Epidemiological Situation of Monkeypox Transmission by Possible Sexual Contact: A Systematic Review

Monkeypox (MPX), a zoonotic infection caused by the monkeypox virus (MPXV), has re-emerged worldwide with numerous confirmed cases with person-to-person transmission through close contacts, including in sexual networks. Therefore, this study aimed to determine the epidemiological situation of monkeypox transmission by possible sexual contact. A systematic literature review was conducted using PubMed, Scopus, Web of Science, and Embase databases until 18 August 2022. The key search terms used were “monkeypox”, “sexual contact”, “sexual intercourse” and “sexual transmission”. A total of 1291 articles were retrieved using the search strategy. After eliminating duplicates (n = 738) and examining by title, abstract, and full text, 28 studies reporting case reports of monkeypox with a detailed description of clinical features, sexually transmitted diseases, method of diagnosis, location and course of skin lesions, and treatment were included. A total of 4222 confirmed cases of monkeypox have been reported, of which 3876 monkeypox cases are the result of transmission by sexual contact distributed in twelve countries: 4152 cases were male with a mean age of 36 years. All confirmed cases of monkeypox were diagnosed by reverse transcriptase-polymerase chain reaction (RT-PCR). The most frequent clinical manifestations were fever, lymphadenopathy, headache, malaise, and painful perianal and genital lesions. The most frequent locations of the lesions were perianal, genital, oral, trunk, upper and lower extremities. Patients were in good clinical condition, with treatment based on analgesics and antipyretics to relieve some symptoms of monkeypox. A high proportion of STIs and frequent anogenital symptoms were found, suggesting transmissibility through local inoculation during close skin-to-skin or mucosal contact during sexual activity. The highest risk of monkeypox transmission occurs in men who have sex with men, and MPXV DNA could be recovered in seminal fluid. It is essential to establish health policies for the early detection and management of patients with monkeypox.


Introduction
Monkeypox (MPX) has re-emerged on a global scale with numerous cases confirmed across the globe in 2022 [1]. The rapid spread of cases across different countries has raised serious concern among public health officials worldwide, prompting accelerated investigations aimed at identifying the origins and cause of the rapid spread of cases [2,3]. As of 25 August 2022, 46,724 confirmed cases of monkeypox have been reported in 98 countries

Protocol and Registration
This protocol follows the recommendations established by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [26], and it has been reported in the International Prospective Register of Systematic Reviews (PROSPERO) database (CRD42022340855).

Eligibility Criteria
To assess the prevalence of sexual contact transmission of monkeypox, we included peer-reviewed published articles with study designs of case reports, case series, and observational studies (cohort and nonrandomized intervention studies). No language limit was established for the articles and publications were included until 18 August 2022. Systematic review articles, narrative reviews, randomized clinical trials, editorials, letters to the editor, and conference proceedings were excluded.

Information Sources and Search Strategy
A systematic search was carried out in PubMed, Scopus, Web of Science and Embase. The search terms used were: ("Monkeypox" OR "Monkey Pox") AND ("sexual contact" OR "sexual intercourse" OR "sexual behavior" OR "transmission" OR "sexual transmission" OR "Sexual Intercourse" OR "Intercourse, Sexual" OR "Coital" OR "Copulation" OR "Sexual relations") ( Table 1). The searches were completed on 18 August 2022, and four different investigators independently evaluated the search results.

Study Selection
Three investigators (D.A.L.F., E.G.V., J.J.B.) created a database based on the electronic searches, managed with the appropriate management software (EndNote), and duplicates were removed. Then, through Rayyan QCRI [27] three researchers (M.T.D.M., M.D.T. and O.C.S.) carried out the screening process, analyzing the titles and abstracts provided by the search independently, choosing those that appeared to meet the inclusion criteria and, if necessary, evaluating the full text. In case of disagreement, the investigators will discuss until a consensus is reached; in case of dispute, a fourth investigator will be invited to the discussion to help resolve it.
The authors (D.K.B.A. and A.J.R.M.) reviewed the full-text reports and analyzed the inclusion criteria to reach a decision.

Outcomes
The primary outcome was to report the epidemiological situation of monkeypox transmission by possible sexual contact.

Data Collection Process and Data Items
Four investigators independently extracted data from the selected studies into a Microsoft Excel spreadsheet. The following data were extracted from the selected studies: author data, date of publication, study design, country, sex, age, sexual behavior, sexually transmitted infections (STIs), signs and symptoms, diagnostic test, days from systemic symptoms to lesion onset, location of skin lesions, evolution of lesions, and treatment. A fifth investigator checked the list of articles and data extractions to ensure that there were no duplicate articles or duplicate information and resolved discrepancies about study inclusion.

Study Selection
A total of 1291 articles were retrieved using the search strategy. The selection strategy is shown in the prism flow chart (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) [26]. After the removal of duplicates (n = 738), 553 articles were screened by the reviewers. After filtering the titles and reading the abstracts, 74 articles were selected for full-text reading, and 28 were considered eligible for inclusion in this systematic review [7,8,22, (Figure 1).

Study Selection
A total of 1291 articles were retrieved using the search strategy. The selection strategy is shown in the prism flow chart (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) [26]. After the removal of duplicates (n = 738), 553 articles were screened by the reviewers. After filtering the titles and reading the abstracts, 74 articles were selected for full-text reading, and 28 were considered eligible for inclusion in this systematic review [7,8,22, (Figure 1).

Asynchronous
No specific treatment was recorded and all individuals improved clinically.

Asynchronous
No specific treatment was recorded.

Discussion
Currently, MPX represents the most recent emerging zoonotic disease worldwide [53]. For this reason, the main objective of the present systematic review is to determine the epidemiological situation of monkeypox transmission by possible sexual contact. It is important to have knowledge of the clinical characteristics, sexual behavior, localization and evolution of skin lesions, diagnosis, and correct management of these patients.
This study reported 3876 cases of monkeypox through possible sexual contact transmission distributed in twelve countries. It was found that 85% of the reported cases were from Europe, with Spain being the country with the most reports. All patients were diagnosed by RT-PCR. The majority of patients reported an average age of 36 years and were male. The most recent outbreak of Monkeypox (MPXV) in 2022 has brought new light to the importance of this sexual transmission mechanism in the spread of an emerging pathogen [54,55]. All reported patients had sexual risk behaviors, of which men who have sex with men (MSM) was the most prevalent.
According to the WHO, current epidemiological data show a predominance of the involvement of young males, with 98.2% (20,138/20,500) of cases with available data on gender being male with a median age of 36 years (interquartile range: 30-43 years). Among cases with declared sexual orientation, 95.8% (9484/9899) identified as men who have sex with men. Sexual encounters were the most common type of transmission, accounting for 5954 of 7250 (82.1%) of all transmission cases [56]. In the recently released study by Thornhill JP et al.,528 instances of monkeypox were documented, of which 98% were homosexual or bisexual men who had engaged in risky sexual activity, and 41% had human immunodeficiency virus infection [57].
The incubation period has been estimated at 5 to 21 days and the duration of symptoms and signs at 2 to 5 weeks [58]. The disease begins with nonspecific symptoms and signs, the most frequent symptoms reported in the study cases were fever, lymphadenopathy, headache, malaise, and general lesions. All lesions had an asynchronous evolution, with the genital and anal regions being the most frequent locations. This suggests that contact in sexual intercourse could be a risk factor for transmission [8] because it can occur through contact with infected humans, or with human body material containing the virus [59]; therefore, sexual intercourse without the use of a condom could be another risk factor, since there are other viruses found in semen [60]. However, there are still no studies demonstrating the presence of Monkeypox in this body secretion, except for case reports from Italy and Germany [7,8,51].
To determine a rapid and definitive diagnosis of MPX, the exudate from lesions can provide the best sample [61]. This is performed through direct recognition of viral DNA by real-time PCR, allowing rapid discrimination between smallpox and other poxviruses [61][62][63][64][65]. In addition, it is important to understand that MPXV DNA could be recovered in blood, urine, upper respiratory tract, and seminal fluid [8,16,61].
According to the study by Ranjit Sah et al., monkeypox virus is highly prevalent in seminal samples from monkeypox cases, supporting the idea that the disease is sexually transmitted. However, since the virus can reproduce in this environment, this high prevalence rate does not always suggest viral contagiousness [66]. The infectivity of seminal monkeypox virus remains debatable and requires further investigation.
Sixty-nine percent of the cases presented had a previous STI, the most frequent being syphilis and hepatitis. In addition, most of them were HIV positive, which led us to infer that this history could be a risk factor that may contribute to infection [54]. MPX can be confused with some sexually transmitted infections (STIs) that can cause skin rashes, for example, syphilis, human immunodeficiency virus (HIV), chancroid, condyloma acuminate, disseminated gonorrhea, and herpes [67].
Most of the patients had symptomatic treatment, although some did not require any specific treatment. Recently, some drugs were developed in the United States to treat smallpox infection. These antiviral agents are also active against MPXV. The Food and Drug Administration (FDA) approved tecovirimat in 2018, which acts by inhibiting the viral protein p27, thus preventing viral egress from infected cells, and oral brincidofovir in 2021, which blocks viral DNA polymerase [68].
It is important to follow up on the contacts of the reported cases to avoid the spread of this disease, taking into account the number of days from the general symptoms to the appearance of lesions, which ranged from 1 to 5 days in the cases reported. The study did not report any deaths in cases of monkeypox potentially transmitted by sexual contact, although this also depends on the immunological status of the patient and associated complications.
The situation of this new zoonotic disease, which now appears to be emerging as an STI, is of great concern and warrants further study to understand the multiple effects of this virus, which is currently affecting several continents and with possible new routes of transmission, including during the COVID-19 pandemic that has not yet ended [69].

Conclusions
The reemerging zoonotic disease (monkeypox) has spread rapidly throughout the world and has shown unusual reports of person-to-person transmission through possible sexual contact. The prevalence of STIs and the frequent occurrence of anogenital symptoms point to local inoculation during intimate skin-to-skin or mucosal contact during sexual activity. Men who have sex with men are most at risk of spreading monkeypox, and MPXV DNA can be found in seminal fluid. The establishment of health policies is crucial for the early identification and treatment of people with monkeypox.