Mpox is a re-emerging zoonotic viral disease caused by the mpox virus (Farahat et al., 2022). Mpox virus is a double-stranded DNA virus of the genus Orthopoxvirus of the family Poxviridae that encodes approximately 190 kinds of proteins. These proteins play important roles in DNA replication, transcription, and virion assembly and contribute to promoting activation of and escape from the host immune system (Srivastava et al., 2023). This virus was first reported in the Democratic Republic of the Congo in 1970 (Bunge et al., 2022). The USA reported the first human outbreak outside Africa in July 2003, with 71 nonfatal cases related to 800 specimens from six genera of African rodents imported from Ghana (Centers for Disease Control and Prevention (CDC), 2003). On May 6, 2022, a British national who returned from Nigeria was diagnosed with mpox after a fever rash, marking the beginning of the 2022 epidemic (Girometti et al., 2022). On July 23, 2022, following an accumulation of 3,040 cases in 47 countries, the World Health Organization (WHO) declared mpox as a Public Health Emergency of International Concern, which was lifted on May 11, 2023 (Taylor, 2022; World Health Organization, 2025). There are two distinct clades of the virus. The symptoms caused by Clade I from Central Africa are more severe, with a mortality rate often exceeding 10%. Its ability to spread among humans is relatively limited, and it is mostly transmitted from animals or through close contact. Clade II causes a milder condition, with a mortality rate typically less than 1%, and it is further divided into clades IIa and IIb. Clade IIa is prevalent mainly in West Africa. Clade IIb was the main strain that caused global outbreaks in 2022 and beyond, with significantly higher infectivity than IIa and demonstrating efficient interpersonal transmission ability, usually through close or intimate contact, including sexual networks, especially in nonendemic regions (Antunes et al., 2022; Bunge et al., 2022). The incubation period of mpox is 7 to 14 days, and the longest is 21 days, during which there is no clinical manifestation of viral disease (Hussain et al., 2022). The incubation period is followed by the prodromal period, when individuals may have various symptoms, including lymphadenopathy, fever, headache, myalgia and fatigue (Huhn et al., 2005). Mpox is a systemic disease that presents in most patients with skin lesions, and the vesiculopustules are firm, difficult to deroof, and lack fluid content after deroofing (Khanna et al., 2023).

The definition of epidemiological cases, especially at the beginning of an epidemic, always has high sensitivity and low specificity (El-Gilany, 2021; Nunez et al., 2022). In practice, there may also be differences in the timeliness and consistency of adoption and application in different countries, regions, and even medical institutions. Some healthcare workers lack appropriate training and experience in diagnosing mpox cases, especially in nonendemic areas (Tarín-Vicente et al., 2022; Thornhill et al., 2022). Although cutaneous manifestations are signs of mpox, other diseases, such as syphilis, rickettsial pox, scabies, molluscum contagiosum and varicella zoster, present with similar rashes (Cowen et al., 2023; Hussain et al., 2022). Polymerase chain reaction (PCR) is the gold standard for mpox diagnosis, but in less developed countries or regions, PCR testing cannot achieve complete coverage. For instance, in the Democratic Republic of the Congo, only the national reference laboratory in Kinshasa, the capital, can perform PCR testing, while endemic areas are often located in remote areas (Mande et al., 2022). The purpose of this study was to compare and analyze the clinical and epidemiological characteristics of patients with mpox and patients without mpox among suspected cases, which may help differentiate mpox infection from alternative diagnoses. During and after the 2022 outbreak, the clades of the virus, their transmission routes, outbreak area, lesion site and disease severity were quite different from those of the previous mpox epidemic (Antunes et al., 2022; Ogoina et al., 2020; Thornhill et al., 2022; Yinka-Ogunleye et al., 2019). For the sake of rigorous results, we did not include data prior to 2022.

This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement (PROSPERO registration number: CRD420251141869).

The recent global mpox outbreaks attracted significant attention from the field of evidence-based medicine (Brochero et al., 2025). Our study focused on the epidemiological and clinical differences between mpox and non-mpox patients among suspected cases. The prevalence of mpox was as high as 54%, which was much higher than the infection risk of the general population. It is highly reasonable and accurate for clinicians to list such patients as suspected cases, reflecting an active and dense virus transmission network. More than half of the suspected cases were confirmed, emphasizing a necessity for maintaining a high level of vigilance regarding such epidemiological and clinical characteristics.

Our study revealed that the predominance of men among the confirmed patients (OR = 9.94) and the large OR of MSM (OR = 11.52) were the most significant demographic characteristics compared with patients without mpox. In terms of transmission routes, sexual contact appeared to be the primary mode of virus spread during and after the 2022 outbreak of mpox. Nonsexual contact and transmission through health services were relatively rare. During June and July 2022, adult mpox virus infections were detected at four educational institutions in England. However, no secondary cases occurred among the 340 exposed students and more than 100 exposed staff members (Ladhani et al., 2022). A study from Colorado, USA, revealed that 313 healthcare workers who had different degrees of contact with mpox patients during patient care or through contaminated materials did not have mpox transmission (28% of healthcare workers were considered to have had high- or intermediate-risk exposures) (Marshall et al., 2022). However, in addition to sexual behavior, other, unexpected types of transmission do exist. For example, poor hygiene practices/instrument cleaning was associated with 20 mpox cases associated with a Spanish tattoo and piercing establishment (Garcia et al., 2022).

The exposure findings are consistent with sexual transmission as a key route: confirmed patients were more likely to report recent sexual intercourse, multiple sexual partners, and anal sex. The sexual networks among MSM are similar to those of other groups, but the core groups are more densely connected, with frequent partner changes and multiple concurrent partners, reducing the likelihood of the virus encountering transmission barriers (Kupferschmidt, 2022). Together, these behavioral factors are consistent with an efficient virus transmission model: dense sexual networks may facilitate transmission pathways; having multiple sexual partners could expand the number of potentially exposed individuals; and anal sex might be associated with a higher likelihood of transmission due to the fragile mucosal tissue of the anus, which is more susceptible to micro- or macrodamage.

Our study revealed that the prevalence of HIV, syphilis and gonorrhea in confirmed patients was significantly greater, suggesting the importance of screening for STIs during the evaluation of suspected mpox cases and highlighting the well-established fact that having an STI amplifies the risk of acquiring additional STIs (Gandhi et al., 2019). Notably, among HIV-negative people, more mpox patients used PrEP. However, this association does not imply that PrEP drugs increase mpox susceptibility. It may be explained by the disproportionately high proportion of MSM among the mpox patients. Costa et al. reported that PrEP users tended to have more sexual partners, and this measure was adopted mainly by MSM with a university education level or who had completed higher education (Costa et al., 2023). The high prevalence of proctitis in mpox patients is also related to MSM. A study by Hens et al. revealed that the anorectum was the site of most intense viral replication in patients with mpox who reported anal sex (Hens et al., 2023). Valerio et al. reported that it was important for doctors to test for mpox in any patient with proctitis among MSM. A rectal swab should be taken for mpox virus PCR, even if the patient does not appear to have mucocutaneous lesions at the time (Valerio et al., 2023).

One point that needs to be emphasized is that although the finding that MSM is significantly associated with mpox infection has certain guiding value for concentrating public health resources and implementing precise interventions (such as targeted health education, vaccination, and promotion of pre-exposure prophylaxis), this epidemiological characteristic must be viewed with caution to avoid stigma and discrimination against the MSM community. In fact, some countries and regions even criminalize same-sex relationships among MSM (Ogoina et al., 2024). The WHO has warned that stigma toward specific groups may hinder patients from seeking timely medical treatment, undermine community trust, and ultimately weaken the effectiveness of epidemic prevention (WHO, 2022b). Importantly, mpox can infect individuals of any sexual orientation. Public health information transmission and intervention measures should not only effectively identify and cover high-risk groups but also balance ethical principles that promote social inclusion and ensure health equity.

Skin lesions in confirmed patients were primarily concentrated in the genital and perianal areas. This “genital–perianal” distribution is somewhat consistent with the hypothesis of “inoculation transmission”, which suggests that during sexual contact, the virus may be directly inoculated into tiny wounds in these parts through close friction between skin and skin or between skin and mucosa, thus completing initial replication and causing lesions (Patrocinio-Jesus and Peruzzu, 2022). In contrast, the lesions of patients without mpox were more common in the palms, soles and neck. This distribution was more in line with the typical manifestations of other pathogens (such as hand-foot-mouth disease) or noninfectious diseases (such as atopic dermatitis) (Esposito and Principi, 2018; Ramirez-Marin and Silverberg, 2022). We also found that pustules were more common in mpox patients, which was in line with the natural course of mpox virus infection. Mpox skin lesions usually go through the stages of maculae, papulae, vesicles, pustules and scabs. The appearance of pustules marks the inflammatory reaction peak and is a relatively specific stage of the disease (Lim et al., 2024).

In terms of symptoms, mpox patients showed stronger characteristics of systemic viremia. Fever, lymphadenopathy, myalgia and diarrhea are all signs that the virus has spread in the body and has triggered a systemic immune response. Among these, lymphadenopathy is considered to be a key clinical characteristic that distinguishes mpox from chickenpox (Patel et al., 2023). However, respiratory symptoms such as cough and sore throat did not significantly differ between mpox patients and non-mpox patients, further reducing the importance of respiratory transmission during and after 2022 epidemic.

Non-mpox patients and mpox patients may show some specific differences in their rashes according to different causes. Taking viral infection as an example, the cutaneous manifestations of secondary syphilis are diverse. In addition to presenting as papulae or pustules, it can also present as condylomata lata, mucous patches, or split papulae. The latter manifestations are specific to syphilis, as no such similarities are found in mpox; thus, these are among the clinical characteristics that differentiate mpox and syphilis (Cohen et al., 2013). Moreover, secondary syphilis rashes are not pruritic and can be minimal enough to be ignored. At the same time, lesions related to mpox are usually painful (Hussain et al., 2022). Herpes zoster lesions often appear everywhere in waves, and the pain intensity is much greater than that of mpox lesions. In some individuals, the pain may be so severe that anesthetic administration is needed (Freer and Pistello, 2018). In many cases, the pain persists for several months after the rash subsides in a phenomenon termed postherpetic neuralgia (Hussain et al., 2022). Once all lesions form scabs, herpes zoster lesions are usually regarded as having low infectivity, even though viral DNA is still recoverable by PCR at this stage (Mols et al., 2013). In contrast, scabs associated with mpox lesions are considered highly infectious until complete re-epithelialization occurs (Cowen et al., 2023).

In our study, various confounding factors may have influenced the pooled estimates to varying degrees. Owing to the increased prevalence of behaviors such as dense sexual networks and multiple sexual partners among young MSM populations, age may indirectly regulate certain ORs by affecting sexual behavior patterns. Our study revealed no statistically significant difference in age between mpox and non-mpox patients, suggesting that age might not be a strong confounding factor in our sample. We conducted a subgroup analysis by region and found that mpox prevalence varied significantly across continents (60% in South America and 44% in Asia). In our heterogeneity analysis, we found that for a few highly heterogeneous results, regional subgroup analysis could significantly reduce heterogeneity, supporting regions as an important moderating variable. Nevertheless, our sample included data from 16 countries, which provided good geographical diversity, and most results showed low to moderate heterogeneity. This suggests that regional differences might not be the primary confounding source of all associations; HIV infection is a potential confounder on which we focused. Our results showed that there were more HIV-infected individuals among mpox patients, and PrEP use was more common among HIV-negative individuals. This indicates that HIV infection or HIV-related risk behaviors (such as multiple sexual partners) might be collinear with mpox infection and that sexual behavior-related ORs might be partially confounded by the high-risk behaviors of the HIV-infected population.

We performed a detailed study on the epidemiological and clinical differences between mpox and non-mpox patients among suspected cases during the recent global mpox outbreaks, which provides some reference for clinicians in the diagnosis and differentiation of mpox. These differential characteristics are probabilistic indicators rather than definitive diagnostic tests. Their clinical utility lies in increasing or reducing the prior probability of clinical diagnosis, thereby optimizing the use of medical resources. During triage or initial diagnosis, especially when PCR testing is delayed, if suspected cases exhibit these characteristics, it is advisable to trigger isolation measures and prioritize testing.

The recent global mpox epidemic was a profound lesson, once again highlighting the complex mode of interaction between novel infectious diseases and specific social behavior networks. By scientifically understanding these models, healthcare workers can not only address this epidemic more effectively but also be more fully prepared for the inevitable challenges of future emerging infectious diseases.