for Disease Control. Of 437 confirmed cases, 109 died, giving a case fatality rate (CFR) of 25% in confirmed cases . This article presents the development of the RRNA methodology, its piloting and evaluation using LF as an example, and the research priorities that were identified.
The RRNA protocol was developed as a collaboration between Cochrane Response, the Ottawa Hospital Research Institute, Evidence Aid, and the UK Public Health Rapid Support Team staff at the University of Oxford. The methodology was derived from existing rapid review methodologies and optimized through the use of global teams of systematic reviewers across different time zones, pre-defined screening and data extraction templates and the use of an online systematic review software (DistillerSR, Evidence Partners, Ottawa, Canada). The protocol was focused on identifying existing evidence gaps across pre-defined clinical domains (Additional file 1). These were defined by researchers and clinicians with previous experience of clinical research outbreak response. The RRNA protocol is registered on the Open Science Framework , and an online training package has been developed . The 5-day process is illustrated in Fig. 1.
A working group of experts with experience in systematic and rapid review methodologies, information management, and clinical infectious disease research was convened. The protocol was developed over 4 months through three face-to-face meetings with members of the working group and e-mail iterations . The methodology was designed to be used for (re-) emerging infectious diseases where existing evidence and knowledge is expected to be limited and for the purposes of this exercise was focused on clinical aspects, rather than epidemiological, animal, or ecological studies. Therefore, the protocol was designed to be inclusive with a focus on identifying all relevant articles presenting the outcomes of clinical research, including conference abstracts and ongoing clinical trials. The protocol was piloted in a two-stage process. Prior to piloting, experienced systematic reviewers based across three different time zones (Canada, the UK, the Philippines) were engaged and trained in the methodology and the use of the DistillerSR online systematic review software. The systematic reviewers programmed the generic RRNA screening and data extraction forms into DistillerSR prior to piloting. A Dropbox folder was set up for sharing of documents. An online instant messenger group was also set up to allow queries to be posted and answered rapidly by all members of the team.
The processes, including the evidence search strategy, the handover of information, and the data extraction template were initially piloted over 1 day using a fictitious Nipah virus outbreak scenario. This process mini-pilot was evaluated through feedback from all involved in the pilot at a conference meeting call. The feedback informed updates to the data extraction table and the handover processes. The final RRNA protocol was subsequently piloted fully over 5 days using a fictitious LF outbreak scenario.
Lassa fever pilot
Outside of this pilot study, the process would be triggered when a decision is taken that there is a need to carry out a RRNA in response to a (re-) emerging outbreak. Depending on the setup, this decision may be taken by a steering group, which can be separate or the same as the coordinating team (CT). For this pilot, the steering group based at the University of Oxford, consisting of clinical researchers with experience in infectious disease outbreak response and systematic reviews also acted as the CT. The pilot was triggered by the CT on 17 July 2017. At the start of the pilot, the CT reviewed and updated the search databases and inclusion criteria considering the nature of the outbreak scenario. The updated protocol, specific to the LF outbreak scenario, was then submitted via e-mail to the information specialist based in Glasgow, UK, and the systematic review teams based in London, UK; Ottawa, Canada; and Manila, the Philippines, together with the fictitious outbreak report and supporting clinical information about LF from the US Centers for Disease Control and Prevention (CDC).
Figure 2 illustrates the tasks carried out by the systematic review teams involved in the Lassa fever pilot.
The review team based at Cochrane Response in the UK updated the protocol in DistillerSR accordingly, while the information specialist carried out the search. The search was completed on day 1, and the result submitted as an Endnote library to the systematic review team in London for uploading into DistillerSR.
An information specialist searched the following electronic databases for articles published from 1969 until 17 July 2017: MEDLINE (PubMed), EMBASE (OVID), the Cochrane Library (including the Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trials), DARE (Database of Abstracts of Reviews of Effect), Epistemonikos, and PROSPERO. Moreover, the following trial registries: Clinicaltrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP), the ISRCTN registry, and the websites of WHO, CDC, and the European Centre for Disease Prevention and Control (ECDC), using the search terms described in Box 1. There were no language restrictions applied.
One systematic reviewer screened titles and abstracts for inclusion using DistillerSR, with a second reviewer screening all papers deemed ineligible by the first reviewer. Any disagreements were passed to the next level of screening. Full-text articles were screened independently by two reviewers and consensus on disagreements reached by involving a third reviewer. Articles not found through the automated or manual search were excluded due to non-accessibility given the time constraints. These were listed with full bibliography in the final report. All articles presenting human, clinical LF quantitative research were included. Qualitative studies, non-human animal and cell studies, were excluded. Studies only presenting data on community transmission from zoonotic sources were excluded, since the objective was on clinical research. There were no language limitations at the screening stages.
The data extraction was limited to core data essential for identifying gaps across the pre-defined clinical research domains (Additional file 1). The pre-defined data extraction table was designed to facilitate extraction of (1) bibliography, (2) study design, (3) study objectives, (4) number of participants, (5) populations covered, (6) interventions and/or exposure, (7) comparators, and (8) outcomes . Risk of bias assessment or grading of evidence beyond the above data extraction was not done.
The protocol specified that one systematic reviewer performed the data extraction from the included papers. A second researcher would then do a random check of 10% of all qualitative data and 100% of the quantitative data extracted. For prioritization purposes, articles would be extracted in order of study design and publication date, with study designs providing a higher level of evidence and most recently published articles prioritized. Data would not be extracted from studies whose design provided a lower level of evidence, such as case series and case reports, when data were available from studies providing a higher level of evidence for the clinical domains addressed in the article. The final data extraction table was submitted to the CT as an Excel file by mid-day on day 5, together with the list of bibliographies of the articles not extracted, with reasons provided and a PRISMA flow chart.
Gaps analysis and clinical research prioritization
The final data extraction table was reviewed by one member of the CT, who organized and summarized the level of evidence and outcomes identified for each clinical domain and incorporated the findings into a final report post-day 5 of the RRNA process. The final report was submitted to the CT. The members of the CT subsequently identified gaps in evidence by reviewing the extracted data for each clinical domain, by study design, study objectives, populations covered, interventions/exposure, and outcomes presented and through a round of iterations and consensus discussions over 2 days defined key clinical research priorities, informed by the gaps in evidence identified.
The full RRNA pilot was evaluated in a two-step process. Firstly, a brief survey was sent to everyone involved in the pilot, asking about facilitators and barriers experienced. The survey responses were collated by the CT and discussed during a telephone conference a week after completion of the pilot. Secondly, an expert panel of three LF experts was asked to independently identify seminal articles and LF clinical research priorities. The panel members independently identified clinical research priorities and seminal articles from their previous experience of Lassa fever research. These were submitted to the team at Oxford University via e-mail, de-duplicated and consolidated into one list. The list of seminal articles was compared with the articles included in the RRNA, and articles excluded due to non-accessibility. The clinical research priorities were compared with those identified by the CT from the RRNA data.
The CT reviewed and updated the protocol as appropriate for the LF outbreak scenario and submitted it to the information specialist and all systematic review teams on day 1. The information specialist completed the search and submitted the results as an Endnote library to the systematic review teams on day 1 (Table 1).
Screening of title and abstracts began before the end of day 1, started by the review team in Canada, followed by the Philippines, then the UK, optimizing use of global time zone, and was completed by day two, with 39% (n = 428/1104) of records passing this step and requiring further assessment. In parallel to the screening of title and abstracts, the information specialist retrieved full-text papers using Endnote’s automatic retrieval function. This was complemented by a manual search of papers not retrieved automatically. The full-text papers were submitted to the review teams and uploaded to DistillerSR in sections. Using the software allowed review processes to be carried out in parallel, while reducing the need for handovers. As soon as papers were deemed potentially eligible, another reviewer could start the full-text screening followed by data extraction, while others continued screening of title and abstracts (Table 1). In tandem, electronic copies of journal articles could be uploaded in the system, and progress tracked in real time. Issues were dealt with via the online instant messenger group and during a brief daily mid-day Skype meeting between the review teams. Two members of the CT were on standby to assist throughout the 5 days.
The full-text screening started on day 2, but the final conflicts were not resolved until early on day 5 (acceptance rate 28% (n = 118/428). Of the included articles, the study design was identified for 93% (n = 110/118) within the time frame. After study design prioritization, 47% (n = 52/110) of the included articles with study design identified, qualified for data extraction. Most of these (88% (n = 46/52)) were extracted by mid-day on day 5.
The search was completed earlier than planned, which meant that the screening of title and abstracts and full-text papers commenced earlier than scheduled. However, the retrieval and screening of full-text papers and resolution of conflicts took longer than anticipated. This was partly due to the higher than expected number of articles identified for a (re-) emerging infectious disease and because Endnote’s automatic paper retrieval only retrieved 51% (n = 565/1104) of the articles as PDFs (n = 436) or URL links (n = 129). The remaining full-text papers, which passed through the first title and abstract screening step (n = 249), were searched for manually by members of the CT through the University of Oxford online library access. Papers not found after the manual search (n = 145) were excluded due to inaccessibility, instead listed with full bibliography in the final report (Additional file 2). Most of these articles were not accessible due to being published in non-English languages and journals. There were no systematic reviews or randomized controlled trials (RCTs) identified amongst the non-accessible articles. The data extraction table was submitted to the CT as a Microsoft Excel file by mid-day on day 5. This was supplemented by a PRISMA flow chart and bibliographies of the studies which were excluded due to not being accessible within the time frame (Additional file 2) or included but not being data extracted (Additional file 3). The unexpected retrieval and resolution of full-text article delays meant that the proportional check of the extracted data by a second reviewer was not completed within the 5 days. Instead, a member of the CT checked 30% of the extracted data post-day 5.
Outcomes and gaps in evidence
The data extracted were comprehensive, as would be required for a systematic review. However, for the purpose of the RRNA, in order to enable identification of gaps in evidence and knowledge in a short timeframe, the data were streamlined by a member of the CT to highlight the key PICO (Population, Intervention, Comparison, Outcome) parameters required for this purpose, in addition to bibliography, study design, and setting. Data queries were resolved via e-mail after completion of the pilot. Due to the high number of articles identified and the amount and complexity of data extracted, tidying and organizing of the data to facilitate identification of gaps in evidence took longer than expected. The final report was submitted to the steering group, together with a PRISMA flowchart and the supplements 3 days post-pilot completion. Gaps in evidence were identified, individually by members of the CT, through a review of the extracted data for each clinical domain. A narrative summary of the level of evidence and gaps in evidence identified from the data by clinical domains is provided below.
Characteristics of the included studies
The electronic literature search identified 1104 records, published between 1969 and July 2017, of which 118 met the inclusion criteria (Fig. 3). Study design and clinical domains addressed in the articles were identified for 110 of the articles. There were no systematic reviews, meta-analysis, or RCTs identified. Two were non-randomized controlled studies, 34 cohort studies (some of which included before and after comparisons), 4 case-control studies, 12 cross-sectional studies, 27 case series, and 31 case reports (Table 2).
The articles were prioritized so that data were extracted first from studies whose design provided the highest level of evidence. Ongoing studies and conference abstracts were also prioritized, since they can present important preliminary findings. Case series and case reports were not extracted when higher level of evidence was available for all the clinical domains addressed in the article. Of the 110 articles, 52 met the data extraction criteria and 46 were extracted within the 5 days [18,19,20,21,22,23,24,25,26,27, 32,33,34, 36,37,38,39,40,41,42,43,44,45,46,47,48, 97,98,99,100,101,102,103,104, 107, 109,110,111,112, 114, 119, 121,122,123,124, 127]. Twenty-seven case series and 31 case reports were not extracted due to higher level of evidence being available for the domains addressed in the articles. Six cohort studies [28,29,30,31, 108, 120] and eight articles [128,129,130,131,132,133,134,135] without study design identified were not extracted due to resource limitations (Additional file 3). Of the 46 data extracted articles (Additional file 4), most were set-in low-income countries in West Africa: Sierra Leone (n = 19), Nigeria (n = 17), Liberia (n = 5), Guinea (n = 2), and Mali (n = 2). Five were indicated as set-in high-income countries: the USA (n = 3), Germany (n = 2), and the UK (n = 1). Three articles presented studies set in more than one country [48, 114, 121]. Five were conference abstracts [33,34,35,36, 41] and two ongoing cohort studies registered by the US Army, evaluating effectiveness and safety of ribavirin, expected to be completed in 2018 and 2019 [121, 122]. Table 3 presents an overview of the study setting, populations, objectives, and interventions identified for the studies in each clinical domain.
Clinical phenotype and natural history of disease
Seventy-seven articles identified addressed this domain (Table 2). After prioritization by study design, 29 articles published from 1975 to 2017 qualified for data extraction, of which 25 were extracted within the time frame. These articles reported data on almost 7000 people, representing more than 1700 confirmed LF cases (Table 3). Most of the studies were set in West Africa. Fourteen studies were set in Nigeria [18, 19, 21, 22, 24, 26, 33, 34, 36, 39, 41, 42, 48, 127], seven in Sierra Leone [20, 25, 27, 40, 43, 45, 48], three in Liberia [23, 46, 48], three in Mali [32, 47, 48], and one in the USA . One study was set in multiple locations . The five conference abstracts identified related to studies in this domain. Four cohort studies published from 1974 to 2001 [28,29,30,31] were not extracted due to resource limitations (Additional file 3).
Symptoms of LF on presentation and during hospital admission in healthcare settings in West Africa were described in 15 studies [19, 21, 23,24,25,26,27, 33, 35, 36, 39,40,41, 45, 48]. The data shows that LF has been studied in adult and pediatric populations in lower income healthcare settings in West Africa. Most of the studies were observational studies, and many lacked data on case definition, diagnostic criteria used to support the findings, or risk factors, such as comorbidities or immunosuppression through age, illness, or medication. Another gap identified was the quantification of the risk of complications, more severe disease, and sequelae in different at-risk populations. Eleven studies presented data on CFR with standard care: six were set in Nigeria [22, 26, 33,34,35, 39], three in Sierra Leone [25, 27, 43], and two in Liberia [23, 46]. The CFR ranged from 5.6 to 75%, but with limited information to explain the wide variations observed in different settings or description of the standard care provided.
Transmission and prevention
Twenty-three articles were identified for this domain; 13 qualified for data extraction and data were extracted for 12 of these, reporting data from 1980 participants, including nearly 300 confirmed cases of LF (Tables 2 and 3). The studies were set in Sierra Leone (n = 5) [38, 43, 98, 100, 103], Nigeria (n = 4) [22, 42, 101, 102], Liberia (n = 1) , Germany (n = 1) , the UK (n = 1) , and the USA . One study was set in more than one country . Several of the studies reported risk of nosocomial transmission to other patients and healthcare workers [22, 38, 42, 43, 104], with attack rates ranging from 11 to 55% in different settings [22, 104]. Four studies reported the use of ribavirin as post-exposure prophylaxis (PEP) [98, 100,101,102], administered to a different level of contacts. A total of 64 Lassa fever contacts were treated with the drug. Though it was evident that there is a risk of transmission from body fluids in hospital settings, there were no robust studies identified studying risk of transmission from different types of body fluids or organs, moreover, a lack of standardization of definitions of a “contact.”
Fourteen studies were available for this domain; eight qualified for data extraction, and seven were extracted within the time frame (Table 2). Four of the extracted studies were set in Sierra Leone [37, 107, 109, 111], two in Liberia [46, 112], and one in Nigeria , providing data from more than 800 confirmed cases (Table 3). Most identified studies were observational, with one case-control study. The studies used different diagnostic tests, with polymerase chain reaction (PCR) the most commonly used. Neither a gold standard diagnostic test nor clinical or laboratory case definitions were reported. Moreover, systematic diagnostic and sampling strategies were not reported. The studies indicated that no single diagnostic test could detect all cases or strains of LF [109, 111, 112].
Twenty-one studies were identified for this domain; six articles qualified for data extraction of those five were extracted within the time frame (Table 2). Two studies were set in Sierra Leone [107, 114], two in Guinea [44, 114], one in Mali , and one in Liberia . One study was set in more than one country . Though there were a limited number of studies identified, they provided data from more than 4500 participants, including 1400 LF-positive people (Table 3). One study reported seroprevalence data from a rural region of Guinea , and a cohort study reported that LF IgM antibodies may persist for months to years . The data shows that there are large gaps in evidence regarding the immune response to LF infection caused by different strains, in different at-risk populations and over time.
Drug therapy and supportive care
Of 36 articles identified for this domain, 11 qualified for data extraction and ten were extracted within the time frame (Table 2). Four studies were set in Sierra Leone [38, 119, 123, 124], four in Nigeria [19, 21, 24, 42], and two ongoing studies by the US Army [121, 122] (set in the USA and Germany), providing data for more than 1500 participants and almost 800 LF cases (Table 3). The highest level of evidence in this domain was a non-randomized controlled study set in Sierra Leone (1986, n = 312), which studied the effect of ribavirin and convalescent plasma therapy. It was a relatively small study, which showed no reduction in case fatality rates using LF convalescent plasma, but indicated that ribavirin was effective, especially if administered within the first 6 days of illness .
Risk factors for more severe disease
There were four studies identified and data extracted for this domain (Table 2). The studies were set in Sierra Leone [37, 38, 107, 114] and Guinea [44, 114]. One study was set in both countries . The data represented more than 2000 participants and over 500 confirmed or probable LF cases (Table 3). A number of studies reported that elevated aspartate aminotransferase levels were associated with increased mortality rates [37, 38, 107], one study also reported a correlation between low levels of blood urea nitrogen, alkaline phosphatase, and alanine aminotransferase and survival . Two studies reported an association between low levels of a number of cytokines and survival rates [107, 114].
Stakeholder pilot evaluation
Some of the key facilitators and barriers identified by the stakeholders taking part in the pilot, through a short post-LF pilot survey and subsequent telephone conference, are presented in Table 4. The evaluation highlighted that previous training in the methodology and experience of systematic review methods were key facilitators. Moreover, that use of the online systematic review software and global time zones was an effective way of optimizing resources. The barriers identified also highlights the need to ensure that everyone is familiar with all the systems used, and in identifying sufficient resources at the outset of the outbreak, tailored to the type of outbreak and number of articles identified after the initial search.
Clinical research priorities
A comparison of the clinical research priorities identified by the steering group from the RRNA data with the priorities independently identified by the LF expert panel shows that though there is overlap, each method identified unique priorities. Despite the number of articles identified by the RRNA, the types of studies that were reported meant that there was limited robust evidence in the clinical domains investigated with inadequacies in the quality of the reporting (such as a lack of case definitions and methods used for diagnostics). This meant that the steering group, through a review of the extracted data, identified several clinical research priorities where important uncertainties and evidence gaps remain. These are presented in the table, together with the clinical research priorities identified by the independent LF expert panel (Table 5). Of the 19 clinical research priorities informed by the RRNA data, 11 of those were also listed as priorities by the expert panel, together with an additional ten research priorities. This shows that the RRNA methodology was able to identify most of the priorities identified by the Lassa fever expert panel, together with an additional eight unique priorities not identified by the expert panel. The priorities identified by the expert panel tended to be more specific, whereas the priorities identified from the RRNA covered a wider focus.
There were 21 seminal articles identified by the LF expert panel. These were all identified by the RRNA search strategy, although 13 did not meet the inclusion criteria for the RRNA and were excluded at the screening stage, mainly due to being animal or cell culture studies. The remaining eight articles [25, 44, 60, 62, 63, 65, 96, 119] were all included in the RRNA. Three of these articles [25, 44, 119] met the data extraction criteria and were extracted. The other five [60, 62, 63, 65, 96] were case series or case reports and not extracted, instead included with full bibliography. This shows that the RRNA successfully identified and included all seminal articles identified by the LF expert panel which met the RRNA inclusion eligibility criteria.
The development and piloting of the RRNA process demonstrates that a global partnership, through effective use of time zones, can deliver a robust summary of much of the published clinical research evidence on Lassa fever within 5 days in response to an outbreak. The results show that the RRNA methodology can be a valuable tool for rapidly identifying gaps in evidence and informing clinical research priorities in response to (re-) emerging outbreaks globally, ideally combined with an expert panel for further refinement of the research priorities.
Key strengths of the process were the use of experienced systematic reviewers, trained in the RRNA methodology in advance and based across different global time zones for resource optimization. Use of an online systematic review software allowed various steps in the review process to be carried out in parallel, minimizing handovers and knowledge transfer loss. The RRNA protocol was developed specifically for emerging outbreaks where previous clinical research is likely limited. Therefore, the protocol was designed to be over-inclusive at the screening stage, with the aim to reduce the risk of any relevant studies being missed. However, for the LF pilot, the number of articles retrieved and deemed eligible was higher than expected from previous experiences for a re-emerging outbreak, which meant that the full-text screening and data extraction took longer than anticipated. This was alleviated by the prioritization of the data extraction step, whereby lower levels of evidence were not extracted if a higher level of evidence were identified for the clinical domains covered. Furthermore, articles in languages other than English were included but not data extracted. For the future, we recommend that resources should be allocated in relation to the number of articles identified at the search stage. Moreover, depending on the nature of the outbreak and region of endemicity of the pathogen, reviewers with appropriate language skills can be identified at the outset.
In this pilot, the reviewers found that the diagnostics and immune response domains were more difficult to process, in regard to assessing which articles to include and relevant data to extract. This delayed the reaching of consensus at the full-text screening stage and the data extraction. Engaging reviewers with relevant content expertise as well as those with expertise in systematic review screening and data extraction processes, and ensuring understanding of all domains in advance, could help with the speedier resolution of queries and identification of the key data to extract.
Despite the high number of articles identified, the RRNA was able to identify key clinical research articles, which enabled the CT to identify a broad range of gaps in evidence and clinical research priorities across all domains, including eight unique research questions not identified by the expert panel. Prospective clinical observational studies of patients with Lassa fever could answer many of the key evidence gaps, such as risk factors and pathophysiological mechanisms for severe disease, infectivity of body tissues, long-term sequelae, and immunological responses. A need for diagnostic studies was also identified by both the RRNA method and the experts and could be nested within clinical observational studies. In addition, clinical trials are needed to evaluate the use of supportive care strategies, ribavirin, and other potential therapeutics. Given the fairly predictable timing and location of LF cases, all these research questions should be tractable given sufficient resources and effort.
Although there was an overlap of research questions identified by the RRNA team and the panel members, both methods identified unique research questions. The questions identified by the RRNA team tended to be broader, whereas the expert panel identified more focused questions. This shows that using both methods can lead to a more robust and comprehensive set of research priorities that covers all domains, while ensuring specificity, than relying on either process alone. All seminal papers that fit the inclusion criteria were identified by the RRNA methodology. The number of seminal papers highlighted by the panel that did not fit the inclusion criteria emphasizes the need to ensure that all stakeholders are fully trained in the process in advance, ideally through a briefing meeting to ensure full understanding of the process.
The pilot evaluation shows that it is feasible to carry out a robust RRNA within 5 days in response to an outbreak, to inform clinical research priorities. Another 3 to 5 days are recommended for summarizing and reviewing the extracted data, in order to identify gaps in evidence and to formulate clinical research priorities. The resource limitations encountered can be minimized by identifying reviewers, depending on the number of articles identified at the search stage. Depending on the nature of the outbreak, e.g., endemicity, reviewers with specific language skills should be engaged. Identifying experts for the panel took longer than anticipated and although the clinical researchers who formed the expert panel for this pilot had years of experience in LF research, in collaboration with research groups in endemic areas, engaging experts from endemic areas would be desirable. For sustainability, it is important to identify a pool of clinical researchers and systematic reviewers globally, with a focus on infectious disease “hot spot” regions, that are trained in the process and on “stand-by” ready to be activated. Moreover, it is important to engage a pool of global emerging infectious disease experts in advance. The fact that the time commitment is limited minimizes the time spent away from other work commitments and can act as an important facilitator. Timely and effective data sharing during a public health emergency and potential copyright issues around sharing of non-open access articles are other challenges that need to be addressed in advance.
This pilot study shows that the RRNA methodology can be used to systematically and transparently identify important research gaps, in days and weeks rather than months or years. The findings highlight that using a RRNA together with input from a disease-specific expert panel can ensure that a wider range of clinical research priorities is identified than if using either method on its own. The pilot illustrates the benefit of global research networks, but also a need to strengthen networks in epidemic “hot spot” regions, which could ensure people with appropriate language skills and contextual expertise are trained and engaged in future RRNAs. The RRNA is not intended to replace systematic reviews, or to generate data for a meta-analysis, but as a tool to inform rapid research prioritization when there are no systematic reviews or robust RCTs available, such as for many of the WHO priority pathogens . As well as expanding to other diseases areas, it is also important that the gaps that a RRNA identifies for a particular disease are re-visited periodically and in the context of the outbreak. For instance, for Lassa fever, this might include the need for additional research on circulating strains, rate of infectivity, risk groups, risk of transmission from body fluids, re-infection, and health outcomes. These results show that the RRNA can fill in gaps not identified by the expert panel, and the expert panel can help refine the research priorities further. The RRNA methodology can be used in response to any (re-) emerging outbreak globally, when there is no recent systematic review available and applied for the scenario of a “disease X”  epidemic.
Blood urea nitrogen
The Centers for Disease Control and Prevention
Case fatality rate
The European Centre for Disease Prevention and Control
Enzyme-linked immunosorbent assay
The WHO International Clinical Trials Registry Platform
Lateral flow immunoassay
Polymerase chain reaction
Randomized controlled trials
Rapid research needs appraisal
Systematic review team
The United Kingdom
The World Health Organization
Lant T, Lurie N. Science preparedness and science response: perspectives on the dynamics of preparedness conference. J Public Health Manag Pract. 2013;19(Suppl 2):S3–5.
Rishu AH, Marinoff N, Julien L, Dumitrascu M, Marten N, Eggertson S, et al. Time required to initiate outbreak and pandemic observational research. J Crit Care. 2017;40:7–10.
Rojek AM, Castle L, Dunning J, Horby PW, Leliogdowicz A, Carson G, et al. Regulatory and operational complexities of conducting a clinical treatment trial during an Ebola virus disease epidemic. Clin Infect Dis. 2017;66(9):1454–7.
Chalmers I, Bracken MB, Djulbegovic B, Garattini S, Grant J, Gulmezoglu AM, et al. How to increase value and reduce waste when research priorities are set. Lancet. 2014;383(9912):156–65.
Ganann R, Ciliska D, Thomas H. Expediting systematic reviews: methods and implications of rapid reviews. Implement Sci. 2010;5:56.
Khangura S, Konnyu K, Cushman R, Grimshaw J, Moher D. Evidence summaries: the evolution of a rapid review approach. Syst Rev. 2012;1:10.
Garritty CM, Norris SL, Moher D. Developing WHO rapid advice guidelines in the setting of a public health emergency. J Clin Epidemiol. 2017;82:47–60.
Tricco AC, Antony J, Zarin W, Strifler L, Ghassemi M, Ivory J, et al. A scoping review of rapid review methods. BMC Med. 2015;13:224.
Pham MT, Rajić A, Greig JD, Sargeant JM, Papadopoulos A, McEwen SA. A scoping review of scoping reviews: advancing the approach and enhancing the consistency. Res Synth Methods. 2014;5(4):371–85.
Polisena J, Garritty C, Kamel C, Stevens A, Abou-Setta AM. Rapid review programs to support health care and policy decision making: a descriptive analysis of processes and methods. Syst Rev. 2015;4:26.
Tricco A, Langlois E, Straus S. Rapid reviews to strengthen health policy and systems: a practical guide. Geneva: WHO; 2017.
World Health Organisation. Lassa Fever R&D: WHO; 2019. Available from: https://www.who.int/blueprint/priority-diseases/key-action/lassa-fever/en/. [cited 2019 Feb.]
Centres for Disease Control and Prevention. Lassa Fever US: US CDC; 2019. Available from: https://www.cdc.gov/vhf/lassa/index.html. [cited 2019 Feb.]
World Health Organisation. List of Blueprint priority diseases: WHO; 2018. Available from: http://www.who.int/blueprint/priority-diseases/en/. [cited 2019 Feb.]
Nigeria Centre for Disease Control. 2018Lassa fever outbreak in Nigeria Nigeria: Nigeria CDC; 2018. Available from: file:///C:/Users/user/Downloads/An%20update%20of%20Lassa%20fever%20outbreak%20in%20Nigeria_100618_24.pdf. [updated 10 June 2018; cited 2018 11 June.]
Sigfrid L, Moore C, Garritty C, Maayan N, Lutje V, Marshall R, et al. Rapid research needs appraisal methodology UK: Open Science Framework; 2017. Available from: osf.io/8qn6v. [cited 2018 11 June]
The Global Health Network. CREDO - rapid ‘Evidence needs’ Appraisal 2018. Available from: (https://globalhealthtrainingcentre.tghn.org/credo-rapid-evidence-needs-appraisal/). [cited 2018 11 June]
Ibekwe TS, Okokhere PO, Asogun D, Blackie FF, Nwegbu MM, Wahab KW, et al. Early-onset sensorineural hearing loss in Lassa fever. Eur Arch Otorhinolaryngol. 2011;268(2):197–201.
Asogun DA, Adomeh DI, Ehimuan J, Odia I, Hass M, Gabriel M, et al. Molecular diagnostics for Lassa fever at Irrua specialist teaching hospital, Nigeria: lessons learnt from two years of laboratory operation. PLoS Negl Trop Dis. 2012;6(9):e1839.
Cummins D, McCormick JB, Bennett D, Samba JA, Farrar B, Machin SJ, et al. Acute sensorineural deafness in Lassa fever. JAMA. 1990;264(16):2093–6.
Ehichioya DU, Asogun DA, Ehimuan J, Okokhere PO, Pahlmann M, Olschlager S, et al. Hospital-based surveillance for Lassa fever in Edo State, Nigeria, 2005-2008. Tropical Med Int Health. 2012;17(8):1001–4.
Fisher-Hoch SP, Tomori O, Nasidi A, Perez-Oronoz GI, Fakile Y, Hutwagner L, et al. Review of cases of nosocomial Lassa fever in Nigeria: the high price of poor medical practice. BMJ. 1995;311(7009):857–9.
Frame JD. Clinical features of Lassa fever in Liberia. Rev Infect Dis. 1989;11(Suppl 4):S783–9.
Inegbenebor U, Okosun J, Inegbenebor J. Prevention of Lassa fever in Nigeria. Trans R Soc Trop Med Hyg. 2010;104(1):51–4.
McCormick JB, King IJ, Webb PA, Johnson KM, O’Sullivan R, Smith ES, et al. A case-control study of the clinical diagnosis and course of Lassa fever. J Infect Dis. 1987;155(3):445–55.
Okokhere P, Ugheoke J, Erameh C. Pulmonary manifestation of Lassa fever and the impact on mortality. Eur Respir J Conf. 2012;40(no pagination).
Roth PJ, Grant DS, Ngegbai AS, Schieffelin J, McClelland RS, Jarrett OD. Factors associated with mortality in febrile patients in a government referral hospital in the Kenema district of Sierra Leone. Am J Trop Med Hyg. 2015;92(1):172–7.
Bausch DG, Demby AH, Coulibaly M, Kanu J, Goba A, Bah A, et al. Lassa fever in Guinea: I. Epidemiology of human disease and clinical observations. Vector Borne Zoonotic Dis. 2001;1(4):269–81.
Fraser DW, Campbell CC, Monath TP, Goff PA, Gregg MB. Lassa fever in the Eastern Province of Sierra Leone, 1970-1972. I. Epidemiologic studies. Am J Trop Med Hyg. 1974;23(6):1131–9.
McCormick JB, Walker DH, King IJ, Webb PA, Elliott LH, Whitfield SG, et al. Lassa virus hepatitis: a study of fatal Lassa fever in humans. Am J Trop Med Hyg. 1986;35(2):401–7.
Webb PA, McCormick JB, King IJ, Bosman I, Johnson KM, Elliott LH, et al. Lassa fever in children in Sierra Leone, West Africa. Trans R Soc Trop Med Hyg. 1986;80(4):577–82.
Safronetz D, Sogoba N, Diawara SI, Bane S, Rosenke K, Maiga O, et al. Annual incidence of Lassa virus infection in southern Mali. Am J Trop Med Hyg. 2017;96(4):944–6.
Akpede G, Odike A, Okokhere P, Olomu SC, Asogun D, Happi C, et al. Prevalence and presentation of Lassa fever in Nigerian children. Int J Infect Dis. 2010;14:e380.
Asogun D, Okokhere P, Tobin E, Okogbenin SA, Akpede G, Happi C, et al. Lassa fever practice challenges in Nigeria. Int J Infect Dis. 2012;16:e69.
Getso KI, Balogun MS, Gidado SO, Oladejo J, Nasidi A, Nguku PM, et al. Lassa fever outbreak involving health care workers in Taraba state, Nigeria; March 2012. Am J Trop Med Hyg. 2013;1:132–3.
Okokhere PO, Bankole IA, Akpede GO. Central nervous system manifestations of Lassa fever in Nigeria and the effect on mortality. J Neurol Sci. 2013;333:e604.
Johnson KM, McCormick JB, Webb PA, Smith ES, Elliott LH, King IJ. Clinical virology of Lassa fever in hospitalized patients. J Infect Dis. 1987;155(3):456–64.
Price ME, Fisher-Hoch SP, Craven RB, McCormick JB. A prospective study of maternal and fetal outcome in acute Lassa fever infection during pregnancy. BMJ. 1988;297(6648):584–7.
Akhuemokhan OC, Ewah-Odiase RO, Akpede N, Ehimuan J, Adomeh DI, Odia I, et al. Prevalence of Lassa virus disease (LVD) in Nigerian children with fever or fever and convulsions in an endemic area. PLoS Negl Trop Dis. 2017;11(7):e0005711.
Brown BL, Boisen ML, Moses LM, Schieffelin JS, Goba A, Momoh M, et al. Suspected Lassa fever (LF) case outcomes: a comparison to a non-febrile population in Sierra Leone. Clin Chem. 2014;1:S38.
Akhuemokhan OC, Ehiemua J, Adomeh DI, Odia I, Olomu SC, Becker-Ziaja B, et al. Lassa fever and convulsions associated with fever: a case-control study. Arch Dis Child. 2017;102:A122.
Ajayi NA, Nwigwe CG, Azuogu BN, Onyire BN, Nwonwu EU, Ogbonnaya LU, et al. Containing a Lassa fever epidemic in a resource-limited setting: outbreak description and lessons learned from Abakaliki, Nigeria (January-March 2012). Int J Infect Dis. 2013;17(11):e1011–6.
Keane E, Gilles HM. Lassa fever in Panguma Hospital, Sierra Leone, 1973-6. Br Med J. 1977;1(6073):1399–402.
Kerneis S, Koivogui L, Magassouba N, Koulemou K, Lewis R, Aplogan A, et al. Prevalence and risk factors of Lassa seropositivity in inhabitants of the forest region of Guinea: a cross-sectional study. PLoS Negl Trop Dis. 2009;3(11):e548.
Li WG, Chen WW, Li L, Ji D, Ji YJ, Li C, et al. The etiology of Ebola virus disease-like illnesses in Ebola virusnegative patients from Sierra Leone. Oncotarget. 2016;7(19):27910–5.
Monson MH, Frame JD, Jahrling PB, Alexander K. Endemic Lassa fever in Liberia. I. Clinical and epidemiological aspects at Curran Lutheran Hospital, Zorzor, Liberia. Trans R Soc Trop Med Hyg. 1984;78(4):549–53.
Sogoba N, Rosenke K, Adjemian J, Diawara SI, Maiga O, Keita M, et al. Lassa virus seroprevalence in Sibirilia commune, Bougouni District, southern Mali. Emerg Infect Dis. 2016;22(4):657–63.
Winn WC Jr, Walker DH. The pathology of human Lassa fever. Bull World Health Organ. 1975;52(4–6):535–45.
Bello OO, Akinajo OR, Odubamowo KH, Oluwasola TA. Lassa fever in pregnancy: report of 2 cases seen at the University College Hospital, Ibadan. Case Rep Obstet Gynecol. 2016;2016:9673683.
Ogunniyi AO, Nguku P, Gbadegesin O, Adedire EO. Lassa fever outbreak investigation in a Nigerian bakery - August, 2012. Int J Infect Dis. 2014;21:400.
Okokhere PO, Bankole IA, Iruolagbe CO, Muoebonam BE, Okonofua MO, Dawodu SO, et al. Aseptic meningitis caused by Lassa virus: case series report. Case Rep Neurol Med. 2016;2016:1978461.
Dongo AE, Kesieme EB, Iyamu CE, Okokhere PO, Akhuemokhan OC, Akpede GO. Lassa fever presenting as acute abdomen: a case series. Virol J. 2013;10:123.
Dzotsi EK, Ohene SA, Asiedu-Bekoe F, Amankwa J, Sarkodie B, Adjabeng M, et al. The first cases of Lassa fever in Ghana. Ghana Med J. 2012;46(3):166–70.
Akpede GO, Kayode-Adedeji BO, Dawodu SO. Manifestations and outcomes of Lassa fever in Nigerian children: a case series. Arch Dis Child. 2012;97:A38–A9.
Branco LM, Boisen ML, Andersen KG, Grove JN, Moses LM, Muncy IJ, et al. Lassa hemorrhagic fever in a late term pregnancy from northern Sierra Leone with a positive maternal outcome: case report. Virol J. 2011;8:404.
Okogbenin SA, Asogun D, Akpede G, Okokhere P, Gunther S, Happi C. New lessons from a case series review of Lassa fever in pregnancy. Int J Infect Dis. 2010;14:e380.
Monson MH, Cole AK, Frame JD, Serwint JR, Alexander S, Jahrling PB. Pediatric Lassa fever: a review of 33 Liberian cases. Am J Trop Med Hyg. 1987;36(2):408–15.
Bowen GS, Tomori O, Wulff H, Casals J, Noonan A, Downs WG. Lassa fever in Onitsha, East Central State, Nigeria in 1974. Bull World Health Organ. 1975;52(4–6):599–604.
Edington GM, White HA. The pathology of Lassa fever. Trans R Soc Trop Med Hyg. 1972;66(3):381–9.
White HA. Lassa fever. A study of 23 hospital cases. Trans R Soc Trop Med Hyg. 1972;66(3):390–401.
Mertens PE, Patton R, Baum JJ, Monath TP. Clinical presentation of Lassa fever cases during the hospital epidemic at Zorzor, Liberia, March-April 1972. Am J Trop Med Hyg. 1973;22(6):780–4.
Troup JM, White HA, Fom AL, Carey DE. An outbreak of Lassa fever on the Jos Plateau, Nigeria, in January-February 1970. A preliminary report. Am J Trop Med Hyg. 1970;19(4):695–6.
Frame JD. Lassa fever, a new virus disease of man from west africa. I Clinical description and pathological findings. AmerJTropMedHyg. 1970;19(4):339–50.
Monath TP, Maher M, Casals J, Kissling RE, Cacciapuoti A. Lassa fever in the Eastern Province of Sierra Leone, 1970-1972. II. Clinical observations and virological studies on selected hospital cases. Am J Trop Med Hyg. 1974;23(6):1140–9.
Carey DE, Kemp GE, White HA, Pinneo L, Addy RF, Fom AL, et al. Lassa fever. Epidemiological aspects of the 1970 epidemic, Jos, Nigeria. Trans R Soc Trop Med Hyg. 1972;66(3):402–8.
Kyei NN, Abilba MM, Kwawu FK, Agbenohevi PG, Bonney JH, Agbemaple TK, et al. Imported Lassa fever: a report of 2 cases in Ghana. BMC Infect Dis. 2015;15:217.
Oppenheimer L. A case of Lassa fever. Br Med J (Clin Res Ed). 1982;285(6354):1576–7.
Sharp PC. Lassa fever in children. J Inf Secur. 1982;4(1):73–7.
Macher AM, Wolfe MS. Historical Lassa fever reports and 30-year clinical update. Emerg Infect Dis. 2006;12(5):835–7.
Grahn A, Brave A, Lagging M, Dotevall L, Ekqvist D, Hammarstrom H, et al. Imported case of Lassa fever in Sweden with encephalopathy and sensorineural hearing deficit. Open Forum Infect Dis. 2016;3(4):ofw198.
Edo AE, Okaka E, Ezeani IU. Hyperglycemic crisis precipitated by Lassa fever in a patient with previously undiagnosed type 2 diabetes mellitus. Niger J Clin Pract. 2014;17(5):658–61.
Ajayi NA, Ukwaja KN, Ifebunandu NA, Nnabu R, Onwe FI, Asogun DA. Lassa fever - full recovery without ribavarin treatment: a case report. Afr Health Sci. 2014;14(4):1074–7.
Lotz E, Raffin H. Aeromedical evacuation using an aircraft transit isolator of a patient with Lassa fever. Aviat Space Environ Med. 2012;83(5):527–30.
Grove JN, Branco LM, Boisen ML, Muncy IJ, Henderson LA, Schieffellin JS, et al. Capacity building permitting comprehensive monitoring of a severe case of Lassa hemorrhagic fever in Sierra Leone with a positive outcome: case report. Virol J. 2011;8:314.
Amorosa V, MacNeil A, McConnell R, Patel A, Dillon KE, Hamilton K, et al. Imported Lassa fever, Pennsylvania, USA, 2010. Emerg Infect Dis. 2010;16(10):1598–600.
Okokhere PO, Ibekwe TS, Akpede GO. Sensorineural hearing loss in Lassa fever: two case reports. J Med Case Rep. 2009;3:36.
Kitching A, Addiman S, Cathcart S, Bischop L, Krahe D, Nicholas M, et al. A fatal case of Lassa fever in London, January 2009. Euro Surveill. 2009;14(6).
Lamb D. Evaluation of infection control practices during an AE. Br J Nurs. 2006;15(10):543–7.
Anonymous. Imported Lassa fever--New Jersey, 2004. Mmwr. 2004;Morb Mortal Wkly Rep 53(38):894–897.
Schmitz H, Kohler B, Laue T, Drosten C, Veldkamp PJ, Gunther S, et al. Monitoring of clinical and laboratory data in two cases of imported Lassa fever. Microbes Infect. 2002;4(1):43–50.
Swaan CM, van den Broek PJ, Kampert E, Berbee GA, Schippers EF, Beersma MF, et al. Management of a patient with Lassa fever to prevent transmission. J Hosp Infect. 2003;55(3):234–5.
Gunther S, Weisner B, Roth A, Grewing T, Asper M, Drosten C, et al. Lassa fever encephalopathy: Lassa virus in cerebrospinal fluid but not in serum. J Infect Dis. 2001;184(3):345–9.
ter Meulen J, Lenz O, Koivogui L, Magassouba N, Kaushik SK, Lewis R, et al. Short communication: Lassa fever in Sierra Leone: UN peacekeepers are at risk. Tropical Med Int Health. 2001;6(1):83–4.
Anonymous. Lassa fever, case imported to Germany. Wkly Epidemiol Rec 2000;75(3):17–18.
Holmes GP, McCormick JB, Trock SC, Chase RA, Lewis SM, Mason CA, et al. Lassa fever in the United States. Investigation of a case and new guidelines for management. N Engl J Med. 1990;323(16):1120–3.
Lloyd G, Barber GN, Clegg JC, Kelly P. Identification of Lassa fever virus infection with recombinant nucleocapsid protein antigen. Lancet. 1989;2(8673):1222.
The Public Health Laboratory Service Communicable Disease Centre. Lassa fever 1982. Br Med J (Clin Res Ed) 1983;287(6384):48.
Emond RT, Weir WR, Bowen ET, Lloyd G, Southee T. Managing Lassa fever. Lancet. 1984;2(8408):926.
Fisher-Hoch SP, Price ME, Craven RB, Price FM, Forthall DN, Sasso DR, et al. Safe intensive-care management of a severe case of Lassa fever with simple barrier nursing techniques. Lancet. 1985;2(8466):1227–9.
Hirabayashi Y, Oka S, Goto H, Shimada K, Kurata T, Fisher-Hoch SP, et al. An imported case of Lassa fever with late appearance of polyserositis. J Infect Dis. 1988;158(4):872–5.
Cooper CB, Gransden WR, Webster M, King M, O'Mahony M, Young S, et al. A case of Lassa fever: experience at St Thomas’s Hospital. Br Med J (Clin Res Ed). 1982;285(6347):1003–5.
Emond RT, Bannister B, Lloyd G, Southee TJ, Bowen ET. A case of Lassa fever: clinical and virological findings. Br Med J (Clin Res Ed). 1982;285(6347):1001–2.
Walker DH, McCormick JB, Johnson KM, Webb PA, Komba-Kono G, Elliott LH, et al. Pathologic and virologic study of fatal Lassa fever in man. Am J Pathol. 1982;107(3):349–56.
Woodruff AW, Monath TP, Mahmoud AA, Pain AK, Morris CA. Lassa fever in Britain: an imported case. Br Med J. 1973;3(5881):616–7.
Grundy DJ, Bowen ET, Lloyd G. Isolated case of Lassa fever in Zaria, Northern Nigeria. Lancet. 1980;2(8195 pt 1):649–50.
Leifer E, Gocke DJ, Bourne H. Lassa fever, a new virus disease of man from West Africa. II. Report of a laboratory-acquired infection treated with plasma from a person recently recovered from the disease. Am J Trop Med Hyg. 1970;19(4):677–9.
Atkin S, Anaraki S, Gothard P, Walsh A, Brown D, Gopal R, et al. The first case of Lassa fever imported from Mali to the United Kingdom, February 2009. Euro Surveill. 2009;14(10).
Crowcroft NS, Meltzer M, Evans M, Shetty N, Maguire H, Bahl M, et al. The public health response to a case of Lassa fever in London in 2000. J Inf Secur. 2004;48(3):221–8.
Haas WH, Breuer T, Pfaff G, Schmitz H, Kohler P, Asper M, et al. Imported Lassa fever in Germany: surveillance and management of contact persons. Clin Infect Dis. 2003;36(10):1254–8.
Hadi CM, Goba A, Khan SH, Bangura J, Sankoh M, Koroma S, et al. Ribavirin for Lassa fever postexposure prophylaxis. Emerg Infect Dis. 2010;16(12):2009–11.
Iroezindu MO, Unigwe US, Okwara CC, Ozoh GA, Ndu AC, Ohanu ME, et al. Lessons learnt from the management of a case of Lassa fever and follow-up of nosocomial primary contacts in Nigeria during Ebola virus disease outbreak in West Africa. Tropical Med Int Health. 2015;20(11):1424–30.
Isa SE, Okwute A, Iraoyah KO, Nathan SY, Simji GS, Okolo MO, et al. Postexposure prophylaxis for Lassa fever: experience from a recent outbreak in Nigeria. Niger Med J. 2016;57(4):246–50.
Zweighaft RM, Fraser DW, Hattwick MA, Winkler WG, Jordan WC, Alter M, et al. Lassa fever: response to an imported case. N Engl J Med. 1977;297(15):803–7.
Monath TP, Mertens PE, Patton R, Moser CR, Baum JJ, Pinneo L, et al. A hospital epidemic of Lassa fever in Zorzor, Liberia, March-April 1972. Am J Trop Med Hyg. 1973;22(6):773–9.
Gilles HM, Kent JC. Lassa fever: retrospective diagnosis of two patients seen in Great Britain in 1971. Br Med J. 1976;2(6045):1173.
Balasegaram M, Dejene S, Tinnemann P, Perkins S, Davidson R. Examples of tropical disease control in the humanitarian medical programmes of MSF and Merlin. Trans R Soc Trop Med Hyg. 2006;100(4):327–34.
Branco LM, Grove JN, Boisen ML, Shaffer JG, Goba A, Fullah M, et al. Emerging trends in Lassa fever: redefining the role of immunoglobulin M and inflammation in diagnosing acute infection. Virol J. 2011;8:478.
Ter Meulen J, Koulemou K, Wittekindt T, Windisch K, Strigl S, Conde S, et al. Detection of Lassa virus antinucleoprotein immunoglobulin G (IgG) and IgM antibodies by a simple recombinant immunoblot assay for field use. J Clin Microbiol. 1998;36(11):3143–8.
Trappier SG, Conaty AL, Farrar BB, Auperin DD, McCormick JB, Fisher-Hoch SP. Evaluation of the polymerase chain reaction for diagnosis of Lassa virus infection. Am J Trop Med Hyg. 1993;49(2):214–21.
Ibekwe TS, Nwegbu MM, Asogun D, Adomeh DI, Okokhere PO. The sensitivity and specificity of Lassa virus IgM by ELISA as screening tool at early phase of Lassa fever infection. Niger Med J. 2012;53(4):196–9.
Demby AH, Chamberlain J, Brown DW, Clegg CS. Early diagnosis of Lassa fever by reverse transcription-PCR. J Clin Microbiol. 1994;32(12):2898–903.
Panning M, Emmerich P, Olschlager S, Bojenko S, Koivogui L, Marx A, et al. Laboratory diagnosis of Lassa fever, Liberia. Emerg Infect Dis. 2010;16(6):1041–3.
Kimura M, Sakamoto M, Adachi T, Sagara H. Diagnosis of febrile illnesses in returned travelers using the PC software GIDEON. Travel Med Infect Dis. 2005;3(3):157–60.
Mahanty S, Bausch DG, Thomas RL, Goba A, Bah A, Peters CJ, et al. Low levels of interleukin-8 and interferon-inducible protein-10 in serum are associated with fatal infections in acute Lassa fever. J Infect Dis. 2001;183(12):1713–21.
Bond N, Schieffelin JS, Moses LM, Bennett AJ, Bausch DG. A historical look at the first reported cases of Lassa fever: IgG antibodies 40 years after acute infection. Am J Trop Med Hyg. 2013;88(2):241–4.
Jahrling PB, Niklasson BS, McCormick JB. Early diagnosis of human Lassa fever by ELISA detection of antigen and antibody. Lancet. 1985;1(8423):250–2.
Wulff H, Johnson KM. Immunoglobulin M and G responses measured by immunofluorescence in patients with Lassa or Marburg virus infections. Bull World Health Organ. 1979;57(4):631–5.
Fabiyi A, Tomori O. Use of the complement fixation (CF) test in Lassa fever surveillance. Evidence for persistent CF antibodies. Bull World Health Organ. 1975;52(4–6):605–8.
McCormick JB, King IJ, Webb PA, Scribner CL, Craven RB, Johnson KM, et al. Lassa fever. Effective therapy with ribavirin. N Engl J Med. 1986;314(1):20–6.
Frame JD, Verbrugge GP, Gill RG, Pinneo L. The use of Lassa fever convalescent plasma in Nigeria. Trans R Soc Trop Med Hyg. 1984;78(3):319–24.
U.S. Army Medical Research and Materiel Command. Treatment of Viral Hemorrhagic Fevers With Intravenous Ribavirin in Military Treatment Facilities US: ClinicalTrials.gov; 2009. Available from: https://clinicaltrials.gov/ct2/show/NCT00992693?cond=Lassa+Fever&rank=1. [cited 2017 July]
U.S. Army Medical Research and Materiel Command. Intravenous Ribavirin Protocol to Treat Individuals With Viral Hemorrhagic Fever US: ClinicalTrials.gov; 2015. Available from: https://clinicaltrials.gov/ct2/show/NCT02483260?cond=Lassa+Fever. [cited 2017 July]
Dahmane A, van Griensven J, Van Herp M, Van den Bergh R, Nzomukunda Y, Prior J, et al. Constraints in the diagnosis and treatment of Lassa fever and the effect on mortality in hospitalized children and women with obstetric conditions in a rural district hospital in Sierra Leone. Trans R Soc Trop Med Hyg. 2014;108(3):126–32.
Fisher-Hoch SP, Gborie S, Parker L, Huggins J. Unexpected adverse reactions during a clinical trial in rural West Africa. Antivir Res. 1992;19(2):139–47.
Clayton AJ. Lassa immune serum. Bull World Health Organ. 1977;55(4):435–9.
Cummins D, Fisher-Hoch SP, Walshe KJ, Mackie IJ, McCormick JB, Bennett D, et al. A plasma inhibitor of platelet aggregation in patients with Lassa fever. Br J Haematol. 1989;72(4):543–8.
Getso KI, Balogun MS, Nasidi A, Gidado S, Nguku P, Oladejo J, et al. Lassa fever outbreak involving healthcare workers in Taraba State, Nigeria, March 2012. Int J Infect Dis. 2014;21:216.
Bausch DG, Rollin PE, Demby AH, Coulibaly M, Kanu J, Conteh AS, et al. Diagnosis and clinical virology of Lassa fever as evaluated by enzyme-linked immunosorbent assay, indirect fluorescent-antibody test, and virus isolation. J Clin Microbiol. 2000;38(7):2670–7.
Bonney JHK, Nyarko EO, Ohene SA, Amankwa J, Ametepi RK, Nimo-Paintsil SC, et al. Molecular confirmation of Lassa fever imported into Ghana. Afr J Lab Med. 2016;5(1):288.
Ehichioya D, Asogun D, Hass M, Becker-Ziaja B, Gunther S, Omilabu S. A retrospective laboratory analysis of clinically diagnosed Lassa fever cases in a tertiary hospital in Nigeria. Int J Infect Dis. 2010;14:e209–e10.
Emmerich P, Gunther S, Schmitz H. Strain-specific antibody response to Lassa virus in the local population of West Africa. J Clin Virol. 2008;42(1):40–4.
Emmerich P, Thome-Bolduan C, Drosten C, Gunther S, Ban E, Sawinsky I, et al. Reverse ELISA for IgG and IgM antibodies to detect Lassa virus infections in Africa. J Clin Virol. 2006;37(4):277–81.
Olschlager S, Lelke M, Emmerich P, Panning M, Drosten C, Hass M, et al. Improved detection of Lassa virus by reverse transcription-PCR targeting the 5′ region of S RNA. J Clin Microbiol. 2010;48(6):2009–13.
Shaffer JG, Grant DS, Schieffelin JS, Boisen ML, Goba A, Hartnett JN, et al. Lassa fever in post-conflict sierra leone. PLoS Negl Trop Dis. 2014;8(3):e2748.
Tobin EA, Asogun D, Happi C, Ogbaini E, Gunther S. Risk factors for Lassa fever in endemic communities of Edo state, Nigeria. Int J Infect Dis. 2014;21:258–9.
We are very grateful to the Lassa fever expert panel for the identification of seminal articles and research priorities. Panel members: Professor Dan Bausch, Director of the UK Public Health Rapid Support Team, Lina Moses, Clinical Assistant Professor, and John Schieffelin, Assistant Professor of Medicine & Pediatrics at Tulane University School of Medicine, New Orleans, US. The UK Public Health Rapid Support Team, a partnership between Public Health England (PHE) and the London School of Hygiene & Tropical Medicine (LSHTM). University of Oxford and King’s College London are academic partners.
This work was supported by Cochrane, London, UK, and the UK Public Health Rapid Support Team. The UK Public Health Rapid Support Team, funded by UK aid from the Department of Health and Social Care, is a partnership between Public Health England (PHE) and the London School of Hygiene & Tropical Medicine (LSHTM). The views expressed are those of the authors and not necessarily those of the NIHR or DHSC.
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Sigfrid, L., Moore, C., Salam, A.P. et al. 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. BMC Med 17, 107 (2019). https://doi.org/10.1186/s12916-019-1338-1
- Emerging infectious diseases
- Clinical research priorities
- Outbreak response
- Lassa fever
- Rapid research needs appraisal methodology