Risk profile and mode of transmission of Mpox: A rapid review and individual patient data meta‐analysis of case studies

Since May 2022, an outbreak of Mpox in non‐endemic countries has become a potential public health threat. The objective of this rapid review was to examine the risk profile and modes of transmission of Mpox. PubMed, Web of Science, and Scopus were searched from inception through July 30 to collect case reports/series on patients with Mpox infection. For meta‐analysis, data on the total number of participants and deaths by binary categories of exposure (age, sex, country, other co‐infections or existing conditions, and mode of contagion) were used. A total of 62 studies (4659 cases) were included. Most cases came from Africa (84.3%), followed by Europe (13.9%). In 63.6% of the cases, the mode of contagion was human contact, while 22.8% of the cases were by animal contact, and 13.5% were unknown or not reported. The mortality rate was 6.5% throughout these studies. The risk of mortality was higher in the younger age group (risk difference: 0.19; 95% CI: 0.02–0.36), in cases with other co‐infections or current chronic conditions (risk difference: 0.03; 95% CI: 0.01–0.05) and in the category of low‐ and middle‐income countries (risk difference: 0.06; 95% CI: 0.05–0.08). There were no significant differences with respect to sex or mode of contagion. These results help to understand the major infection pathways and mortality risk profiles of Mpox and underscores the importance of preventing outbreaks in specific settings, especially in settings densely populated by children, such as day care centres and schools.


| INTRODUCTION
Mpox is a viral zoonosis endemic to West and Central Africa. It was first identified in the Democratic Republic of Congo in 1970. 1,2 Since then, several outbreaks of Mpox in humans have been regularly reported in African countries. 3 The first outbreak of Mpox outside Africa occurred in the United States of America in 2003 and was linked to the importation of infected Gambian giant rats that infected the prairie dogs' pets. 4 Between 2018 and 2022, sporadic cases have also been reported in travellers from Africa to Israel, 5 Singapore, 6 and the United Kingdom. 7 In May 2022, multiple cases of Mpox were identified in several non-endemic countries, On July 25th, the World Health Organization declared the spread of Mpox infection as a 'public health emergency of international concern'. Since the beginning of the current Mpox outbreak, until 27 September 2022, 20,083 confirmed cases have been reported in 29 EU/EEA countries, mainly in Spain, Germany, France and the Netherlands. 8 Thus, in recent months, there has been a major resurgence of Mpox outbreaks.
Mpox virus is a DNA virus belonging to the genus Orthopoxvirus that is transmitted to humans through close contact with a person (lesions, body fluids, respiratory droplets), by contact with an infected animal or by material contaminated with the virus (e.g. bedding). 9,10 This infection is characterised as self-limiting (symptoms last 2-4 weeks) and usually presents clinically with fever, rash and swollen lymph nodes. 11 Complications are frequent (e.g. secondary bacterial infections), severe cases are more common in children and the mortality rate is approximately 3%-6%. 12 Polymerase chain reaction (PCR) is the laboratory test of choice for diagnosis, given its very high accuracy and sensitivity. 12,13 More confirmed cases of Mpox have been reported since 2016 than in the previous 40 years. 1 Most of the current cases are those with a previous or concomitant sexually transmitted infection. 14 Indeed, the first case of Mpox virus, SARS-CoV-2 and human immunodeficiency virus (HIV) co-infection was recently reported, and health systems should be alert to this eventuality. 14 Thus, Mpox has become the most important orthopoxvirus of concern for public health. Since there is no specific treatment, objective data on modes of transmission and groups with increased vulnerability are needed. Thus, the objective of this rapid review was to analyse the risk profile and modes of transmission of Mpox in cases reported in the literature in any clinical setting.

| METHODS
This study follows the recommended guidelines for conducting rapid reviews, 15 and in accordance with the PRISMA 2020 guidance. 16 As this was a rapid review, patients and the public were not involved in the design, conduct, or reporting of this study.

| Search strategy
Two of the authors (RL-B and RN-C) conducted a systematic search in PubMed, Web of Science and Scopus from inception to 30 July 2022 (Table S1). Only articles in the English language were considered. The aforementioned authors independently screened records, abstracts, and full text articles using the free web version of Rayyan (http://rayyan.qcri.org). 17 Thereupon, they independently extracted data, and when there was no consensus, a third reviewer was consulted (JC). The reference lists of all retrieved studies were screened to identify additional studies that met inclusion criteria.

| Inclusion criteria
We included any study that described any patients with Mpox infection either confirmed or highly suspected, from any clinical setting. Study designs eligible for inclusion were both case reports and case series. We excluded reviews, editorials, other qualitative, cross sectional, case-control, cohort studies as well as grey literature.

| Data extraction
Two authors (RL-B and RN-C) independently extracted data using a standardised form. Retrieved data encompassed author, year of publication, country, number of cases, sex, age, ascertainment of the infection, mode of transmission, other current co-infections or chronic conditions, and number of deaths. For quantitative analyses, we used data on total number of participants and deaths per exposure categories. This included sex, categorised age (i.e., 18 years old as cut-off point), country (developed or low-and middle-income countries according to United Nations identification criteria and indicators), 18 modes of infection, and co-infection or other current chronic conditions.

| Quality assessment
Quality was assessed using the tool provided by Murad et al. 19 for methodological quality assessment and synthesis of case series and case reports. This comprises eight items clustered in four domains: selection, ascertainment, causality, and reporting. Because items 4, 5, and 6 are only relevant to studies of adverse drug events, we did not consider them for the present study. Thus, a score of 5 was considered as the highest quality. Two reviewers (RL-B and RN-C) conducted this assessment independently. Discrepancies or disagreements between the reviewers' judgements were resolved by consensus with a third reviewer (JC).

| Statistical analyses
When data were available for two or more studies, we used Stata

| Study selection
The initial database search identified 1790 records. A total of 577 studies were eliminated as duplicates, and 1097 were excluded in the title and abstract screening. Subsequently, in the full-text screening, 15 records were eliminated for 'other' study design, 18 for 'other' outcome, and one for 'other' language. Finally, a total of 62 studies were included in this rapid review ( Figure 1). 5-7,20-78     Three had stopped antiretroviral therapy more than 3 months before Mpox virus infection and one had never been on antiretroviral therapy

| Quality assessment
Finally, the quality of all included articles was formally evaluated. The percentage of compliance in each of the four domains assessed was: selection: 100%, ascertainment: 75%, causality: 100%, and reporting: 9.7%. The results of the assessment of the methodological quality of the individual studies are presented in Table S2.

| DISCUSSION
The aim of this rapid review was to analyse the risk profile and modes pregnant women, children younger than 12 months, and people with certain medical conditions, such as a weakened immune system. For example, the CDC does not recommend the ACAM2000 vaccine for people with HIV because of the increased risk of serious side effects such as pain and swelling at the inoculation site, lymphadenitis, and constitutional symptoms, such as malaise, fatigue, fever, myalgia, headache. 82 In contrast, JYNNEOS is considered safe for people with HIV. 82 Thus, individuals with the highest potential for exposure to Mpox virus may be offered vaccination to help prevent disease.
The clinical presentation of current Mpox cases differs from the results of African patients prior to 2022. For example, the frequency of fever was higher and the current outbreak is more associated with rash in the pelvic area and groin, given possible transmission during sexual intercourse, particular in men having sex with men. 83 Although half of the current cases have severe skin lesions, the disease in the current outbreak is milder, with a hospitalisation rate of approximately 1:6 among European versus African cases. 83 The case fatality rate identified across all studies included in our rapid review was 6.5%, close to that reported in previous reviews. 83

| Strength and weakness
This systematic review retrieved data from 62 studies with more than 4000 cases of Mpox. In addition, to our knowledge, this is the

| CONCLUSIONS
In the studies included in this review, two out of three cases of Mpox showed human contact as the mode of transmission. The risk of mortality was particularly high in younger cases, so prevention in settings such as day care centres and schools appear to be of utmost importance. Additionally, higher risk was also observed in subjects with other co-infections or current chronic conditions and in those individuals from undeveloped countries. These results help to understand the major infection pathways and mortality risk profiles of this resurgent disease.