(1) Background: In early May 2022, an increasing number of human monkeypox (mpox) cases were reported in non-endemic disparate regions of the world, which raised concerns. Here, we provide a systematic review and meta-analysis of mpox-confirmed patients presented in peer-reviewed publications over the 10 years before and during the 2022 outbreak from demographic, epidemiological, and clinical perspectives. (2) Methods: A systematic search was performed for relevant studies published in Pubmed/Medline, Embase, Scopus, and Google Scholar from 1 January 2012 up to 15 February 2023. Pooled frequencies with 95% confidence intervals (CIs) were assessed using the random or fixed effect model due to the estimated heterogeneity of the true effect sizes. (3) Results: Out of 10,163 articles, 67 met the inclusion criteria, and 31 cross-sectional studies were included for meta-analysis. Animal-to-human transmission was dominant in pre-2022 cases (61.64%), but almost all post-2022 reported cases had a history of human contact, especially sexual contact. The pooled frequency of MSM individuals was 93.5% (95% CI 91.0-95.4, I2: 86.60%) and was reported only in post-2022 included studies. The male gender was predominant in both pre- and post-2022 outbreaks, and the mean age of confirmed cases was 29.92 years (5.77-41, SD: 9.38). The most common clinical manifestations were rash, fever, lymphadenopathy, and malaise/fatigue. Proctalgia/proctitis (16.6%, 95% CI 10.3-25.6, I2: 97.76) and anal/perianal lesions (39.8%, 95% CI 30.4-49.9, I2: 98.10) were the unprecedented clinical manifestations during the 2022 outbreak, which were not described before. Genitalia involvement was more common in post-2022 mpox patients (55.6%, 95% CI 51.7-59.4, I2: 88.11). (4) Conclusions: There are speculations about the possibility of changes in the pathogenic properties of the virus. It seems that post-2022 mpox cases experience a milder disease with fewer rashes and lower mortality rates. Moreover, the vast majority of post-2022 cases are managed on an outpatient basis. Our study could serve as a basis for ongoing investigations to identify the different aspects of previous mpox outbreaks and compare them with the current ones.
Keywords: clinical manifestations; lymphadenopathy; monkeypox; mortality; mpox; outbreak; rash.