Abstract
Mpox epidemiology has experienced a dramatic change in recent years with a marked shift in transmission dynamics. The objective was to assess the route of transmission of mpox by virus clade and geographic distribution. A systematic review of studies with transmission data published between September 2022 and September 2024 was conducted. A total 222 studies including 45,553 mpox patients were included. Approximately 93.0 % of the patients were males and 98.6 % were adults. Approximately 89.1 % were men who have sex with men, 5.3 % were heterosexual men, and 5.5 % were heterosexual women. Approximately 95.3 % reported sexual contact (65.1 % confirmed and 30.3 % suspected), 2.9 % close non-sexual contact, and 1.8 % multiple/other routes (not including inhalation). Sexual contact represented > 90 % of transmission in all regions but African region. Most studies reported clade data showed clade IIb with a similar transmission pattern as described above. This can support the formulation of infection prevention and control recommendations.
Keywords: Mpox, Route of transmission, Virus clade, Geography, Sexual contact, Systematic review
Introduction
Mpox is a re-emerging zoonotic disease caused by Orthopoxvirus, the same family of viruses that cause smallpox [1]. For decades, mpox has been recognized as an endemic disease in Western and Central Africa [2]. In 2022, a major change in the epidemiology of mpox was observed with rapid spread of cases to non-endemic areas outside Africa [1], [2]. This reflects a significant change in the virus and a marked shift in its transmission dynamics [3]. Consequently, the World Health Organization (WHO) declared mpox as a public health emergency of international concern (PHEIC) in July 2022 [4]. In August of 2024, the WHO redeclared a PHEIC in response to the upsurge of mpox in the Democratic Republic of the Congo (DRC) [5]. By end of 2024, more than 125,000 patients and 272 related deaths were reported to the WHO [6].
Prior to the 2022 multi-country outbreak, transmission of mpox in Africa was primarily related to animal exposure and to a less extent direct, physical contact with people infected with mpox [7], [8]. Sporadic cases have been documented outside Africa primarily related to travel or animal imports from Africa [7], [8]. However, the 2022–2024 multi-country outbreak demonstrated that mpox can be transmitted on a larger scale through person-to-person contact, especially in urban settings [9], [10]. This change in transmission patterns has been well-documented in global surveillance data, reporting sexual contact as an emerging route of transmission of mpox, particularly among men who have sex with men (MSM) outside the African region [11], [12].
There are currently four different sub-clades of mpox virus circulating; clade Ia, Ib, IIa, and IIb [6], [13]. Theses clades demonstrate variable disease severity and behaviour-related route of transmission [14]. As such, global plans on mpox prevention and control should consider different contexts [15]. Shortly after the 2022 multi-country outbreak, WHO developed an interim rapid response guidance for prevention and control measures to mitigate and control mpox transmission within healthcare and community settings [16]. Subsequently, a systematic review was commissioned covering publications up to September 2022 to better understand the routes of transmission and update the guideline accordingly [9] Due to increased global mpox cases from late 2022 onwards a need was identified to review more recent publications. The objective of the current review was to assess the route of transmission of mpox by virus clade and geographic distribution from September 2022 to September 2024.
Methods
Study design
A systematic review was developed to support the WHO Guideline Development Group’s update to the WHO mpox infection control interim rapid response guidance. The current systematic review covers the period from September 2022 to September 2024. This review is a follow up of the systematic review undertaken through August 2022 [9]. Therefore, the two-stage methodology used in the first review was replicated [9]. The first stage searched for interventional and comparative studies studying the effectiveness of three interventions for preventing mpox infection (using respirator versus medical mask, using airborne precaution versus adequate ventilation, and isolating patients with non-severe mpox). The second stage searched for routes of transmission in all types of studies. As in the first review conducted up to September 2022, this subsequent review failed to retrieve any interventional or comparative studies for the three interventions. Therefore, the focus of this review was identifying the routes of transmission.
Inclusion and exclusion criteria
All studies published in English and French between September 2022 and September 2024 that presented data on the mpox route of transmission were eligible to be included. Both comparative and non-comparative studies in different settings were included. The following mpox studies were excluded; studies without transmission data, studies solely concerning animal-to-animal or animal-to-human transmission, studies solely examining laboratory transmission, non-original studies, duplicate studies, anecdotal reports, and studies that published in a language other than English and French.
Literature search strategy
The search was done through the 1st of September 2024 using broad search terms including mpox or monkeypox and study types including controlled clinical trial, randomized controlled trial, cohort study, comparative study, controlled study, case report, case study, case series, editorial, commentary, English, French, human, excluding animal, excluding nonhuman, …etc. The details are shown in Supplementary data. The search included the following databases: MEDLINE (OVID), Embase (OVID), Biosis previews (Web of Science), CAB Abstracts (Web of Science), and Global Index Medicus. Additionally, studies discovered during the review process (cross-citations) were included if the inclusion criteria are met. The review authors team instituted several meetings with topic experts up to November 2024.
Data extraction tool
Data extraction was undertaken using Covidence software [17]. Data extraction included the study author, title, year of publication, country in which the study was conducted, year and country where infection was acquired, study design, study setting, number of mpox cases, age and gender, sexual orientation/behavior, route of transmission, and clade and subclade of mpox virus.
Data extraction process
After importing the abstracts obtained by the literature search, ten authors screened the titles and the abstracts for eligibility. The full texts of eligible abstracts were then uploaded to the Covidence software. Each full text was independently reviewed by two-authors for final inclusion in the review. The initial observed agreement was 86.6 % with high kappa statistic (0.727). In case of initial disagreement between the two authors, a final decision was taken through discussion. Extraction of the data was then done using the data extraction and quality assessment templates of Covidence. Duplicate publications (same patients were reported in two publications) and review articles were excluded. Additionally, international studies that most likely reused the same patient data included in original single-country studies were also excluded to avoid double reporting. The details of the extraction process are shown in the PRISMA diagram (Supplementary Figure 1) and the list of included studies are shown in Supplementary data.
Risk of bias assessment
Each included title was independently reviewed by two-authors to assess risk of bias using five questions about the clarity and precision of data concerning patient selection, diagnosis, epidemiologic profile, route of transmission, and sample size (Supplementary Table 1). Standard tools such as Newcastle-Ottawa and ROBIS tools could not be used as the majority (68.5 %) of studies were case reports/series.
Mpox diagnosis
Patients with mpox were identified according to the WHO case definitions of confirmed and probable mpox [18]. A confirmed mpox patient is a patient with positive viral DNA by realtime polymerase chain reaction (RT-PCR) and/or sequencing. Probable mpox patient is a patient presenting with an unexplained acute skin rash, mucosal lesions or lymphadenopathy plus one or more of the followings; epidemiological link to a probable or confirmed case, multiple and/or casual sexual partners, or positive test result for orthopoxviral infection.
Mpox transmission
Routes of transmission were generally considered as defined by the authors of the studies. Nevertheless, the following definitions were also used to further classify the routes of transmission when needed. Close contact transmission was divided into confirmed sexual, suspected sexual, and non-sexual transmission. Confirmed sexual transmission was considered when the original manuscript explicitly described the transmission as sexual or the patient was identified as men who has sex with men (MSM) with lesions in the anogenital region. Suspected sexual transmission was considered when the original manuscript did not explicitly describe any route of transmission but the patient had other sexually transmitted diseases (STD) or was attending a STD clinic. Non-sexual close contact transmission was considered when the patient had skin to skin contact of non-sexual nature. Animal-to-human transmission of mpox was considered when the patient was exposed to animal bites or scratches, or during activities such as hunting, skinning, trapping, cooking, playing with carcasses or eating animals. Multiple routes of transmission were considered when patient was described as having more than one of the above routes of transmission. To clarify the route classification, a diagram showing the sequence of questions used to determine the route of transmission has been added (Supplementary Figure 2).
Statistical analysis
Data were pooled from all studies and analysed. Categorical variables were presented as frequencies and percentages while continuous variables were presented as means and standard deviation (SD) or median and interquartile range (IQR), as appropriate. The association between categorical variables (clade and geographic distribution) and study outcome (route of transmission) were examined using Chi-square test or Fisher exact tests, as appropriate. The association between continuous variables (age and quality score) and the study outcome (route of transmission) were examined using Student t-tests or Mann-Whitney test, as appropriate. All P-values were two-tailed. P-value < 0.05 was considered significant. SPSS (Version 29.0. Armonk, NY: IBM Corp) was used for all statistical analyses.
Results
A total of 222 studies with complete or partial transmission data including 45,553 mpox patients were included in the current analysis. Table 1 shows the characteristics of the studies and patients included. European and American regions were the main source of data; accounting for 82.8 % of studies and 97.1 % of the patients. Fig. 1 shows the distribution of mpox patients by country. The majority of the patients included had their infection diagnosed in 2022 (85.2 %) while the majority of studies were published in 2023 and 2024 (40.0 % and 38.1 %, respectively). Most studies were reported from the healthcare setting (86.5 %). The design was mainly case reports (57.7 %), cross-section studies (16.2 %), and case series (10.8 %). The majority (83.0 %) of patients were reported as part of outbreak management/surveillance. Case reports were the most common study design (57.7 % of all studies) but with very minimal patient contribution (0.3 % of all patients). Out of 222 studies, 29 presented data on the clade of mpox virus; clade IIb (86.2 %), clade Ia (6.9 %), and clade Ib (6.9 %). Fig. 2 shows the distribution of clade data by country. The mean quality score of the studies was 2.9 ± 1.1 (out of 5). Studies above the median score represented 65.3 % of all studies and 97.2 % of all patients.
Table 1.
Characteristics of the studies and Mpox patients included in the systematic review.
|
Number of studies N = 222 |
Number of patients N = 45553 |
|
|---|---|---|
| Region of acquisition of infection | ||
| African region | 7 (3.2 %) | 292 (0.6 %) |
| Eastern Mediterranean region | 11 (5.0 %) | 644 (1.4 %) |
| European region | 100 (45.0 %) | 16009 (35.1 %) |
| Region of the Americas | 84 (37.8 %) | 28227 (62.0 %) |
| Western Pacific region | 20 (9.0 %) | 381 (0.8 %) |
| Total | 222 (100.0 %) | 45553 (100.0 %) |
| Year of acquisition of infection | ||
| Before 2022 | 3 (1.4 %) | 219 (0.5 %) |
| 2022 | 118 (53.2 %) | 38822 (85.2 %) |
| 2022–2024 | 30 (13.5 %) | 6094 (13.4 %) |
| Not mentioned | 71 (32.0 %) | 418 (0.9 %) |
| Total | 222 (100.0 %) | 45553 (100.0 %) |
| Year of publication | ||
| 2022 | 56 (25.2 %) | 9975 (21.9 %) |
| 2023 | 117 (52.7 %) | 18226 (40.0 %) |
| 2024 | 49 (22.1 %) | 17352 (38.1 %) |
| Total | 222 (100.0 %) | 45553 (100.0 %) |
| Patient recruitment setting | ||
| Healthcare (clinics and hospitals) | 192 (86.5 %) | 6804 (14.9 %) |
| Community (household and congregate settings) | 12 (5.4 %) | 933 (2.0 %) |
| Surveillance/outbreak data | 18 (8.1 %) | 37816 (83.0 %) |
| Total | 222 (100.0 %) | 45553 (100.0 %) |
| Study design | ||
| Case report | 128 (57.7 %) | 152 (0.3 %) |
| Case series | 24 (10.8 %) | 537 (1.2 %) |
| Cohort study | 13 (5.9 %) | 1975 (4.3 %) |
| Cross-sectional study | 36 (16.2 %) | 18145 (39.8 %) |
| Outbreak management/surveillance | 4 (1.8 %) | 9919 (21.8 %) |
| Others | 17 (7.7 %) | 14825 (32.5 %) |
| Total | 222 (100.0 %) | 45553 (100.0 %) |
| Clade of mpox virus | ||
| Clade Ia | 2 (6.9 %) | 218 (2.0 %) |
| Clade Ib | 2 (6.9 %) | 56 (0.5 %) |
| Clade IIb | 25 (86.2 %) | 10514 (97.5 %) |
| Total | 29 (100.0 %) | 10788 (100.0 %) |
| Study quality | ||
| Mean quality score (out of 5) | 2.9 ± 1.1 | 2.9 ± 1.1 |
| Score < median (<3) | 77 (34.7 %) | 1276 (2.8 %) |
| Score ≥ median (≥3) | 145 (65.3 %) | 44277 (97.2 %) |
| Total | 222 (100.0 %) | 45553 (100.0 %) |
Fig. 1.
Distribution of mpox patients included in the systematic review by country (N = 45553).
Fig. 2.
Distribution of clade data included in the systematic review by country (N = 29 studies).
As shown in Table 2, 45,553 patients were diagnosed; 77.0 % as confirmed mpox and 23 % as probable mpox. The average age of patients was 33.8 ± 9.4 years and the majority of the patients were adults above 18 years (98.6 %). The majority of the patients were males (93.0 %), followed by females (6.5 %), and lastly transgender and/or nonbinary gender (0.5 %). As shown in Fig. 3, adults above 18 years represented the majority of all gender groups that had both age and gender data reported. Among 20190 patients with sexual orientation/behavior data, the majority of the patients were MSM, (89.1 %), followed by heterosexual women (5.5 %) and heterosexual men (5.3 %). Supplementary Figure 3 shows the prevalence of MSM by country. It should be noted that more than half (55.7 %) of sexual orientation/behavior data was missing.
Table 2.
Characteristics and routes of transmission of Mpox among patients included in the systematic review.
| Number of patients (%) | |
|---|---|
| Type of diagnosis | |
| Lab confirmed | 35075 (77.0 %) |
| Probable* | 10493 (23.0 %) |
| Total diagnoses | 45553 (100.0 %) |
| Age (years) | |
| Mean±standard deviation (years) | 33.8 ± 9.4 |
| Age 0–5 years | 59 (0.1 %) |
| Age 5–18 years | 539 (1.3 %) |
| Age > 18 years | 40721 (98.6 %) |
| Total patients with age data | 41319 (100.0 %) |
| Missing age data** | 4234 (9.3 %) |
| Gender | |
| Males (cis) | 39542 (93.0 %) |
| Females (cis) | 2752 (6.5 %) |
| Trans and/or nonbinary | 204 (0.5 %) |
| Total patients with gender data | 42498 (100.0 %) |
| Missing gender data** | 3055 (6.7 %) |
| Sexual orientation/behavior | |
| Men who have sex with men (MSM) | 17994 (89.1 %) |
| Heterosexual men | 1077 (5.3 %) |
| Heterosexual women | 1119 (5.5 %) |
| Total patients with sexual orientation/behavior data | 20190 (100.0 %) |
| Missing sexual orientation/behavior data** | 25363 (55.7 %) |
| Routes of transmission | |
| Sexual contact | 30813 (95.3 %) |
| Close non-sexual contact | 930 (2.9 %) |
| Multiple/other routes | 574 (1.8 %) |
| Total patients with transmission data | 32317 (100.0 %) |
| Missing mode of transmission data** | 13538 (29.5 %) |
* The majority (97 %) of probable diagnosis was derived from a single study that presented combined data for confirmed and probable. Therefore, it was conservatively considered as probable
** Missing data percentage was calculated relative to data of all patients included in the systematic review.
Fig. 3.
Age and gender distribution of Mpox patients included in the systematic review (N = 45553).
Among 32317 patients with transmission data, sexual contact was by far the most common (95.3 %) route of transmission of mpox, which was further divided into confirmed (65.1 %) and suspected (30.3 %) sexual transmission (Table 2 and Fig. 4). Additionally, Supplementary Figures 4 and 5 show the major route of transmission by country. Other described routes of transmission included close non-sexual contact (2.9 %), multiple routes (0.83 %), animal exposure (0.48 %), fomite/environmental exposure (0.36 %), percutaneous injury (0.09 %), transplacental/perinatal (0.01 %), and droplet (0.003 %). There was no inhalation route of transmission reported. It should be noted that 29.5 % of the routes of transmission data was missing (typically reported to subset of included patients).
Fig. 4.
Routes of transmission of Mpox among all patients included in the systematic review (N = 32317).
Amongst all studies, clade data were reported in 29 (13.1 %) studies including 10788 (23.7 %) patients. Table 3 shows the sexual orientation/behavior by clade. Sexual orientation/behavior data were largely missing in clade Ia studies (99.5 %) and to a less extent in clade IIb studies (85.6 %, p < 0.001). MSM were significantly higher in clade IIb studies while heterosexual men and women were significantly higher in clade Ib studies (p < 0.001 for all). Table 3 and Fig. 5 show routes of transmission by clade. Transmission data was more frequently missing in clade IIb studies than other studies (p < 0.001). Confirmed sexual contact transmission was significantly higher in clade IIb and clade Ib studies but lacking in clade Ia studies (p < 0.001). Close non-sexual contact transmission was significantly higher in clade Ia studies (p < 0.001). Exposure to animals or its products was seen only in clade Ia studies (p < 0.001). Multiple routes of transmission were significantly higher in clade Ia and Ib studies compared with clade IIb studies (p < 0.001).
Table 3.
Sexual orientation/behavior and possible routes of Mpox transmission by the reported clade among patients included in the systematic review.
| Clade Ia | Clade Ib | Clade IIb | Total | p-value | |
|---|---|---|---|---|---|
| Number of studies | 2 | 2 | 25 | 29 | |
| Number of patients | 218 | 56 | 10514 | 10788 | |
| Sexual orientation/ behavior | |||||
| MSM | 0 (0.0 %) | 3 (5.8 %) | 1486 (98.2 %) | 1489 (95.1 %) | <0.001 |
| Heterosexual men | 0 (0.0 %) | 27 (51.9 %) | 16 (1.1 %) | 43 (2.7 %) | <0.001 |
| Heterosexual women | 1 (100.0 %) | 22 (42.3 %) | 11 (0.7 %) | 34 (2.2 %) | <0.001 |
| Total patients with data | 1 (100.0 %) | 52 (100.0 %) | 1513 (100.0 %) | 1566 (100.0 %) | -- |
| Missing data* | 217 (99.5 %) | 4 (7.1 %) | 9001 (85.6 %) | 9222 (85.5 %) | <0.001 |
| Routes of transmission | |||||
| Confirmed sexual contact | 0 (0.0 %) | 29 (51.8 %) | 6020 (88.1 %) | 6049 (81.8 %) | <0.001 |
| Suspected sexual contact | 0 (0.0 %) | 0 (0.0 %) | 228 (3.3 %) | 228 (3.1 %) | <0.001 |
| Close non-sexual contact | 86 (17.0 %) | 0 (0.0 %) | 580 (8.5 %) | 666 (9.0 %) | <0.001 |
| Exposure to animals or its products | 156 (30.89 %) | 0 (0.00 %) | 0 (0.00 %) | 156 (2.11 %) | <0.001 |
| Multiple routes | 205 (40.6 %) | 27 (48.2 %) | 0 (0.0 %) | 232 (3.1 %) | <0.001 |
| Other routes | 58 (11.5 %) | 0 (0.0 %) | 2 (0.0 %) | 60 (0.8 %) | <0.001 |
| Total patients with data | 505 (100.0 %) | 56 (100.0 %) | 6830 (100.0 %) | 7391 (100.0 %) | -- |
| Missing data* | 1 (0.2 %) | 0 (0.0 %) | 3684 (35.0 %) | 3685 (33.3 %) | <0.001 |
* Missing data percentage was calculated relative to all patients included in the systematic review. Most studies have no clade information. There was no 2 A clade reported. MSM, men who have sex with men.
Fig. 5.
Routes of transmission of Mpox among patients with clade data included in the systematic review (N = 7391).
Table 4 shows the sexual orientation/behavior and routes of transmission by WHO region. Sexual orientation/behavior data were considerably missing in all regions with the exception of the Western Pacific region. MSM were the most frequent group affected in all regions with the exception of the African region (p < 0.001). Heterosexual men and women were significantly more affected in the African region than the other regions (p < 0.001). Transmission data was more frequently missing in Eastern Mediterranean region, European region, and region of the Americas than other regions (p < 0.001). Confirmed sexual contact transmission was the most common route of transmission in all WHO regions with the exception of the African region (p < 0.001). Close non-sexual contact transmission and multiple routes of transmission were significantly higher in the African region compared with other regions (p < 0.001 for both). Exposure to animals or its products was seen only in the African region (p < 0.001).
Table 4.
Sexual orientation/behavior and possible routes of Mpox transmission by WHO region among patients included in the systematic review.
| AFRO Region | Eastern Mediterranean Region | European Region | Region of the Americas | Western Pacific Region | Total | p-value | |
|---|---|---|---|---|---|---|---|
| Number of studies | 7 | 11 | 100 | 84 | 20 | 222 | |
| Number of patients | 292 | 644 | 16009 | 28227 | 381 | 45553 | |
| Sexual orientation/behavior | |||||||
| MSM | 4 (5.6 %) | 201 (82.0 %) | 6561 (97.8 %) | 10877 (84.9 %) | 351 (98.9 %) | 17994 (89.1 %) | <0.001 |
| Heterosexual men | 35 (49.3 %) | 42 (17.1 %) | 129 (1.9 %) | 867 (6.8 %) | 4 (1.1 %) | 1077 (5.3 %) | <0.001 |
| Heterosexual women | 32 (45.1 %) | 2 (0.8 %) | 16 (0.2 %) | 1069 (8.3 %) | 0 (0.0 %) | 1119 (5.5 %) | <0.001 |
| Total patients with data | 71 (100.0 %) | 245 (100.0 %) | 6706 (100.0 %) | 12813 (100.0 %) | 355 (100.0 %) | 20190 (100.0 %) | -- |
| Missing data* | 221 (75.7 %) | 399 (62.0 %) | 9299 (58.1 %) | 15410 (54.6 %) | 26 (6.8 %) | 25355 (55.7 %) | <0.001 |
| Routes of transmission | |||||||
| Confirmed sexual contact | 47 (8.1 %) | 361 (99.4 %) | 9047 (82.7 %) | 11259 (56.1 %) | 311 (84.5 %) | 21025 (65.1 %) | <0.001 |
| Suspected sexual contact | 0 (0.0 %) | 1 (0.3 %) | 1091 (10.0 %) | 8646 (43.1 %) | 50 (13.6 %) | 9788 (30.3 %) | <0.001 |
| Close non-sexual contact | 86 (14.9 %) | 0 (0.0 %) | 720 (6.6 %) | 119 (0.6 %) | 5 (1.4 %) | 930 (2.9 %) | <0.001 |
| Exposure to animals or its products | 156 (26.94 %) | 0 (0.0 %) | 0 (0.0 %) | 0 (0.0 %) | 0 (0.0 %) | 156 (0.48 %) | <0.001 |
| Multiple routes | 232 (40.1 %) | 0 (0.0 %) | 37 (0.3 %) | 0 (0.0 %) | 0 (0.0 %) | 269 (0.8 %) | <0.001 |
| Other routes | 58 (10.0 %) | 1 (0.3 %) | 38 (0.3 %) | 50 (0.2 %) | 2 (0.5 %) | 149 (0.5 %) | <0.001 |
| Total patients with data | 579 (100.0 %) | 363 (100.0 %) | 10933 (100.0 %) | 20074 (100.0 %) | 368 (100.0 %) | 32317 (100.0 %) | -- |
| Missing data* | 1 (0.2 %) | 281 (43.6 %) | 5090 (31.8 %) | 8153 (28.9 %) | 13 (3.4 %) | 13538 (29.5 %) | <0.001 |
Missing data percentage was calculated relative to data of all included patients. There were no transmission data included from South-East Asia Region. MSM, men who have sex with men.
Supplementary Tables 2 and 3 show the main study findings by the study design and study quality. As shown in Supplementary Table 2, MSM was the main study group in all designs (86.4–100.0 %). Additionally, sexual contact was the main route of transmission in all designs, with lower frequency in cohort studies than the rest of designs (64.4 % versus 87.1 %-99.9 %). As shown in Supplementary Table 3, no major differences in the main study findings by quality of the study. For example, MSM group (87.4 % versus 89.2 %) and sexual transmission (90.9 % versus 95.5 %) were very prevalent in both low-quality and high-quality studies, respectively.
Discussion
The current review included data of more than 45,000 mpox patients published in 222 studies between September 2022 and September 2024. It is an update of the previously published systematic review that covered the period up to September 2022 of the ongoing mpox multi-country outbreak [9]. Compared with the preliminary report [9], the current review includes a 10-fold larger data and consequently the findings were stratified by geographic region and virus clade. Similar to the preliminary report [9], the current report was based on observational studies with no evidence from randomized controlled trials or other comparative studies about transmission and its prevention. The patients included in the current review were largely confirmed cases of mpox.
The key finding of the current review is the predominance of sexual contact (95 %) as a route of transmission. This is consistent with the findings of previous reports that identified sexual contact as the main route of transmission during the 2022 multi-country outbreak [9], [10], particularly among MSM [11], [12]. There has been a debate about considering mpox as a sexually transmitted infection (possibly transmitted through sex) or sexually transmitted disease (predominantly transmitted through sex) [19], [20]. Whilst recognising that mpox can be transmitted through sexual and non-sexual routes, it can be potentially transmitted by multiple routes during intimate sexual behavior [20]. Many reports were not explicit about the route of transmission and therefore the authors had to differentiate between confirmed (explicitly reported) and suspected (not explicitly reported), as described in the methods. However, the higher burden among MSM, the isolation of the virus from sexual fluids, and the high frequency of early anogenital lesions in the 2022–2024 multi-country outbreak suggest direct inoculation during sexual activities [21]. On the other hand, such categorization could be stigmatizing and may be harmful for preventive activities [20].
This review did not find any evidence suggesting airborne transmission of mpox. This is despite the evidence confirming the detection of the mpox virus in air samples collected from the patient's environment [22], [23]. It should be that PCR cannot distinguish between infectious (viable) and non-infectious viruses [23]. Additionally, droplet transmission was derived from a single study only describing 12 breakthrough infections after postexposure vaccination against mpox [24]. Droplet transmission was defined in that study as the presence of the exposed person without masks at less than 2 m during at least 3 h with a PCR-confirmed mpox patient [24]. There were 11 reported droplet cases, 10 of which were mixed with indirect or sexual transmission [24]. The probable lack of “through the air transmission” in the current multi-country outbreak may be considered a cornerstone of its limited global spread between 2022 and early 2024 [6], [25], [26].
The findings of the current review indicate that geographic differences in mpox transmission reflect differences in virus clade and human behavior as opposed to real geographic differences. For example, contact transmission of sexual nature was the main route of transmission in all WHO regions, with exception of the African region. On the other hand, the African region was characterized by animal to human transmission and higher close non-sexual contact as well as multiple routes of transmission. The different African/global profile of mpox transmission was possibly caused by the different clades that favour specific routes of transmission. For example, African studies reporting clade data were either clade Ia which was mainly transmitted by non-sexual routes [27], [28] or clade Ib which was equally transmitted by sexual and non-sexual routes [29], [30]. On the other hand, studies outside Africa reporting clade data exclusively reported clade IIb which was predominantly transmitted by sexual contact [31], [32], [33], [34]. Furthermore, practices and sexual orientation/behavior were driving factors in such geographic differences. For example, exposure to infected animals and their products in Africa and higher reported prevalence of MSM social networks outside Africa.
The findings of the current review should be understood while considering patient selection in individual studies. The majority of transmission data were derived from studies or surveillance bodies targeting social networks of sexual nature for case finding and management. This may have overestimated the role of MSM and close contact of sexual nature in the current pandemic. On the other hand, mpox stigmatization in some communities may force patients to hide their sexual orientation/behavior or possible route of transmission. This may explain the underreporting of sexual orientation/behavior, which was available in less than half of patients. However, the impact of these selection biases is probably minimal, due to opposite direction (as shown above) and the consistency of the findings across different study designs and quality.
A key strength of this review was the inclusion of a large number of patient data (>45,000 patients in 222 studies). This allowed the study of mpox transmission in relation to virus clade, geography, and sexual orientation/behavior. As the included studies were published between 2022 and 2024, these findings should be relevant to determining the preventive and control activities of the current multi-country outbreak. This is important as the epidemiology of mpox has dramatically changed in the last few decades [1], [2]. Nevertheless, a number of limitations in this study should be considered. The quality and design of included studies were quite variable and heterogeneity was probably high. The impact of this is probably minimal as a sub-analysis of the major findings by the study quality and design showed no major deviation from the overall study findings. Data concerning the route of transmission were typically based on patient self-reporting. Additionally, the route of transmission in many studies were not explicitly reported or partially missing, probably due to lack of such information or the complexity of defining a specific route. While this unlikely to change the predominance of close contact of sexual nature as the main route of transmission, it may limit the ability to assess rare routes of transmission. Similarly, clade data were available only for a subset of studies with the majority of reported cases were of clade IIb. Since only minority of patients were from the African region (mainly clade I), missing clade data unlikely to change the predominance of clade IIb in the current pandemic. On the other hand, the small number of studies from the African region may limit the power to assess clade Ia and Ib transmission.
Conclusions
The current study reviewed the data of mpox transmission in a large number of patients during the 2022–2024 multi-country outbreak. In more than 95 % of the patients with non-missing data, transmission is predominantly through close contact of sexual nature among typically adult males (mostly caused by clade IIb). Multiple routes of transmission including animal to human transmission were observed in the African region (mostly caused by clade Ia and Ib). The findings can support the formulation/update of infection control recommendations, including customizing the infection control recommendations by clades/geographic region. Additionally, interventional and comparative studies are required to further test the effectiveness of different interventions (including available vaccines) in reducing transmission of various clades. The frequent missing of clade data may indicate the need of large molecular biology studies, specially in under-represented regions such as African region. The frequent missing of some culturally sensitive information may indicate the need to set minimum standards for data quality and completeness by surveillance bodies. Finally, it is suggested this review is regularly updated to cope with the changing epidemiology of mpox and its underlying global clade distribution.
Authors' contributions
Majid M. Alshamrani, Aiman El-Saed, April Baller, Victoria Willet, Hibak Mahamed, Fatmah Othman, Hannah Hamilton Hurwitz, Tom Fletcher, Tochi Okwor: idea, concepts, data interpretation, and final review. Aiman El-Saed, Sarah Alfayez, Kholod AlAmeer: Data extraction, data analysis, and final review. Mohammed Al Zunitan, Mohammed Abalkhail, Fayssal Farahat, Syed Nazeer, Wafaa Al Nasser, Maher Alharbi: Data extraction and final review.
Ethical approval
This project received the approval of the Research Ethics Committee of King Abdullah International Medical Research Center (protocol reference number NRR24/100/12).
Funding source
None.
Declaration of Competing Interest
The authors declare no conflicts of interest.
Acknowledgment
Authors are deeply grateful for Dr Gordon Guyatt (McMaster University, Hamilton, Canada) for his helpful support during planning and conduct of this review.
Footnotes
Supplementary data associated with this article can be found in the online version at doi:10.1016/j.jiph.2025.102985.
Appendix A. Supplementary material
Supplementary material
Supplementary material
Supplementary material
Supplementary material
Supplementary material
Data availability
The datasets used and analyzed during the current study are available from the corresponding author on reasonable request and after approval of the IRB.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplementary material
Supplementary material
Supplementary material
Supplementary material
Supplementary material
Data Availability Statement
The datasets used and analyzed during the current study are available from the corresponding author on reasonable request and after approval of the IRB.
