key: cord-0944430-yuky7hml authors: Gardner, Emma G.; Kelton, David; Poljak, Zvonimir; von Dobschuetz, Sophie; Greer, Amy L. title: A rapid scoping review of Middle East respiratory syndrome coronavirus in animal hosts date: 2018-11-12 journal: Zoonoses Public Health DOI: 10.1111/zph.12537 sha: 82c21763f8d4e442f2a164a78ba7297cc0b60ae9 doc_id: 944430 cord_uid: yuky7hml Middle East respiratory syndrome coronavirus (MERS‐CoV) is an emerging zoonotic pathogen discovered in 2012. The purpose of this scoping review was to summarize the empirical evidence for MERS‐CoV in animals in order to map knowledge gaps and to extract data for modelling disease transmission in dromedary camels. A review protocol was developed a priori, and a systematic search, data extraction and summary were conducted using the Arksey and O'Malley framework. Ninety‐nine publications were identified for full review out of 1,368 unique records. Of these publications, 71 were articles in scientific journals. Ninety of the studies were observational and the remaining nine were experimental. We summarize characteristics of animal studies including study design, study population and outcomes of interest for future transmission modelling in the reservoir population. The majority of field studies reported measures of prevalence, while experimental studies provided estimates of transmission parameters that pertain to the natural course of disease. camels in particular, Haagmans et al., 2014) in MERS-CoV transmission rapidly led to a number of experimental and field studies that aimed to improve our understanding of the epidemiology of this virus in animal hosts (Adney et al., 2014; Alagaili et al., 2014; Hemida et al., 2013; Meyer et al., 2015; Reusken et al., 2013) . These studies have led to the consensus that dromedary camels are the natural reservoir. They have furthermore provided some insight about the host and geographical range of the virus and have suggested some epidemiological characteristics, including the clinical picture and age distribution in dromedary camels (Wernery, Lau, & Woo, 2017) . The evidence base that builds from these experimental and field studies provides the foundation for more complex epidemiological analyses, including statistical and mathematical modelling, risk assessments and meta-analyses. Rigorous, detailed epidemiological data based on pragmatic research questions are crucial to these analyses and ultimately for sound policy and health interventions. In the 6 years since the discovery of MERS-CoV, several reviews have been published that have described key advances in understanding the virus in animal populations, and identified research gaps, such as the zoonotic modes of transmission (Arabi et al., 2017; Mackay & Arden, 2015; Mohd, et al., 2016) . However, no formal mapping of the literature has yet been attempted. Scoping reviews provide the means to summarize and communicate findings, evaluate the existing body of literature and identify research gaps in a way that is replicable and minimizes bias (Levac, Colquhoun, & O'Brien, 2010) . High-impact emerging diseases, upon which there is typically a high degree of research activity in a short amount of time, could benefit from early and iterative synthesis research. Formal scoping reviews and/or systematic reviews can provide improved clarity for targeting research needs and therefore improve the effective and efficient use of limited resources. A scoping review of the MERS-CoV animal literature will generate a detailed map of epidemiological and experimental knowledge, assess the suitability of the evidence for systematic review and chart outcomes for informing disease transmission models. The purpose of this scoping review was to summarize the empir- The review team consisted of one person (EG) developing the research questions, search strategy, screening criteria, data characterization forms, screening and extraction, and synthesis in consultation with AG, DK, ZP and SvD. charting the data; collating, summarizing and reporting the results. In order to more accurately identify knowledge gaps (Pham et al., 2014) , methodological questions were included in the data extraction forms. The consultation exercise recommended as an optional sixth phase in the Arksey and O'Malley framework was not conducted. While at least two reviewers are recommended to reduce reporting bias, only one reviewer (EG) conducted the citation screening and data extraction (Peters, Godfrey, McInerney, Baldini Soares, & Khalil, 2017) . A review protocol was developed a priori according to the research question "What are the general, epidemiological and methodological characteristics of MERS-CoV in animal host populations?" Searches were restricted to 2012 or later, and to publications in English or French. Publications were included if they described primary research that measured animal-level outcomes of MERS-CoV in non-human hosts, including laboratory animal models of nonhuman hosts. The initial search was conducted on 26 April 2017 using five electronic databases: PubMed via NCBI, Web of Science, Agricola via Proquest, CAB direct and Medline via Ovid. The search was limited to 2012 or later, given that MERS-CoV was previously unrecognized (Zaki et al., 2012) . Search terms and strategies were tailored to the requirements and structure of each database, and consisted of "MERS-CoV" OR "Middle East respiratory syndrome coronavirus." The search was conducted again on 24 August 2017. At this time, bibliographies of review articles were searched for any articles missed by the initial electronic search (Arabi et al., 2017; Hemida et al., 2015; Mackay & Arden, 2015; Mohd, Al-Tawfiq, & Memish, 2016) . Conference proceedings, and government and university websites in the Middle East were hand searched for citations on 11 September 2017. Two citations were added from searching conference proceedings. Although government and university websites in the Middle East were searched for reports and academic theses, no records were found. This could be due to language differences, as many of the websites were in Arabic and the search was conducted using on- Search results were downloaded to Mendeley for removal of duplicates and initial and full-text screening, and Excel was used for data extraction and summarization. One reviewer (EG) completed these steps. The full scoping review protocol can be found in the Supporting information Appendix S1: Technical Appendix. A total of 1,368 unique citations were screened for relevance. Title and abstract screening removed 1,254 records, while full-text screening removed an additional 15 records, leaving 99 for full-text Impacts • MERS-CoV is an emerging zoonotic disease that is maintained in dromedary camels with sporadic transmission to humans. Since it was first reported in 2012, numerous studies have been conducted to identify and better understand the virus in reservoir animal populations. • We conducted a scoping review in order to summarize the empirical evidence of MERS-CoV in animals, including knowledge gaps and data for disease transmission models. • Gaps in the evidence base of MERS-CoV in animals include epidemiological field studies that are generalizable beyond the sample population, and studies that examine questions of immunity in dromedary camels, especially long-term immunity. Tackling these two challenges would greatly advance our understanding of zoonotic risk and improve our ability to develop sound surveillance and disease prevention strategies. characterization. Figure 1 depicts the article identification and screening process following PRISMA reporting guidelines (Moher, Liberati, Tetzlaff, Altman, & Group, 2009 daries and a single flock of alpacas housed near exposed dromedaries in Saudi Arabia (Table 3 ). In general, details about the dromedary camel populations being studied were reported more frequently than those of other species (Table 4) . Age or age group of the animals was reported in 53% of the dromedary camel studies, although almost all of the publications that did not report age were OIE reports. The group size refers to whether the number of camels in the epidemiological unit being sampled was reported, such as herd size, the number of camels at a market or the number of camels grouped together awaiting slaughter (Table 4 ). Most field studies sampled animals at primary production sites such as ranches, pastoralist herds or pleasure herds. Ten studies sampled multiple sites along the livestock production chain. TA B L E 2 The number of observational studies conducted in each country, and the study duration for each observational study with the per cent of overall observational studies Characteristic Positive findings reported (antigen and/or antibody) N = 90 % Appendix S1: Technical appendix reference a Saudi Arabia Yes 25 27.78 7, 9, 11, 14, 18, 19, 22, 37, 45, 48, 71, 73 United Arab Emirates Yes 11 12.22 11, 12, 15, 30, 31, 35, 43, 46, 52, 60 2, 4-6, 8, 11, 12, 16, 23, 26, 29, 30, 32-34, 38-40, 42, 44, 45, 47, 51, 56, 58, 59, 66, 68 All experimental studies that involved livestock included in their methodology the testing of animals prior to challenge or vaccination. Two studies that used purpose-bred white mice did not report test- Many different outcomes were reported in the studies characterized here. However, this review categorized outcomes of interest for understanding pathogen transmission and public health risk, and according to epidemiological inputs that would be useful for disease transmission modelling, and is by no means an exhaustive list (Table 5 ). Outcome categories were defined a priori. Prevalence refers specifically to active infection and was defined as any proportion of virus-positive field samples over a denominator, usually the number of animals tested. Seroprevalence was similarly defined as a proportion of antibody-positive field samples over a denominator. The immunity outcome was defined as any study that described or inferred dynamics of natural or vaccine immunity from collected data. A study was counted as measuring pathogen transmission from one animal to another if this was documented or inferred from the data, for example, transmission to susceptible animals during an experimental study, or seroconversion during longitudinal studies. If studies described the duration of one or more stages of infection, such as exposure, shedding or immunity, either as measured experimentally or estimated from repeated field measures, it was listed under the "duration" outcome (Table 5) . Study outcomes were measured using several different variables. Results of antigenic testing were reported as continuous measurements and/or dichotomous outcomes based upon a prespecified cut-off for positive and negative reactions (Table 5) . Numerous studies considered both dichotomous and quantified (continuous or categorical) test results. Almost all studies collected serum or blood and/or nasal swabs, generally corresponding to antibody or antigen outcome variables. Those studies that did not report collecting these samples were sampling bats non-invasively (Table 5) . One-fifth of the studies provided access to the raw data. Countries with light shading indicate where samples were collected, but none tested positive to MERS-CoV. Countries with dark shading indicate where samples collected from animals in at least one study tested positive to MERS-CoV either by antigenic or antibody testing The aim of this scoping review was to identify and characterize the literature that explored MERS-CoV in animal hosts. Field studies have provided compelling evidence that dromedary camels act as the reservoir host for MERS-CoV. Experimental evidence has confirmed the susceptibility of dromedary camels and provided key details regarding the course of infection in camelids (Table 3) . A challenge and transmission study conducted on goats suggests they may act as dead-end hosts; however, this has not been demonstrated in the field. One experimental study provided evidence that pigs may also act as a host for MERS-CoV (Table 3) ; however, the production range of domestic pigs does not overlap with camelids and is unlikely to be a risk factor where the disease is currently endemic. Bats present a TA B L E 3 Characteristics of sample sizes by study type and animal category Appendix S1: Technical appendix reference a Median Range Observational Dromedaries 67 70 82 3 -7,803 3, 6, 9-15, 17-22, 24-27, 29, 31, 32, 35-37, 39, 41-46, 48, 51-53, 60, 61, 63, 65-70, 72, 73 Bats 1 (RNA segment isolated from faeces) 15 194 32-5,030 1, 2, 4, 5, 7, 8, 16, 23, 33, 34, 47, 56, 58, 59, 70 Ruminants 1 (One sheep was seropositive) 10 89 3-276 3, 6, 9, 10, 12, 14, 52, 65, 66, 70 Cattle N = 6 Sheep N = 9 Goats N = 5 unique challenge in determining their role in the ecology of MERS- demonstrates the potential of this species as a host, field sampling of bats has found a single fragment of MERS-CoV RNA from a faecal sample of an Egyptian tomb bat (Taphozous perforates; Table 3 ). The immunology of bats presents a unique challenge in drawing conclusions regarding their role as a MERS-CoV host (Brook & Dobson, 2015) . While all known zoonotic transmission events have occurred Appendix S1: Technical appendix reference a Age 38 52.78 6, 9, 10, 12, 14, 15, [18] [19] [20] [21] [22] 24, 26, 27, [35] [36] [37] 39, 41, 43, 44, 46, 48, [51] [52] [53] 60, 61, 63, [65] [66] [67] [68] [69] [70] 72, 73 13 35.14 1, 5, 8, 10, 14, 30, 32, 38, [51] [52] [53] 65, 71 Sex 22 30.56 10, 12, 15, 21, 22, 24, 26, 32, 39, 46, [51] [52] [53] 60, 63, 66, [67] [68] [69] [70] 72 6, 9-15, 18-22, 24-26, 29, 31, 32, 35-37, 39, 41-45, 48, 51-53, 60, 63, 65-70, 72, 73 22 59.46 1-10, 12, 14, 16, 32-34, 38, 40, 51-53, 56, 58, 59, 65, 70, 71 Group size 42 58.33 11, 13, 18, 19, 21, 22, 41-44, 46, 51-53, 61, 69, 72 11, 13, 18, 19, 21, 22, 24, 26, 29, 31, 35, 41, 43, 48, 51-53, 61, 63, 65, 67, 69, 70, 72 2, 4, 5, 7, 8, 11, [13] [14] [15] [16] [17] [18] [19] [20] [21] 23, 25, 27, [31] [32] [33] [34] [35] [36] [37] [38] 43, 44, [46] [47] [48] 52, 53, 56, 58, 59, 61, 63, 65, 67, 69, 70, 73 Seroprevalence 39 39.39 3, 6, 9, 10, [12] [13] [14] [15] [18] [19] [20] [21] 24, 26, 29, 30, 32, 36, [38] [39] [40] [41] [42] [43] [44] [45] [46] 51, 53, 63, [65] [66] [67] [68] [69] [70] [71] [72] [73] Immunity 5 , 6, 12, 13, 15, 18-22, 24, 29, 36, 42, 45, 46, 49, 50, 53-55, 57, 61-64, 66, 73, 74 Antibodies-dichotomous 31 31.31 3, 6, 9, 10, 14, 15, 20, 21, 24, 26, 28, 30, 32, 35, 36, [38] [39] [40] [41] 43, 44, 50, 51, 65, [67] [68] [69] [70] [71] [72] [73] 25, 27, 28, 36, 48, 49, [53] [54] [55] 57, 61, 62, 64, 73 Antigen-dichotomous 67 67.68 1, 2, 4, 5, 7, 8, 11, 13-17, 20-23, 27, 31-38, 40, 43, 44, 46, 47, 52, 53, 56, 58, 59, 61, 63, 65, 67, 69, 70, 73 Infectious virus-all measures 14 14.14 18, 25, 28, 35, 43, [48] [49] [50] 54, 55, 57, 61, 62, 64 Specimen Serum/blood 50 50.51 3, 6, 9, 10, [12] [13] [14] [15] [18] [19] [20] [21] [22] 24, 26, [28] [29] [30] 32, 35, 36, [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] 49, 50, 51, [53] [54] [55] 57, [61] [62] [63] [64] [65] [66] [67] [68] [69] [70] [71] [72] [73] [74] 14, [17] [18] [19] [20] [21] [22] 25, 27, 28, 31, 32, [35] [36] [37] [38] 40, 43, 44, 46, 48, 49, 52, [53] [54] [55] 57, 60, 61, [63] [64] [65] 67, 69, 70, 73 Faeces 13 13.13 1, 2, 4, 5, 7, 15, 16, 27, 28, 32, 34, 58, 59 Rectal swabs 23 23.23 7, 8, 13, 14, 18, 21-23, 27, 33, 34, 36, 47, 49, 50, 52-54, 56, 59, 63, 64, 73 11 22, 27, 28, 33, 47, 50, 53, 54, 56, 59, 70 Other 19 19.19 4, 17, 18, 22, 27, 28, 37, 43, 47, 49, 50, 52, 54, 55, 57, 59, 62, 64, 74 Raw data provided 20 20.20 3, [12] [13] [14] 18, 19, 21, 22, 28, 32, 41, 42, 46, 49, 50, [53] [54] [55] 65, 73 a Each OIE MERS-CoV animal event entered in EMPRES-i was treated as a separate record in the review, but were included under one bibliographic entry, per FAO citation protocol. populations cannot be extracted from these data. It is recommended that future research uses existing evidence on MERS-CoV in animal populations to inform sample size calculations, sampling strategies and research questions in order to improve on the strength of the evidence and address more sophisticated study objectives. Seroprevalence data can be useful for estimating transmissibility, with accuracy improved with detailed age data (Keeling & Rohani, 2008) . Age is an important factor in dromedary transmission (Mackay & Arden, 2015) and was reported in years or months in fifteen of the studies included in this review, while twenty-one studies provided age data as dichotomous or categorical variables. Meyer et al., 2016) . Although the upper respiratory tract is now understood to be the primary site of viral replication and shedding, it is important to understand the role of other potential routes of transmission for understanding risk. 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How to cite this article A rapid scoping review of Middle East respiratory syndrome coronavirus in animal hosts