Publications by authors named "Maria D Van Kerkhove"

78 Publications

One Year of Pandemic Learning Response: Benefits of Massive Online Delivery of the World Health Organization's Technical Guidance.

JMIR Public Health Surveill 2021 04 21;7(4):e28945. Epub 2021 Apr 21.

Health Emergencies Programme, World Health Organization, Geneva, Switzerland.

The World Health Organization (WHO) launched the first web-based learning course on COVID-19 on January 26, 2020, four days before the director general of the WHO declared a public health emergency of international concern. The WHO is expanding access to web-based learning for COVID-19 through its open-learning platform for health emergencies, OpenWHO. Throughout the pandemic, OpenWHO has continued to publish learning offerings based on the WHO's emerging evidence-based knowledge for managing the COVID-19 pandemic. This study presents the various findings derived from the analysis of the performance of the OpenWHO platform during the pandemic, along with the core benefits of massive web-based learning formats.
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http://dx.doi.org/10.2196/28945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8061891PMC
April 2021

Surface-aerosol stability and pathogenicity of diverse MERS-CoV strains from 2012 - 2018.

bioRxiv 2021 Feb 12. Epub 2021 Feb 12.

Middle East Respiratory Syndrome coronavirus (MERS-CoV) is a coronavirus that infects both humans and dromedary camels and is responsible for an ongoing outbreak of severe respiratory illness in humans in the Middle East. While some mutations found in camel-derived MERS-CoV strains have been characterized, the majority of natural variation found across MERS-CoV isolates remains unstudied. Here we report on the environmental stability, replication kinetics and pathogenicity of several diverse isolates of MERS-CoV as well as SARS-CoV-2 to serve as a basis of comparison with other stability studies. While most of the MERS-CoV isolates exhibited similar stability and pathogenicity in our experiments, the camel derived isolate, C/KSA/13, exhibited reduced surface stability while another camel isolate, C/BF/15, had reduced pathogenicity in a small animal model. These results suggest that while betacoronaviruses may have similar environmental stability profiles, individual variation can influence this phenotype, underscoring the importance of continual, global viral surveillance.
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http://dx.doi.org/10.1101/2021.02.11.429193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885919PMC
February 2021

Pharmacologic Treatments and Supportive Care for Middle East Respiratory Syndrome.

Emerg Infect Dis 2020 Jun 17;26(6):1102-1112. Epub 2020 Jun 17.

Available animal and cell line models have suggested that specific therapeutics might be effective in treating Middle East respiratory syndrome (MERS). We conducted a systematic review of evidence for treatment with pharmacologic and supportive therapies. We developed a protocol and searched 5 databases for studies describing treatment of MERS and deaths in MERS patients. Risk of bias (RoB) was assessed by using ROBINS-I tool. We retrieved 3,660 unique citations; 20 observational studies met eligibility, and we studied 13 therapies. Most studies were at serious or critical RoB; no studies were at low RoB. One study, at moderate RoB, showed reduced mortality rates in severe MERS patients with extracorporeal membrane oxygenation; no other studies showed a significant lifesaving benefit to any treatment. The existing literature on treatments for MERS is observational and at moderate to critical RoB. Clinical trials are needed to guide treatment decisions.
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http://dx.doi.org/10.3201/eid2606.200037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7258456PMC
June 2020

Middle East respiratory syndrome.

Lancet 2020 03 4;395(10229):1063-1077. Epub 2020 Mar 4.

Department of Infection, Division of Infection and Immunity, Centre for Clinical Microbiology, University College London, London, UK; National Institute for Health Research Biomedical Research Centre, University College London Hospitals, London, UK. Electronic address:

The Middle East respiratory syndrome coronavirus (MERS-CoV) is a lethal zoonotic pathogen that was first identified in humans in Saudi Arabia and Jordan in 2012. Intermittent sporadic cases, community clusters, and nosocomial outbreaks of MERS-CoV continue to occur. Between April 2012 and December 2019, 2499 laboratory-confirmed cases of MERS-CoV infection, including 858 deaths (34·3% mortality) were reported from 27 countries to WHO, the majority of which were reported by Saudi Arabia (2106 cases, 780 deaths). Large outbreaks of human-to-human transmission have occurred, the largest in Riyadh and Jeddah in 2014 and in South Korea in 2015. MERS-CoV remains a high-threat pathogen identified by WHO as a priority pathogen because it causes severe disease that has a high mortality rate, epidemic potential, and no medical countermeasures. This Seminar provides an update on the current knowledge and perspectives on MERS epidemiology, virology, mode of transmission, pathogenesis, diagnosis, clinical features, management, infection control, development of new therapeutics and vaccines, and highlights unanswered questions and priorities for research, improved management, and prevention.
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http://dx.doi.org/10.1016/S0140-6736(19)33221-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7155742PMC
March 2020

A database of geopositioned Middle East Respiratory Syndrome Coronavirus occurrences.

Sci Data 2019 12 13;6(1):318. Epub 2019 Dec 13.

Institute for Health Metrics and Evaluation, University of Washington, 2301 5th Ave., Suite 600, Seattle, WA, United States.

As a World Health Organization Research and Development Blueprint priority pathogen, there is a need to better understand the geographic distribution of Middle East Respiratory Syndrome Coronavirus (MERS-CoV) and its potential to infect mammals and humans. This database documents cases of MERS-CoV globally, with specific attention paid to zoonotic transmission. An initial literature search was conducted in PubMed, Web of Science, and Scopus; after screening articles according to the inclusion/exclusion criteria, a total of 208 sources were selected for extraction and geo-positioning. Each MERS-CoV occurrence was assigned one of the following classifications based upon published contextual information: index, unspecified, secondary, mammal, environmental, or imported. In total, this database is comprised of 861 unique geo-positioned MERS-CoV occurrences. The purpose of this article is to share a collated MERS-CoV database and extraction protocol that can be utilized in future mapping efforts for both MERS-CoV and other infectious diseases. More broadly, it may also provide useful data for the development of targeted MERS-CoV surveillance, which would prove invaluable in preventing future zoonotic spillover.
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http://dx.doi.org/10.1038/s41597-019-0330-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6911100PMC
December 2019

Middle East respiratory syndrome coronavirus (MERS-CoV) neutralising antibodies in a high-risk human population, Morocco, November 2017 to January 2018.

Euro Surveill 2019 Nov;24(48)

Medical Virology and BSL-3 Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco.

BackgroundMiddle East respiratory syndrome coronavirus (MERS-CoV) remains a major concern for global public health. Dromedaries are the source of human zoonotic infection. MERS-CoV is enzootic among dromedaries on the Arabian Peninsula, the Middle East and in Africa. Over 70% of infected dromedaries are found in Africa. However, all known zoonotic cases of MERS have occurred in the Arabian Peninsula with none being reported in Africa.AimWe aimed to investigate serological evidence of MERS-CoV infection in humans living in camel-herding areas in Morocco to provide insights on whether zoonotic transmission is taking place.MethodsWe carried out a cross sectional seroprevalence study from November 2017 through January 2018. We adapted a generic World Health Organization MERS-CoV questionnaire and protocol to assess demographic and risk factors of infection among a presumed high-risk population. ELISA, MERS-CoV spike pseudoparticle neutralisation tests (ppNT) and plaque neutralisation tests (PRNT) were used to assess MERS-CoV seropositivity.ResultsSerum samples were collected from camel slaughterhouse workers (n = 137), camel herders (n = 156) and individuals of the general population without occupational contact with camels but living in camel herding areas (n = 186). MERS-CoV neutralising antibodies with ≥ 90% reduction of plaque numbers were detected in two (1.5%) slaughterhouse workers, none of the camel herders and one individual from the general population (0.5%).ConclusionsThis study provides evidence of zoonotic transmission of MERS-CoV in Morocco in people who have direct or indirect exposure to dromedary camels.
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http://dx.doi.org/10.2807/1560-7917.ES.2019.24.48.1900244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6891945PMC
November 2019

A Review of Asymptomatic and Subclinical Middle East Respiratory Syndrome Coronavirus Infections.

Epidemiol Rev 2019 01;41(1):69-81

The epidemiology of Middle East respiratory syndrome coronavirus (MERS-CoV) since 2012 has been largely characterized by recurrent zoonotic spillover from dromedary camels followed by limited human-to-human transmission, predominantly in health-care settings. The full extent of infection of MERS-CoV is not clear, nor is the extent and/or role of asymptomatic infections in transmission. We conducted a review of molecular and serological investigations through PubMed and EMBASE from September 2012 to November 15, 2018, to measure subclinical or asymptomatic MERS-CoV infection within and outside of health-care settings. We performed retrospective analysis of laboratory-confirmed MERS-CoV infections reported to the World Health Organization to November 27, 2018, to summarize what is known about asymptomatic infections identified through national surveillance systems. We identified 23 studies reporting evidence of MERS-CoV infection outside of health-care settings, mainly of camel workers, with seroprevalence ranges of 0%-67% depending on the study location. We identified 20 studies in health-care settings of health-care worker (HCW) and family contacts, of which 11 documented molecular evidence of MERS-CoV infection among asymptomatic contacts. Since 2012, 298 laboratory-confirmed cases were reported as asymptomatic to the World Health Organization, 164 of whom were HCWs. The potential to transmit MERS-CoV to others has been demonstrated in viral-shedding studies of asymptomatic MERS infections. Our results highlight the possibility for onward transmission of MERS-CoV from asymptomatic individuals. Screening of HCW contacts of patients with confirmed MERS-CoV is currently recommended, but systematic screening of non-HCW contacts outside of health-care facilities should be encouraged.
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http://dx.doi.org/10.1093/epirev/mxz009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7108493PMC
January 2019

Transmissibility of MERS-CoV Infection in Closed Setting, Riyadh, Saudi Arabia, 2015.

Emerg Infect Dis 2019 10 17;25(10):1802-1809. Epub 2019 Oct 17.

To investigate a cluster of Middle East respiratory syndrome (MERS) cases in a women-only dormitory in Riyadh, Saudi Arabia, in October 2015, we collected epidemiologic information, nasopharyngeal/oropharyngeal swab samples, and blood samples from 828 residents during November 2015 and December 2015-January 2016. We found confirmed infection for 19 (8 by reverse transcription PCR and 11 by serologic testing). Infection attack rates varied (2.7%-32.3%) by dormitory building. No deaths occurred. Independent risk factors for infection were direct contact with a confirmed case-patient and sharing a room with a confirmed case-patient; a protective factor was having an air conditioner in the bedroom. For 9 women from whom a second serum sample was collected, antibodies remained detectable at titers >1:20 by pseudoparticle neutralization tests (n = 8) and 90% plaque-reduction neutralization tests (n = 2). In closed high-contact settings, MERS coronavirus was highly infectious and pathogenicity was relatively low.
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http://dx.doi.org/10.3201/eid2510.190130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759265PMC
October 2019

Worldwide Reduction in MERS Cases and Deaths since 2016.

Emerg Infect Dis 2019 09 17;25(9):1758-1760. Epub 2019 Sep 17.

Since 2012, Middle East respiratory syndrome (MERS) coronavirus has infected 2,442 persons worldwide. Case-based data analysis suggests that since 2016, as many as 1,465 cases and 293-520 deaths might have been averted. Efforts to reduce the global MERS threat are working, but countries must maintain vigilance to prevent further infections.
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http://dx.doi.org/10.3201/eid2509.190143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6711233PMC
September 2019

A systematic review of MERS-CoV seroprevalence and RNA prevalence in dromedary camels: Implications for animal vaccination.

Epidemics 2019 12 5;29:100350. Epub 2019 Jun 5.

MRC Centre for Global Infectious Disease Analysis, Department of Infectious Disease Epidemiology, School of Public Health, Imperial College London, Medical School Building, St Mary's Hospital, Norfolk Place, London, W2 1PG, United Kingdom. Electronic address:

Human infection with Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is driven by recurring dromedary-to-human spill-over events, leading decision-makers to consider dromedary vaccination. Dromedary vaccine candidates in the development pipeline are showing hopeful results, but gaps in our understanding of the epidemiology of MERS-CoV in dromedaries must be addressed to design and evaluate potential vaccination strategies. We aim to bring together existing measures of MERS-CoV infection in dromedary camels to assess the distribution of infection, highlighting knowledge gaps and implications for animal vaccination. We systematically reviewed the published literature on MEDLINE, EMBASE and Web of Science that reported seroprevalence and/or prevalence of active MERS-CoV infection in dromedary camels from both cross-sectional and longitudinal studies. 60 studies met our eligibility criteria. Qualitative syntheses determined that MERS-CoV seroprevalence increased with age up to 80-100% in adult dromedaries supporting geographically widespread endemicity of MERS-CoV in dromedaries in both the Arabian Peninsula and countries exporting dromedaries from Africa. The high prevalence of active infection measured in juveniles and at sites where dromedary populations mix should guide further investigation - particularly of dromedary movement - and inform vaccination strategy design and evaluation through mathematical modelling.
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http://dx.doi.org/10.1016/j.epidem.2019.100350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899506PMC
December 2019

Comparative Analysis of Eleven Healthcare-Associated Outbreaks of Middle East Respiratory Syndrome Coronavirus (Mers-Cov) from 2015 to 2017.

Sci Rep 2019 05 14;9(1):7385. Epub 2019 May 14.

Formerly Outbreak Investigation Task Force, Centre for Global Health, Institut Pasteur, 75015, Paris, France.

Since its emergence in 2012, 2,260 cases and 803 deaths due to Middle East respiratory syndrome coronavirus (MERS-CoV) have been reported to the World Health Organization. Most cases were due to transmission in healthcare settings, sometimes causing large outbreaks. We analyzed epidemiologic and clinical data of laboratory-confirmed MERS-CoV cases from eleven healthcare-associated outbreaks in the Kingdom of Saudi Arabia and the Republic of Korea between 2015-2017. We quantified key epidemiological differences between outbreaks. Twenty-five percent (n = 105/422) of MERS cases who acquired infection in a hospital setting were healthcare personnel. In multivariate analyses, age ≥65 (OR 4.8, 95%CI: 2.6-8.7) and the presence of underlying comorbidities (OR: 2.7, 95% CI: 1.3-5.7) were associated with increased mortality whereas working as healthcare personnel was protective (OR 0.07, 95% CI: 0.01-0.34). At the start of these outbreaks, the reproduction number ranged from 1.0 to 5.7; it dropped below 1 within 2 to 6 weeks. This study provides a comprehensive characterization of MERS HCA-outbreaks. Our results highlight heterogeneities in the epidemiological profile of healthcare-associated outbreaks. The limitations of our study stress the urgent need for standardized data collection for high-threat respiratory pathogens, such as MERS-CoV.
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http://dx.doi.org/10.1038/s41598-019-43586-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6517387PMC
May 2019

MERS-CoV infection among healthcare workers and risk factors for death: Retrospective analysis of all laboratory-confirmed cases reported to WHO from 2012 to 2 June 2018.

J Infect Public Health 2020 Mar 2;13(3):418-422. Epub 2019 May 2.

Department of Infectious Hazard Management, WHO Health Emergencies Programme, World Health Organization, Geneva, Switzerland. Electronic address:

Background: Approximately half of the reported laboratory-confirmed infections of Middle East respiratory syndrome coronavirus (MERS-CoV) have occurred in healthcare settings, and healthcare workers constitute over one third of all secondary infections. This study aimed to describe secondary cases of MERS-CoV infection among healthcare workers and to identify risk factors for death.

Methods: A retrospective analysis was conducted on epidemiological data of laboratory-confirmed MERS-CoV cases reported to the World Health Organization from September 2012 to 2 June 2018. We compared all secondary cases among healthcare workers with secondary cases among non-healthcare workers. Multivariable logistic regression identified risk factors for death.

Results: Of the 2223 laboratory-confirmed MERS-CoV cases reported to WHO, 415 were healthcare workers and 1783 were non-healthcare workers. Compared with non-healthcare workers cases, healthcare workers cases were younger (P < 0.001), more likely to be female (P < 0.001), non-nationals (P < 0.001) and asymptomatic (P < 0.001), and have fewer comorbidities (P < 0.001) and higher rates of survival (P < 0.001). Year of infection (2013-2018) and having no comorbidities were independent protective factors against death among secondary healthcare workers cases.

Conclusion: Being able to protect healthcare workers from high threat respiratory pathogens, such as MERS-CoV is important for being able to reduce secondary transmission of MERS-CoV in healthcare-associated outbreaks. By extension, reducing infection in healthcare workers improves continuity of care for all patients within healthcare facilities.
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http://dx.doi.org/10.1016/j.jiph.2019.04.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7102841PMC
March 2020

Qatar experience on One Health approach for middle-east respiratory syndrome coronavirus, 2012-2017: A viewpoint.

One Health 2019 Jun 4;7:100090. Epub 2019 Apr 4.

Ministry of Public of Health, Doha, Qatar.

The emergence of the Middle East Respiratory Syndrome Corona Virus (MERS-CoV) in the Middle East in 2012 was associated with an overwhelming uncertainty about its epidemiological and clinical characteristics. Once dromedary camels () was found to be the natural reservoir of the virus, the public health systems across the Arabian Peninsula encountered an unprecedented pressure to control its transmission. This view point describes how the One Health approach was used in Qatar to manage the MERS-CoV outbreak during the period 2012-2017. One Health focuses on the association between the human, animals and environment sectors for total health and wellbeing of these three sectors. To manage the MERS outbreak in Qatar through a One Health approach, the Qatar National Outbreak Control Taskforce (OCT) was reactivated in November 2012. The animal health sector was invited to join the OCT. Later on, technical expertise was requested from the WHO, FAO, CDC, EMC, and PHE. Subsequently, a comprehensive One Health roadmap was delivered through leadership and coordination; surveillance and investigation; epidemiological studies and increase of local diagnostic capacity. The joint OCT, once trained had easy access to allocated resources and high risk areas to provide more evidence on the potential source of the virus and to investigate all reported cases within 24-48 h. Lack of sufficient technical guidance on veterinary surveillance and poor risk perception among the vulnerable population constituted major obstacles to maintain systematic One Health performance.
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http://dx.doi.org/10.1016/j.onehlt.2019.100090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6462540PMC
June 2019

An updated roadmap for MERS-CoV research and product development: focus on diagnostics.

BMJ Glob Health 2019 1;4(Suppl 2):e001105. Epub 2019 Feb 1.

Health Emergencies Programme, WHO, Geneva, Switzerland.

Diagnostics play a central role in the early detection and control of outbreaks and can enable a more nuanced understanding of the disease kinetics and risk factors for the Middle East respiratory syndrome-coronavirus (MERS-CoV), one of the high-priority pathogens identified by the WHO. In this review we identified sources for molecular and serological diagnostic tests used in MERS-CoV detection, case management and outbreak investigations, as well as surveillance for humans and animals (camels), and summarised the performance of currently available tests, diagnostic needs, and associated challenges for diagnostic test development and implementation. A more detailed understanding of the kinetics of infection of MERS-CoV is needed in order to optimise the use of existing assays. Notably, MERS-CoV point-of-care tests are needed in order to optimise supportive care and to minimise transmission risk. However, for new test development, sourcing clinical material continues to be a major challenge to achieving assay validation. Harmonisation and standardisation of laboratory methods are essential for surveillance and for a rapid and effective international response to emerging diseases. Routine external quality assessment, along with well-characterised and up-to-date proficiency panels, would provide insight into MERS-CoV diagnostic performance worldwide. A defined set of Target Product Profiles for diagnostic technologies will be developed by WHO to address these gaps in MERS-CoV outbreak management.
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http://dx.doi.org/10.1136/bmjgh-2018-001105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6361340PMC
February 2019

Reported Direct and Indirect Contact with Dromedary Camels among Laboratory-Confirmed MERS-CoV Cases.

Viruses 2018 08 13;10(8). Epub 2018 Aug 13.

Department of Infectious Hazard Management, Health Emergencies Programme, World Health Organization, 1202 Geneva, Switzerland.

Dromedary camels () are now known to be the vertebrate animal reservoir that intermittently transmits the Middle East respiratory syndrome coronavirus (MERS-CoV) to humans. Yet, details as to the specific mechanism(s) of zoonotic transmission from dromedaries to humans remain unclear. The aim of this study was to describe direct and indirect contact with dromedaries among all cases, and then separately for primary, non-primary, and unclassified cases of laboratory-confirmed MERS-CoV reported to the World Health Organization (WHO) between 1 January 2015 and 13 April 2018. We present any reported dromedary contact: direct, indirect, and type of indirect contact. Of all 1125 laboratory-confirmed MERS-CoV cases reported to WHO during the time period, there were 348 (30.9%) primary cases, 455 (40.4%) non-primary cases, and 322 (28.6%) unclassified cases. Among primary cases, 191 (54.9%) reported contact with dromedaries: 164 (47.1%) reported direct contact, 155 (44.5%) reported indirect contact. Five (1.1%) non-primary cases also reported contact with dromedaries. Overall, unpasteurized milk was the most frequent type of dromedary product consumed. Among cases for whom exposure was systematically collected and reported to WHO, contact with dromedaries or dromedary products has played an important role in zoonotic transmission.
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http://dx.doi.org/10.3390/v10080425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6115845PMC
August 2018

Current challenges and implications for dengue, chikungunya and Zika seroprevalence studies worldwide: A scoping review.

PLoS Negl Trop Dis 2018 07 16;12(7):e0006533. Epub 2018 Jul 16.

Epidemiology Unit, Institut Pasteur de la Guyane, Cayenne, French Guiana.

Background: Arboviral infections are a public health concern and an escalating problem worldwide. Estimating the burden of these diseases represents a major challenge that is complicated by the large number of unapparent infections, especially those of dengue fever. Serological surveys are thus required to identify the distribution of these diseases and measure their impact. Therefore, we undertook a scoping review of the literature to describe and summarize epidemiological practices, findings and insights related to seroprevalence studies of dengue, chikungunya and Zika virus, which have rapidly expanded across the globe in recent years.

Methodology/principal Findings: Relevant studies were retrieved through a literature search of MEDLINE, WHOLIS, Lilacs, SciELO and Scopus (2000 to 2018). In total, 1389 publications were identified. Studies addressing the seroprevalence of dengue, chikungunya and/or Zika written in English or French and meeting the inclusion and exclusion criteria were included. In total, 147 studies were included, from which 185 data points were retrieved, as some studies used several different samples. Most of the studies were exclusively conducted on dengue (66.5%), but 16% were exclusively conducted on chikungunya, and 7 were exclusively conducted on Zika; the remainder were conducted on multiple arboviruses. A wide range of designs were applied, but most studies were conducted in the general population (39%) and in households (41%). Although several assays were used, enzyme-linked immunosorbent assays (ELISAs) were the predominant test used (77%). The temporal distribution of chikungunya studies followed the virus during its rapid expansion since 2004. The results revealed heterogeneity of arboviruses seroprevalence between continents and within a given country for dengue, chikungunya and Zika viruses, ranging from 0 to 100%, 76% and 73% respectively.

Conclusions/significance: Serological surveys provide the most direct measurement for defining the immunity landscape for infectious diseases, but the methodology remains difficult to implement. Overall, dengue, chikungunya and Zika serosurveys followed the expansion of these arboviruses, but there remain gaps in their geographic distribution. This review addresses the challenges for researchers regarding study design biases. Moreover, the development of reliable, rapid and affordable diagnosis tools represents a significant issue concerning the ability of seroprevalence surveys to differentiate infections when multiple viruses co-circulate.
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http://dx.doi.org/10.1371/journal.pntd.0006533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6062120PMC
July 2018

Risk of bias and confounding of observational studies of Zika virus infection: A scoping review of research protocols.

PLoS One 2017 7;12(7):e0180220. Epub 2017 Jul 7.

World Health Organization, Geneva, Switzerland.

Introduction: Given the severity and impact of the current Zika virus (ZIKV) outbreak in the Americas, numerous countries have rushed to develop research studies to assess ZIKV and its potential health consequences. In an effort to ensure that studies are comprehensive, both internally and externally valid, and with reliable results, the World Health Organization, the Pan American Health Organization, Institut Pasteur, the networks of Fiocruz, the Consortia for the Standardization of Influenza Seroepidemiology (CONSISE) and the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) have generated six standardized clinical and epidemiological research protocols and questionnaires to address key public health questions on ZIKV.

Methods: We conducted a systematic search of ongoing study protocols related to ZIKV research. We analyzed the content of protocols of 32 cohort studies and 13 case control studies for systematic bias that could produce erroneous results. Additionally we aimed to characterize the risks of bias and confounding in observational studies related to ZIKV and to propose ways to minimize them, including the use of six newly standardized research protocols.

Results: Observational studies of ZIKV face an array of challenges, including measurement of exposure and outcomes (microcephaly and Guillain-Barré Syndrome). Potential confounders need to be measured where known and controlled for in the analysis. Selection bias due to non-random selection is a significant issue, particularly in the case-control design, and losses to follow-up is equally important for the cohort design.

Conclusion: Observational research seeking to answer key questions on the ZIKV should consider these restrictions and take precautions to minimize bias in an effort to provide reliable and valid results. Utilization of the standardized research protocols developed by the WHO, PAHO, Institut Pasteur, and CONSISE will harmonize the key methodological aspects of each study design to minimize bias at different stages of the study. Biases need to be considered by researchers implementing the standardized protocols as well as by users of observational epidemiological studies of ZIKV.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0180220PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5501456PMC
October 2017

Key data for outbreak evaluation: building on the Ebola experience.

Philos Trans R Soc Lond B Biol Sci 2017 May;372(1721)

Medical Research Council Centre for Outbreak Analysis and Modelling, Department of Infectious Disease Epidemiology, School of Public Health, Imperial College London, London W2 1PG, UK.

Following the detection of an infectious disease outbreak, rapid epidemiological assessment is critical for guiding an effective public health response. To understand the transmission dynamics and potential impact of an outbreak, several types of data are necessary. Here we build on experience gained in the West African Ebola epidemic and prior emerging infectious disease outbreaks to set out a checklist of data needed to: (1) quantify severity and transmissibility; (2) characterize heterogeneities in transmission and their determinants; and (3) assess the effectiveness of different interventions. We differentiate data needs into individual-level data (e.g. a detailed list of reported cases), exposure data (e.g. identifying where/how cases may have been infected) and population-level data (e.g. size/demographics of the population(s) affected and when/where interventions were implemented). A remarkable amount of individual-level and exposure data was collected during the West African Ebola epidemic, which allowed the assessment of (1) and (2). However, gaps in population-level data (particularly around which interventions were applied when and where) posed challenges to the assessment of (3). Here we highlight recurrent data issues, give practical suggestions for addressing these issues and discuss priorities for improvements in data collection in future outbreaks.This article is part of the themed issue 'The 2013-2016 West African Ebola epidemic: data, decision-making and disease control'.
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http://dx.doi.org/10.1098/rstb.2016.0371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5394647PMC
May 2017

Heterogeneities in the case fatality ratio in the West African Ebola outbreak 2013-2016.

Philos Trans R Soc Lond B Biol Sci 2017 May;372(1721)

MRC Centre for Outbreak Analysis and Modelling, Department of Infectious Disease Epidemiology, Imperial College London, London W2 1PG, UK

The 2013-2016 Ebola outbreak in West Africa is the largest on record with 28 616 confirmed, probable and suspected cases and 11 310 deaths officially recorded by 10 June 2016, the true burden probably considerably higher. The case fatality ratio (CFR: proportion of cases that are fatal) is a key indicator of disease severity useful for gauging the appropriate public health response and for evaluating treatment benefits, if estimated accurately. We analysed individual-level clinical outcome data from Guinea, Liberia and Sierra Leone officially reported to the World Health Organization. The overall mean CFR was 62.9% (95% CI: 61.9% to 64.0%) among confirmed cases with recorded clinical outcomes. Age was the most important modifier of survival probabilities, but country, stage of the epidemic and whether patients were hospitalized also played roles. We developed a statistical analysis to detect outliers in CFR between districts of residence and treatment centres (TCs), adjusting for known factors influencing survival and identified eight districts and three TCs with a CFR significantly different from the average. From the current dataset, we cannot determine whether the observed variation in CFR seen by district or treatment centre reflects real differences in survival, related to the quality of care or other factors or was caused by differences in reporting practices or case ascertainment.This article is part of the themed issue 'The 2013-2016 West African Ebola epidemic: data, decision-making and disease control'.
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http://dx.doi.org/10.1098/rstb.2016.0308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5394646PMC
May 2017

A simple approach to measure transmissibility and forecast incidence.

Epidemics 2018 03 24;22:29-35. Epub 2017 Feb 24.

MRC Centre for Outbreak Analysis and Modelling, Imperial College London, Faculty of Medicine, London, UK; National Institute for Health Research Health Protection Research Unit in Modelling Methodology, Imperial College London, Faculty of Medicine, London, UK. Electronic address:

Outbreaks of novel pathogens such as SARS, pandemic influenza and Ebola require substantial investments in reactive interventions, with consequent implementation plans sometimes revised on a weekly basis. Therefore, short-term forecasts of incidence are often of high priority. In light of the recent Ebola epidemic in West Africa, a forecasting exercise was convened by a network of infectious disease modellers. The challenge was to forecast unseen "future" simulated data for four different scenarios at five different time points. In a similar method to that used during the recent Ebola epidemic, we estimated current levels of transmissibility, over variable time-windows chosen in an ad hoc way. Current estimated transmissibility was then used to forecast near-future incidence. We performed well within the challenge and often produced accurate forecasts. A retrospective analysis showed that our subjective method for deciding on the window of time with which to estimate transmissibility often resulted in the optimal choice. However, when near-future trends deviated substantially from exponential patterns, the accuracy of our forecasts was reduced. This exercise highlights the urgent need for infectious disease modellers to develop more robust descriptions of processes - other than the widespread depletion of susceptible individuals - that produce non-exponential patterns of incidence.
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http://dx.doi.org/10.1016/j.epidem.2017.02.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5871640PMC
March 2018

Middle East Respiratory Syndrome.

N Engl J Med 2017 02;376(6):584-594

From the Departments of Intensive Care (Y.M.A., A. Bouchama), Infection Prevention and Control (H.H.B.), and Pathology and Laboratory (A.H.H.), King Abdulaziz Medical City, King Saud bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center (Y.M.A., H.H.B., A. Bouchama, A.H.H.), the Department of Intensive Care, Dr. Sulaiman Al-Habib Group Hospitals (A.A.-O.), and Alfaisal University (A.A.-O.) - all in Riyadh, Saudi Arabia; the Department of Medicine, Division of Infectious Diseases and International Health, University of Virginia School of Medicine, Charlottesville (F.G.H.); the Department of Viral and Rickettsial Diseases, Naval Medical Research Center, Silver Spring, MD (T.L.); the Roslin Institute, University of Edinburgh, and Intensive Care Unit, Royal Infirmary of Edinburgh, Edinburgh (J.K.B.), the Health Protection and Influenza Research Group, Division of Epidemiology and Public Health, University of Nottingham, Nottingham (J.S.N.-V.-T.), and the Virus Reference Laboratory, Public Health England, London (A. Bermingham) - all in the United Kingdom; the Department of Pandemic and Epidemic Diseases, World Health Organization, Geneva (M.S., N.S., R.A.F.); the Department of Pediatrics, Vanderbilt University School of Medicine, Nashville (M.R.D., J.D.C.); the Center for Global Health, Institut Pasteur, Paris (M.D.V.K.); and the Institute of Health Policy Management and Evaluation, University of Toronto, and the Department of Critical Care Medicine and Department of Medicine, Sunnybrook Health Sciences Centre - both in Toronto (R.A.F.).

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http://dx.doi.org/10.1056/NEJMsr1408795DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5362064PMC
February 2017

Exposure Patterns Driving Ebola Transmission in West Africa: A Retrospective Observational Study.

PLoS Med 2016 Nov 15;13(11):e1002170. Epub 2016 Nov 15.

Centers for Disease Control and Prevention, Freetown, Sierra Leone.

Background: The ongoing West African Ebola epidemic began in December 2013 in Guinea, probably from a single zoonotic introduction. As a result of ineffective initial control efforts, an Ebola outbreak of unprecedented scale emerged. As of 4 May 2015, it had resulted in more than 19,000 probable and confirmed Ebola cases, mainly in Guinea (3,529), Liberia (5,343), and Sierra Leone (10,746). Here, we present analyses of data collected during the outbreak identifying drivers of transmission and highlighting areas where control could be improved.

Methods And Findings: Over 19,000 confirmed and probable Ebola cases were reported in West Africa by 4 May 2015. Individuals with confirmed or probable Ebola ("cases") were asked if they had exposure to other potential Ebola cases ("potential source contacts") in a funeral or non-funeral context prior to becoming ill. We performed retrospective analyses of a case line-list, collated from national databases of case investigation forms that have been reported to WHO. These analyses were initially performed to assist WHO's response during the epidemic, and have been updated for publication. We analysed data from 3,529 cases in Guinea, 5,343 in Liberia, and 10,746 in Sierra Leone; exposures were reported by 33% of cases. The proportion of cases reporting a funeral exposure decreased over time. We found a positive correlation (r = 0.35, p < 0.001) between this proportion in a given district for a given month and the within-district transmission intensity, quantified by the estimated reproduction number (R). We also found a negative correlation (r = -0.37, p < 0.001) between R and the district proportion of hospitalised cases admitted within ≤4 days of symptom onset. These two proportions were not correlated, suggesting that reduced funeral attendance and faster hospitalisation independently influenced local transmission intensity. We were able to identify 14% of potential source contacts as cases in the case line-list. Linking cases to the contacts who potentially infected them provided information on the transmission network. This revealed a high degree of heterogeneity in inferred transmissions, with only 20% of cases accounting for at least 73% of new infections, a phenomenon often called super-spreading. Multivariable regression models allowed us to identify predictors of being named as a potential source contact. These were similar for funeral and non-funeral contacts: severe symptoms, death, non-hospitalisation, older age, and travelling prior to symptom onset. Non-funeral exposures were strongly peaked around the death of the contact. There was evidence that hospitalisation reduced but did not eliminate onward exposures. We found that Ebola treatment units were better than other health care facilities at preventing exposure from hospitalised and deceased individuals. The principal limitation of our analysis is limited data quality, with cases not being entered into the database, cases not reporting exposures, or data being entered incorrectly (especially dates, and possible misclassifications).

Conclusions: Achieving elimination of Ebola is challenging, partly because of super-spreading. Safe funeral practices and fast hospitalisation contributed to the containment of this Ebola epidemic. Continued real-time data capture, reporting, and analysis are vital to track transmission patterns, inform resource deployment, and thus hasten and maintain elimination of the virus from the human population.
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http://dx.doi.org/10.1371/journal.pmed.1002170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5112802PMC
November 2016

Harmonisation of Zika virus research protocols to address key public health concerns.

Lancet Glob Health 2016 12 1;4(12):e911-e912. Epub 2016 Nov 1.

World Health Organization, Geneva Switzerland.

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http://dx.doi.org/10.1016/S2214-109X(16)30255-8DOI Listing
December 2016

Environmental contamination and risk factors for transmission of highly pathogenic avian influenza A(H5N1) to humans, Cambodia, 2006-2010.

BMC Infect Dis 2016 11 4;16(1):631. Epub 2016 Nov 4.

Institut Pasteur in Cambodia, Phnom Penh, Cambodia.

Background: Highly pathogenic avian influenza A (H5N1) virus has been of public health concern since 2003. Probable risk factors for A(H5N1) transmission to human have been demonstrated in several studies or epidemiological reports. However, transmission patterns may differ according to demographic characteristics of the population and local practices. This article aggregates these data from three studies with data collected in the previous surveys in 2006 and 2007 to further examine the risks factors associated with presence of anti-A(H5) antibodies among villagers residing within outbreak areas.

Methods: We aggregated 5-year data (2006-2010) from serology survey and matched case-control studies in Cambodia to further examine the risks factors associated with A(H5N1) infection among villagers in the outbreak areas.

Results: Serotesting among villagers detected 35 (1.5 % [0-2.6]) positive cases suggesting recent exposure to A(H5N1) virus. Practices associated with A(H5N1) infection among all ages were: having poultry cage or nesting area under or adjacent to the house (OR: 6.7 [1.6-28.3]; p = 0.010) and transporting poultry to market (OR: 17.6 [1.6-193.7]; p = 0.019). Practices found as risk factors for the infection among age under 20 years were swimming/bathing in ponds also accessed by domestic poultry (OR: 4.6 [1.1-19.1]; p = 0.038). Association with consuming wild birds reached borderline significance (p = 0.066).

Conclusion: Our results suggest that swimming/bathing in contaminated pond water and close contact with poultry may present a risk of A(H5N1) transmission to human.
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http://dx.doi.org/10.1186/s12879-016-1950-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5095992PMC
November 2016

MERS-CoV at the Animal-Human Interface: Inputs on Exposure Pathways from an Expert-Opinion Elicitation.

Front Vet Sci 2016 5;3:88. Epub 2016 Oct 5.

Cirad, UPR AGIRs Research Unit , Montpellier , France.

Nearly 4 years after the first report of the emergence of Middle-East respiratory syndrome Coronavirus (MERS-CoV) and nearly 1800 human cases later, the ecology of MERS-CoV, its epidemiology, and more than risk factors of MERS-CoV transmission between camels are poorly understood. Knowledge about the pathways and mechanisms of transmission from animals to humans is limited; as of yet, transmission risks have not been quantified. Moreover the divergent sanitary situations and exposures to animals among populations in the Arabian Peninsula, where human primary cases appear to dominate, vs. other regions in the Middle East and Africa, with no reported human clinical cases and where the virus has been detected only in dromedaries, represents huge scientific and health challenges. Here, we have used expert-opinion elicitation in order to obtain ideas on relative importance of MERS-CoV risk factors and estimates of transmission risks from various types of contact between humans and dromedaries. Fourteen experts with diverse and extensive experience in MERS-CoV relevant fields were enrolled and completed an online questionnaire that examined pathways based on several scenarios, e.g., camels-camels, camels-human, bats/other species to camels/humans, and the role of diverse biological substances (milk, urine, etc.) and potential fomites. Experts believed that dromedary camels play the largest role in MERS-CoV infection of other dromedaries; however, they also indicated a significant influence of the season (i.e. calving or weaning periods) on transmission risk. All experts thought that MERS-CoV-infected dromedaries and asymptomatic humans play the most important role in infection of humans, with bats and other species presenting a possible, but yet undefined, risk. Direct and indirect contact of humans with dromedary camels were identified as the most risky types of contact, when compared to consumption of various camel products, with estimated "most likely" incidence risks of at least 22 and 13% for direct and indirect contact, respectively. The results of our study are consistent with available, yet very limited, published data regarding the potential pathways of transmission of MERS-CoV at the animal-human interface. These results identify key knowledge gaps and highlight the need for more comprehensive, yet focused research to be conducted to better understand transmission between dromedaries and humans.
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http://dx.doi.org/10.3389/fvets.2016.00088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5051548PMC
October 2016

Unraveling the drivers of MERS-CoV transmission.

Proc Natl Acad Sci U S A 2016 08 25;113(32):9081-6. Epub 2016 Jul 25.

Medical Research Council Centre for Outbreak Analysis and Modelling, Imperial College London, Faculty of Medicine, London W2 1PG, United Kingdom;

With more than 1,700 laboratory-confirmed infections, Middle East respiratory syndrome coronavirus (MERS-CoV) remains a significant threat for public health. However, the lack of detailed data on modes of transmission from the animal reservoir and between humans means that the drivers of MERS-CoV epidemics remain poorly characterized. Here, we develop a statistical framework to provide a comprehensive analysis of the transmission patterns underlying the 681 MERS-CoV cases detected in the Kingdom of Saudi Arabia (KSA) between January 2013 and July 2014. We assess how infections from the animal reservoir, the different levels of mixing, and heterogeneities in transmission have contributed to the buildup of MERS-CoV epidemics in KSA. We estimate that 12% [95% credible interval (CI): 9%, 15%] of cases were infected from the reservoir, the rest via human-to-human transmission in clusters (60%; CI: 57%, 63%), within (23%; CI: 20%, 27%), or between (5%; CI: 2%, 8%) regions. The reproduction number at the start of a cluster was 0.45 (CI: 0.33, 0.58) on average, but with large SD (0.53; CI: 0.35, 0.78). It was >1 in 12% (CI: 6%, 18%) of clusters but fell by approximately one-half (47% CI: 34%, 63%) its original value after 10 cases on average. The ongoing exposure of humans to MERS-CoV from the reservoir is of major concern, given the continued risk of substantial outbreaks in health care systems. The approach we present allows the study of infectious disease transmission when data linking cases to each other remain limited and uncertain.
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http://dx.doi.org/10.1073/pnas.1519235113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4987807PMC
August 2016