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      The re‐emerging human monkeypox virus: An urgent global health alert

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          Abstract

          To the Editor, The coronavirus disease 2019 (COVID‐19) showed that any viral outbreak may cause a pandemic; the periodic outbreaks of novel or reemerging viruses remind us that zoonotic infections will continue to emerge. 1 In 2022, Monkeypox (MPX) outbreaks were reported in nonendemic places, causing a worldwide wave of public health concern and demands for action from international authorities. On May 2nd, 2022, the World Health Organization (WHO) received a report of a case of monkeypox in a patient from United Kingdom who had a travel history to Nigeria. Zoonotic monkeypox disease is endemic in Central and Western Africa. 2 , 3 , 4 , 5 The monkeypox virus (MPXV), a virus belonging to the genus Orthopoxvirus (OPXV), which also includes variola, the causative agent of smallpox, and resembles smallpox symptoms. 3 , 4 The West African and Congo basin clades are the two main groups of MPXV of which the West African clade is the least deadly, with a 1% death rate, and is believed to be responsible for the current pandemic. In the past, the illness was relatively uncommon outside of Africa, with occasional outbreaks mainly in the Democratic Republic of the Congo (DRC) and Nigeria. 2 , 3 , 4 On the current scenario, for a global Public health alert, we further illustrated the historical timeline of outbreaks of the human monkeypox virus until 2022 (Figure 1). Due to interaction with infected pet Prairie dogs imported from Ghana, the first MPX cases in humans were identified in the United States in 2003, resulting in an outbreak of more than 70 cases. 6 , 7 A major human MPX epidemic brought on by the West African clade was also reported in Nigeria in October 2017, with approximately 146 clinically suspected and 42 confirmed cases. 8 As a consequence of MPXV exports from Africa, human MPX cases were later reported in Israel (2018), the United Kingdom (2018, 2019, 2021, and 2022), Singapore (2019), and the United States (2021). 7 , 9 Figure 1 shows the historical timeline of human MPX outbreaks; for further references and ideas, we recommend the following resource for viewing updates. 6 As of August 1st, 2022, four deaths have been documented in nonendemic nations (two in Spain, one in Brazil, and one in India), contributing to 10 deaths globally during this COVID‐19 pandemic (four from non endemic countries and six from endemic countries). 10 Figure 1  Timeline of reported human monkeypox outbreaks in the World from 1958 till 2022. Source: based on data from the Centres for Disease Control and Prevention. The MPXV transmission to humans is still a mystery. A zoonotic animal‐to‐human transfer may result from direct contact with infected animals (e.g., Bites, Scratches) or indirect contact with contaminated animal fluids or wound material. 11 , 12 , 13 Direct contact with an infected person is the primary mode of transmission by respiratory droplets and exposure to infectious wounds or body fluids. 13 Human to human transmission occurs via direct skin to skin contact with gaping sores and indirect contact with infected fomites such as bedding or clothes. 14 Additionally, it is important to consider a vertical transfer from the mother to the fetus. 15 , 16 To date, there is no evidence that only human to human transmission in the general population can spread monkeypox infection. Monkeypox transmission in both endemic and nonendemic environments is summarized in Figure 2. Figure 2  Summarizes the monkeypox transmission in both endemic and nonendemic environments The typical clinical presentation of monkeypox is characterized by fever, enlarged lymph nodes, and rashes. Prodromal symptoms such as chills, myalgia, fatigue, headache, back pain, and, in rare cases, sore throat and cough may appear. 17 Many symptoms of monkeypox are similar to those of smallpox. 18 Itching in the mouth rashes leading to impaired food intake. Secondary bacterial infections of the skin lesions are common in patients. 19 , 20 , 21 The cutaneous signs of monkeypox may be misinterpreted as chickenpox, distinctive rash might be restricted to the vaginal, perigenital, and perianal regions; individuals may also present with/absent or minor prodromal symptoms after a localized rash appears. 22 Laboratory confirmation can be established using immunological techniques such as ELISA, polymerase chain reaction, electron microscopy, and sequencing. 21 , 23 There is no specific therapy for Monkeypox at the moment. The major suggestions for treating MPXV infection are supportive care, symptomatic management, and treatment of subsequent bacterial infections. Since the monkeypox virus is similar to smallpox virus, antiviral drugs developed against smallpox can be used for protection against monkeypox too. Based on smallpox treatment results, antiviral drugs such as Cidofovir, Brincidofovir, and Tecovirimat can be effective against MPXV. 24 , 25 Tecovirimat which inhibits viral envelope protein p37 by stopping viral egress from infected cells is approved by the Food and Drug Administration (FDA) for the treatment of smallpox in children and adults. For monkeypox, all antiviral drugs are still investigational drugs that have not been approved by FDA and should be used only in people with severe monkeypox disease or in high risk people with weakened immune system. Under Expanded Access Investigational New Drug (EA‐IND) protocols held by the Centers for Disease Control and Prevention (CDC), Tecovirimat, Cidofovir, and VIGIV are currently accessible from the Strategic National Stockpile for use in treating OPXV infections in an outbreak scenario. 26 There are now two approved orthopoxvirus vaccines in the United States that can be used to prevent Monkeypox and smallpox. One vaccine (JYNNEOSTM) is based on a live, attenuated vaccinia virus that cannot replicate in the body but may trigger robust immune responses. 27 , 28 , 29 The second vaccine, ACAM2000®, is a replication‐competent live vaccinia virus vaccine, meaning that the vaccine virus may be transmitted from vaccinated to unvaccinated people. 30 Another vaccine developed to stop viral replication is LC16m8, which protects against severe Monkeypox disease in nonhuman primate animals. 29 Its effectiveness against human monkeypox disease is yet to be proved. Preventing infectious disease outbreaks is a major concern for global public health. Reusing Vaccinia Vaccination on a Large Scale should be implemented in affected countries. Furthermore, it is crucial to take preventative actions to minimize zoonotic and human‐to‐human infections. 31 , 32 About 75% of today's emerging infectious diseases are zoonotic, 33 spread by wildlife or exotic pets, such as SARS, Ebola, Salmonellosis, and Monkeypox. Hence, we feel that as most zoonotic diseases have a high chance of spreading through imported exotic pets, strict guidelines to prevent illegal animal traffic and stern animal quarantine procedures for the import of pets from disease‐endemic areas should be implemented worldwide. The CDC says there are several ways to avoid getting infected with MPXV 34 : 1. Avoiding sick animals or anything that has come into contact with a sick animal. 2. Staying away from sick or dead animals in disease‐prone areas. 3. Isolation of the patient. 4. Washing hands after touching contaminated people or animals. 5. Providing medical care while wearing masks and gloves. 6. Public education and awareness can help stop the virus's spread. 7. Infected exotic pets or animals should be quarantined or euthanized during shipping, per CDC guidelines. 35 The COVID‐19 pandemic has sadly taught us that awareness and preparedness are the two keywords to deal with these dire situations. Scientific community should come up with strategies to develop several therapeutic drugs and vaccines. The country should also increase its immunization units in primary health care centers and hospitals in all areas and improve awareness on public health programs and preventive measures. So far, no promising treatment or prevention strategies have been developed against the human monkeypox virus. From the perspective of the current outbreak, developing an effective vaccine and therapeutic agent against the re‐emerging monkeypox virus is another major challenge for virologists and scientists. Since viruses have evolved in such as way that they are difficult to kill, virologists are considered as key stakeholders in identifying and controlling new emerging viral infections. Therefore, governments have included virologists as key members in pandemic preparedness and response teams worldwide. Although existing smallpox virus replication antiviral agents inhibit orthopoxvirus replication in vitro, developing a new vaccine against all MPX viruses will be the ultimate preventive strategy locally and globally. AUTHOR CONTRIBUTIONS Dr. Prithiviraj Nagarajan: Conceptualization; data curation; resources; writing – original draft. Dr. Leena Rajathy Port Louis: Data curation; Formal analysis; writing – review & editing. Dr. Anusheela Howlader: Formal analysis; investigation; writing – review & editing. Dr. Kumar Rangarajalu: Investigation; supervision; validation. CONFLICT OF INTEREST The authors declare no conflict of interest.

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

          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.
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            Clinical features and management of human monkeypox: a retrospective observational study in the UK

            Background Cases of human monkeypox are rarely seen outside of west and central Africa. There are few data regarding viral kinetics or the duration of viral shedding and no licensed treatments. Two oral drugs, brincidofovir and tecovirimat, have been approved for treatment of smallpox and have demonstrated efficacy against monkeypox in animals. Our aim was to describe the longitudinal clinical course of monkeypox in a high-income setting, coupled with viral dynamics, and any adverse events related to novel antiviral therapies. Methods In this retrospective observational study, we report the clinical features, longitudinal virological findings, and response to off-label antivirals in seven patients with monkeypox who were diagnosed in the UK between 2018 and 2021, identified through retrospective case-note review. This study included all patients who were managed in dedicated high consequence infectious diseases (HCID) centres in Liverpool, London, and Newcastle, coordinated via a national HCID network. Findings We reviewed all cases since the inception of the HCID (airborne) network between Aug 15, 2018, and Sept 10, 2021, identifying seven patients. Of the seven patients, four were men and three were women. Three acquired monkeypox in the UK: one patient was a health-care worker who acquired the virus nosocomially, and one patient who acquired the virus abroad transmitted it to an adult and child within their household cluster. Notable disease features included viraemia, prolonged monkeypox virus DNA detection in upper respiratory tract swabs, reactive low mood, and one patient had a monkeypox virus PCR-positive deep tissue abscess. Five patients spent more than 3 weeks (range 22–39 days) in isolation due to prolonged PCR positivity. Three patients were treated with brincidofovir (200 mg once a week orally), all of whom developed elevated liver enzymes resulting in cessation of therapy. One patient was treated with tecovirimat (600 mg twice daily for 2 weeks orally), experienced no adverse effects, and had a shorter duration of viral shedding and illness (10 days hospitalisation) compared with the other six patients. One patient experienced a mild relapse 6 weeks after hospital discharge. Interpretation Human monkeypox poses unique challenges, even to well resourced health-care systems with HCID networks. Prolonged upper respiratory tract viral DNA shedding after skin lesion resolution challenged current infection prevention and control guidance. There is an urgent need for prospective studies of antivirals for this disease. 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
                prithivinaga@gmail.com
                Journal
                Health Sci Rep
                Health Sci Rep
                10.1002/(ISSN)2398-8835
                HSR2
                Health Science Reports
                John Wiley and Sons Inc. (Hoboken )
                2398-8835
                08 November 2022
                November 2022
                : 5
                : 6 ( doiID: 10.1002/hsr2.v5.6 )
                : e928
                Affiliations
                [ 1 ] Multi‐Disciplinary Centre for Biomedical Research, Aarupadai Veedu Medical College & Hospital Vinayaka Mission's Research Foundation (Deemed to be University) Kirumampakkam, Bahour Puducherry India
                [ 2 ] Department of Pharmacology, Aarupadai Veedu Medical College & Hospital Vinayaka Mission's Research Foundation (Deemed to be University) Kirumampakkam, Bahour Puducherry India
                [ 3 ] Department of Microbiology, Aarupadai Veedu Medical College & Hospital Vinayaka Mission's Research Foundation (Deemed to be University) Kirumampakkam, Bahour Puducherry India
                [ 4 ] Aarupadai Veedu Medical College & Hospital Vinayaka Mission's Research Foundation (Deemed to be University) Kirumampakkam, Bahour Puducherry India
                Author notes
                [*] [* ] Correspondence Prithiviraj Nagarajan, Multi‐Disciplinary Centre for Biomedical Research, Aarupadai Veedu Medical College & Hospital, Vinayaka Mission's Research Foundation (Deemed to be University), Kirumampakkam, Puducherry‐607402, India.

                Email: prithivinaga@ 123456gmail.com

                Author information
                http://orcid.org/0000-0002-9428-6243
                http://orcid.org/0000-0002-1177-9932
                http://orcid.org/0000-0001-9494-9775
                http://orcid.org/0000-0002-9848-030X
                Article
                HSR2928
                10.1002/hsr2.928
                9642809
                151a81e8-f041-451f-944e-63be6b53f74f
                © 2022 The Authors. Health Science Reports published by Wiley Periodicals LLC.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 10 October 2022
                : 05 September 2022
                : 23 October 2022
                Page count
                Figures: 2, Tables: 0, Pages: 4, Words: 2337
                Categories
                Letter to the Editor
                Letter to the Editor
                Custom metadata
                2.0
                November 2022
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.2.0 mode:remove_FC converted:08.11.2022

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