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      The changing epidemiology of human monkeypox—A potential threat? A systematic review

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          Abstract

          Monkeypox, a zoonotic disease caused by an orthopoxvirus, results in a smallpox-like disease in humans. Since monkeypox in humans was initially diagnosed in 1970 in the Democratic Republic of the Congo (DRC), it has spread to other regions of Africa (primarily West and Central), and cases outside Africa have emerged in recent years. We conducted a systematic review of peer-reviewed and grey literature on how monkeypox epidemiology has evolved, with particular emphasis on the number of confirmed, probable, and/or possible cases, age at presentation, mortality, and geographical spread. The review is registered with PROSPERO (CRD42020208269). We identified 48 peer-reviewed articles and 18 grey literature sources for data extraction. The number of human monkeypox cases has been on the rise since the 1970s, with the most dramatic increases occurring in the DRC. The median age at presentation has increased from 4 (1970s) to 21 years (2010–2019). There was an overall case fatality rate of 8.7%, with a significant difference between clades—Central African 10.6% (95% CI: 8.4%– 13.3%) vs. West African 3.6% (95% CI: 1.7%– 6.8%). Since 2003, import- and travel-related spread outside of Africa has occasionally resulted in outbreaks. Interactions/activities with infected animals or individuals are risk behaviors associated with acquiring monkeypox. Our review shows an escalation of monkeypox cases, especially in the highly endemic DRC, a spread to other countries, and a growing median age from young children to young adults. These findings may be related to the cessation of smallpox vaccination, which provided some cross-protection against monkeypox, leading to increased human-to-human transmission. The appearance of outbreaks beyond Africa highlights the global relevance of the disease. Increased surveillance and detection of monkeypox cases are essential tools for understanding the continuously changing epidemiology of this resurging disease.

          Author summary

          Monkeypox, a zoonotic disease caused by an orthopoxvirus, results in a smallpox-like disease in humans. We conducted a systematic review to assess how monkeypox epidemiology has evolved since it was first diagnosed in 1970 in the Democratic Republic of the Congo. In total, human monkeypox has now appeared in 10 African countries and 4 countries elsewhere. Examples include Nigeria, where the disease re-emerged in the last decade after a 40-year hiatus, and the United States, where an outbreak occurred in 2003. The number of cases has increased at a minimum of 10-fold and median age at presentation has evolved from young children (4 years old) in the 1970s to young adults (21 years old) in 2010–2019. This may be related to the cessation of smallpox vaccinations, which provided some cross-protection against monkeypox. The case fatality rate for the Central African clade was 10.6% versus 3.6% for the West African clade. Overall, monkeypox is gradually evolving to become of global relevance. Surveillance and detection programs are essential tools for understanding the continuously changing epidemiology of this resurging disease.

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          Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement

          Systematic reviews should build on a protocol that describes the rationale, hypothesis, and planned methods of the review; few reviews report whether a protocol exists. Detailed, well-described protocols can facilitate the understanding and appraisal of the review methods, as well as the detection of modifications to methods and selective reporting in completed reviews. We describe the development of a reporting guideline, the Preferred Reporting Items for Systematic reviews and Meta-Analyses for Protocols 2015 (PRISMA-P 2015). PRISMA-P consists of a 17-item checklist intended to facilitate the preparation and reporting of a robust protocol for the systematic review. Funders and those commissioning reviews might consider mandating the use of the checklist to facilitate the submission of relevant protocol information in funding applications. Similarly, peer reviewers and editors can use the guidance to gauge the completeness and transparency of a systematic review protocol submitted for publication in a journal or other medium.
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            Outbreak of human monkeypox in Nigeria in 2017–18: a clinical and epidemiological report

            Background In September, 2017, human monkeypox re-emerged in Nigeria, 39 years after the last reported case. We aimed to describe the clinical and epidemiological features of the 2017–18 human monkeypox outbreak in Nigeria. Methods We reviewed the epidemiological and clinical characteristics of cases of human monkeypox that occurred between Sept 22, 2017, and Sept 16, 2018. Data were collected with a standardised case investigation form, with a case definition of human monkeypox that was based on previously established guidelines. Diagnosis was confirmed by viral identification with real-time PCR and by detection of positive anti-orthopoxvirus IgM antibodies. Whole-genome sequencing was done for seven cases. Haplotype analysis results, genetic distance data, and epidemiological data were used to infer a likely series of events for potential human-to-human transmission of the west African clade of monkeypox virus. Findings 122 confirmed or probable cases of human monkeypox were recorded in 17 states, including seven deaths (case fatality rate 6%). People infected with monkeypox virus were aged between 2 days and 50 years (median 29 years [IQR 14]), and 84 (69%) were male. All 122 patients had vesiculopustular rash, and fever, pruritus, headache, and lymphadenopathy were also common. The rash affected all parts of the body, with the face being most affected. The distribution of cases and contacts suggested both primary zoonotic and secondary human-to-human transmission. Two cases of health-care-associated infection were recorded. Genomic analysis suggested multiple introductions of the virus and a single introduction along with human-to-human transmission in a prison facility. Interpretation This study describes the largest documented human outbreak of the west African clade of the monkeypox virus. Our results suggest endemicity of monkeypox virus in Nigeria, with some evidence of human-to-human transmission. Further studies are necessary to explore animal reservoirs and risk factors for transmission of the virus in Nigeria. Funding None.
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              A systematic review of the epidemiology of human monkeypox outbreaks and implications for outbreak strategy

              Monkeypox is a vesicular-pustular illness that carries a secondary attack rate in the order of 10% in contacts unvaccinated against smallpox. Case fatality rates range from 1 to 11%, but scarring and other sequelae are common in survivors. It continues to cause outbreaks in remote populations in Central and West Africa, in areas with poor access and weakened or disrupted surveillance capacity and information networks. Recent outbreaks in Nigeria (2017-18) and Cameroon (2018) have occurred where monkeypox has not been reported for over 20 years. This has prompted concerns over whether there have been changes in the biology and epidemiology of the disease that may in turn have implications for how outbreaks and cases should best be managed. A systematic review was carried out to examine reported data on human monkeypox outbreaks over time, and to identify if and how epidemiology has changed. Published and grey literature were critically analysed, and data extracted to inform recommendations on outbreak response, use of case definitions and public health advice. The level of detail, validity of data, geographical coverage and consistency of reporting varied considerably across the 71 monkeypox outbreak documents obtained. An increase in cases reported over time was supported by literature from the Democratic Republic of Congo (DRC). Data were insufficient to measure trends in secondary attack rates and case fatality rates. Phylogenetic analyses consistently identify two strains of the virus without evidence of emergence of a new strain. Understanding of monkeypox virulence with regard to clinical presentation by strain is minimal, with infrequent sample collection and laboratory analysis. A variety of clinical and surveillance case definitions are described in the literature: two definitions have been formally evaluated and showed high sensitivity but low specificity. These were specific to a Congo-Basin (CB) strain–affected area of the DRC where they were used. Evidence on use of antibiotics for prophylaxis against secondary cutaneous infection is anecdotal and limited. Current evidence suggests there has been an increase in total monkeypox cases reported by year in the DRC irrespective of advancements in the national Integrated Disease Surveillance and Response (IDSR) system. There has been a marked increase in number of individual monkeypox outbreak reports, from outside the DRC in between 2010 and 2018, particularly in the Central African Republic (CAR) although this does not necessarily indicate an increase in annual cases over time in these areas. The geographical pattern reported in the Nigeria outbreak suggests a possible new and widespread zoonotic reservoir requiring further investigation and research. With regards to outbreak response, increased attention is warranted for high-risk patient groups, and nosocomial transmission risks. The animal reservoir remains unknown and there is a dearth of literature informing case management and successful outbreak response strategies. Up-to-date complete, consistent and longer-term research is sorely needed to inform and guide evidence-based response and management of monkeypox outbreaks.
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                Author and article information

                Contributors
                Role: InvestigationRole: MethodologyRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – review & editing
                Role: Formal analysisRole: MethodologyRole: ValidationRole: VisualizationRole: Writing – review & editing
                Role: InvestigationRole: Project administrationRole: ValidationRole: Writing – review & editing
                Role: InvestigationRole: MethodologyRole: ValidationRole: Writing – review & editing
                Role: Writing – original draftRole: Writing – review & editing
                Role: SupervisionRole: ValidationRole: VisualizationRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS Negl Trop Dis
                PLoS Negl Trop Dis
                plos
                PLoS Neglected Tropical Diseases
                Public Library of Science (San Francisco, CA USA )
                1935-2727
                1935-2735
                11 February 2022
                February 2022
                : 16
                : 2
                : e0010141
                Affiliations
                [1 ] Pallas Health Research and Consultancy, Rotterdam, The Netherlands
                [2 ] Bavarian Nordic AG, Zug, Switzerland
                [3 ] Bavarian Nordic, Inc., Morrisville, North Carolina, United States of America
                [4 ] Bavarian Nordic GmbH, Martinsried, Germany
                [5 ] Baer PharMed Consulting, Ltd., Skokie, Illinois, United States of America
                [6 ] Epidemiology, Biostatistics and Prevention Institute, WHO Collaborating Center on Travelers’ Health, University of Zurich, Zurich, Switzerland
                [7 ] Department of Epidemiology, Human Genetics and Environmental Sciences, University of Texas School of Public Health, Houston, Texas, United States of America
                WRAIR, UNITED STATES
                Author notes

                I have read the journal’s policy and the authors of this manuscript have the following competing interests: Bernard Hoet, Liddy Chen, Florian Lienert, and Heinz Weidenthaler are employees of Bavarian Nordic. Eveline M. Bunge is an employee of Pallas Health Research Consultancy. Lorraine R. Baer is an employee of Baer PharMed Consulting, Ltd., which received funding for the preparation of the manuscript. Robert Steffen has been paid for lectures and participation in advisory boards by various vaccine manufacturers, including Bavarian Nordic. Please note that the study was fully funded by Bavarian Nordic with two contracts, first with Pallas Health Research and Consultancy to perform the systematic review, second with Baer PharMed Consulting, Ltd to support manuscript development. It is only after reviewing the data acknowledging the public health importance that the authors decided to submit a manuscript on the subject. The following authors received salary from the funder (BH, LC, FL, HW). The funder had a role in study design, data collection and analysis, decision to publish, and preparation of the manuscript.

                Author information
                https://orcid.org/0000-0001-7988-909X
                https://orcid.org/0000-0002-5345-3236
                https://orcid.org/0000-0002-9161-7107
                https://orcid.org/0000-0002-6866-4028
                https://orcid.org/0000-0001-7917-1141
                Article
                PNTD-D-21-00919
                10.1371/journal.pntd.0010141
                8870502
                35148313
                3603e06f-483b-427a-987c-1f73c7ad61ec
                © 2022 Bunge et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 22 June 2021
                : 4 January 2022
                Page count
                Figures: 9, Tables: 3, Pages: 20
                Funding
                Funded by: Bavarian Nordic
                This study was initiated and funded by Bavarian Nordic. The decision to publish the manuscript was made after the report of the paid systematic literature review by Pallas Health Research and Consultancy. The funder had a role in study design, data collection and analysis, decision to publish, and preparation of the manuscript. Baer PharMed Consulting, Ltd received funding for the development of the manuscript.
                Categories
                Research Article
                Medicine and Health Sciences
                Medical Conditions
                Infectious Diseases
                Viral Diseases
                Monkeypox
                Medicine and Health Sciences
                Medical Conditions
                Infectious Diseases
                Zoonoses
                Monkeypox
                Biology and Life Sciences
                Immunology
                Vaccination and Immunization
                Medicine and Health Sciences
                Immunology
                Vaccination and Immunization
                Medicine and Health Sciences
                Public and Occupational Health
                Preventive Medicine
                Vaccination and Immunization
                Medicine and Health Sciences
                Medical Conditions
                Infectious Diseases
                Viral Diseases
                Smallpox
                Medicine and Health Sciences
                Epidemiology
                Research and Analysis Methods
                Research Assessment
                Peer Review
                People and Places
                Geographical Locations
                Africa
                Nigeria
                Medicine and Health Sciences
                Epidemiology
                Medical Risk Factors
                Research and Analysis Methods
                Research Assessment
                Systematic Reviews
                Custom metadata
                vor-update-to-uncorrected-proof
                2022-02-24
                All relevant data are within the manuscript and its Supporting Information files.

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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