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20 March 2023

Demographic, Epidemiologic, and Clinical Characteristics of Human Monkeypox Disease Pre- and Post-2022 Outbreaks: A Systematic Review and Meta-Analysis

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1
Department of Public Health, School of Public Health and Environmental and Occupational Hazards Control Research Center, Shahid Beheshti University of Medical Sciences, Tehran 1985717443, Iran
2
Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran 1985717443, Iran
3
Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1985717443, Iran
4
Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran 1985717443, Iran
Biomedicines2023, 11(3), 957;https://doi.org/10.3390/biomedicines11030957
This article belongs to the Section Molecular Genetics and Genetic Diseases
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Abstract

(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.

1. Introduction

Human monkeypox (mpox) is a zoonotic infectious disease caused by the monkeypox virus of the Poxviridae family [1]. The name monkeypox originated in a Danish laboratory in 1958, and the first human case of mpox was detected two decades later in an infant from the Democratic Republic of Congo (DRC) [2,3]. After the eradication of smallpox in 1980, mpox became the most threatening Poxviridae family member, causing 300–500 million deaths [4]. Since then, most cases have been sporadic and diagnosed in African countries for many years. In 2003, the first confirmed mpox cases outside of Africa were reported in the United States [5]. Mpox was classified as endemic in Nigeria in 2017, and incidence rates increased significantly in recent years [6,7]. Since early May 2022, an increasing number of mpox cases have been reported in non-endemic regions of the world. This concurrent high incidence of mpox cases in very different geographic regions was a concern of the World Health Organization (WHO). Interestingly, most of the reported patients had a history of sexual contact and mainly, but not exclusively, involved men who have sex with men (MSM) [8].
By 26 February 2023, the World Health Organization (WHO) reported 86,127 confirmed cases and 97 deaths in 110 countries where mpox was previously rare [9]. This rapid global spread of infection warranted public health measures, while the COVID-19 pandemic is still ongoing [10]. Currently, the Emergency Committee WHO has called on scientists worldwide to collaborate on mpox to better understand the disease and prevent further harm [11].
In the current situation, the correct and rapid identification of patients is necessary to achieve control measures to prevent the spread of the disease and to improve patient care. Given the possibility that the route of transmission, demographic characteristics, and clinical manifestations of the disease may change in the upcoming epidemics, conducting a systematic review and meta-analysis of previous information can provide a basis for a better comparison of the current outbreak with previous outbreaks.
Here, we provide a comprehensive 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, epidemiologic, and clinical perspectives to highlight the differences in mpox characteristics over two periods.

2. Methods

This review conforms to the “Preferred Reporting Items for Systematic Reviews and Meta-Analyzes” (PRISMA) statement [12].

2.1. Search Strategy and Selection Criteria

A systematic search was performed for relevant studies published in Pubmed/Medline, Embase, and Scopus, from 1 January 2012 up to 15 February 2023. We also searched Google Scholar for relevant grey literature.
Articles that contained the following keywords in the title or abstracts were selected: “Monkeypox” OR “Monkeypox virus”. The records found during the database search were merged using EndNote X8 (Thomson Reuters, New York, NY, USA), and duplicates were removed. Two reviewers (MA and PF) independently reviewed the records by title and abstract to exclude those not related to the present study. The full text of potentially eligible data sets was retrieved and assessed separately by two other reviewers (SAASN, GIJ). In each step, contraries were discussed with a third viewer (PJ). Inclusion criteria were as follows: (i) original descriptive studies that (ii) included confirmed mpox cases and (iii) contained sufficient data about the epidemiologic, demographic, and clinical characteristics of the patients. Exclusion criteria were as follows: review articles, duplicate publications, animal studies, in vitro/in vivo studies, case reports, case series with fewer than 3 cases, case-control studies, conference abstracts, news, commentaries, epidemiologic reports, book sections, modeling studies, molecular and genetic studies, and articles for which full text could not be found, and those with no relevant data. Studies with insufficient information on patient characteristics and outcomes were also excluded. Only English-language articles were considered. In the next step, the included cross-sectional studies were considered for further meta-analysis.

2.2. Data Extraction

Data on first author’s name, first author’s country, location of the outbreak or reported cases, cohort/time of the outbreak, time of publication, type of study, viral clade, mean age, sex, nationality, number of confirmed, probable, suspected, primary, and secondary cases according to the study’s case definition, epidemiologic history (travel, animal contact, human contact, occupation, mentioned route of transmission, and mentioned behavioral risk factors), smallpox vaccination status, comorbidities, diagnostic confirmatory criteria, clinical manifestations, rash localization, rash severity, lymphadenopathy localization, complications, management status, outcome, duration of disease, and patients’ incubation period were extracted for further analysis. Selected data were extracted from the full texts of eligible publications by all team members.

2.3. Quality Assessment

The critical appraisal checklist for systematic reviews provided by the Joanna Briggs Institute (JBI) was used to assess the quality of the studies. In addition, included cross-sectional studies were reassessed using the critical appraisal checklist for prevalence studies provided by the JBI for inclusion in the meta-analysis [13].

2.4. Data Synthesis and Analysis

Statistical analyzes were performed using Comprehensive Meta-Analysis software, version 2.0 (Biostat Inc., Englewood, NJ, USA). 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. Heterogeneity between studies was assessed based on Cochran’s Q and the I2 statistic. Publication bias was statistically assessed using Begg’s tests (p < 0.05 was considered to indicate statistically significant publication bias) [14].

3. Results

As shown in Figure 1, our initial search yielded 10,163 articles, of which 6243 duplicate articles were excluded, and 202 articles were selected following title and abstract screening. After the full-text screening, 67 articles were included, of which 31 cross sectional studies were considered for further meta-analysis.
Figure 1. Flow chart of study selection for inclusion in the systematic review and meta-analysis.

3.1. Quality of the Included Studies

The JBI checklist for prevalence studies showed that the cross-sectional studies included in the meta-analysis had a low risk of bias (Table 1).
Table 1. Quality assessment of the cross-sectional studies included in the meta-analysis (the JBI tool).

3.2. Characteristics of the Included Studies

Almost half of the articles were cross-sectional studies (n = 32), and the remaining were in this order: 14 case series, 7 letters, 5 brief reports, 4 rapid communications, 3 short communications, and 2 correspondences (Table 2). Most of the included studies (41/67) were conducted during the 2022 outbreak and were located mostly in Spain (12/41), the USA (8/41), and the UK (5/41). In contrast, most of the pre-2022 outbreak studies were located in Africa (23/26), especially the Central African Republic (CAR), Democratic Republic of Congo (DRC), and Nigeria (Figure 2). The total number of cases was 36,682, of which 33,673 were confirmed cases. Most of our studied population was reported during the 2022 outbreak (89.52%, 30,145/33,673) (Table 2).
Table 2. Characteristics of the included studies.
Figure 2. Geographical locations of the pre- and post-2022 mpox outbreak studies. The mapchart.net website was used for drawing the world map.
Although the case definition of mpox differed among pre-2022 studies, the criteria of studies had roughly similar characteristics. The detection of viral DNA via PCR (RT-PCR) or virus isolation from patient samples was used to confirm mpox cases. Probable and suspected case definitions were more varied. A probable case was defined when confirmatory laboratory tests were not available and the probability of mpox disease was high (epidemiologic risk factors or contact with known cases). Suspected cases were defined when an unexplained, sudden-onset fever was followed by a rash accompanied by lymphadenopathy or involvement of the palms or soles. Table 3 describes the different approaches used by the included studies, compared with the 2022 WHO and CDC case definitions.
Table 3. Confirmed, probable, and suspected case definitions of the included studies (only available data are mentioned), compared to WHO and CDC case definitions.
According to the similarity of clinical manifestations of mpox and varicella zoster disease, we excluded 286 MPX/VZV coinfected individuals from our study population and our analysis was based on 30,728 confirmed mpox-only cases.
Based on the data available to us, the West African strain was the most common clade of the virus in both pre- and post-2022 mpox outbreaks (Table 2).

3.3. Characteristics of the Study Population (Confirmed Cases)

Before the 2022 outbreak, most of the cases (61.64%) were primary, having a history of animal exposure (animal-to-human transmission) and the rest (38.35%) were secondary cases (human-to human-transmission), of which most were among households or healthcare workers or had a travel history to endemic areas. However, during the 2022 outbreak, almost all of the reported cases were deemed secondary cases. Most of the cases had a history of skin-to-skin contact with symptomatic or asymptomatic patients, mainly sexual contact or attendance in mass gathering events (e.g., Pride) or indirect contact with contaminated objects in locations where outbreaks of mpox were ongoing (Table 2 and Table 4). The pooled frequency of MSM individuals in our included cross-sectional studies was 93.5 (95% CI 91.0–95.4, I2: 86.60%), and it was reported only in post-2022 studies (Table 6).
Table 4. Demographic and epidemiologic characteristics of the study population (confirmed cases).
The pooled frequency of the male gender was 98.7% (95% CI 97.1–99.4, I2: 92.19%) in post-2022 studies, which is higher than the previous ones (59.1%, 95% CI 54.6–63.6, I2: 77.35%) However, there was evidence of significant publication bias (Begg’s test p < 0.05) regarding the gender-specific post-2022 data (Table 6). The mean age of the confirmed cases was 29.92 years (5.77–41, SD: 9.38) (Table 4).
Most of the cases in pre-2022 outbreaks were from Africa or had a history of travel to African endemic countries. In contrast, the majority of the post-2022 cases were reported from non-endemic areas, including America, Europe, and Asia (Table 2 and Table 4).
A reverse transcriptase polymerase chain reaction (RT-PCR) test from the skin lesions was the most common diagnostic confirmation tool in our reviewed studies. However, in post-2022 studies, an RT-PCR test through anal, and oropharyngeal swabs was also more common.
Epidemiologic, demographic, and clinical characteristics of the included study populations are defined in Table 4 and Table 5 in detail.
Table 5. Clinical characteristics of the study population (confirmed cases).
The most common clinical manifestations of mpox during pre- and post-2022 outbreaks were rash, fever, lymphadenopathy, and malaise/fatigue. However, the pooled frequency of each of the above symptoms was lower in post-2022 cases compared to that among the previous ones. More details are available in Table 6.
Table 6. Pooled frequency of the confirmed mpox patient characteristics.
Proctalgia/proctitis was the unprecedented clinical manifestation of mpox during the 2022 outbreak, which was not described before. We calculated a pooled frequency of 16.6% (95% CI 10.3–25.6, I2: 97.76) for proctalgia/proctitis in our post-2022 included studies.
The most frequent rash locations in pre-2022 outbreaks were the head and neck (98.0%, 95% CI 97.1–98.6, I2: 45.18%), trunk (95.2%, 95% CI 82.4–98.8, I2: 93.32%), upper limbs (94.9%, 95% CI 82.7–98.6, I2: 92.92%), and lower limbs (91.0%, 95% CI 71.0–97.7, I2: 92.77%). Of note, palmar and/or plantar involvement was reported in 85.9% (95% CI 65.1–95.28, I2: 97.77%) and 73.8% (95% CI 55.3–86.5, I2: 97.48%) of patients, respectively. Oropharyngeal (52.4%, 95% CI 45.5–59.2, I2: 90.31%) and genital (53.5%, 95% CI 36.8–69.5, I2: 94.03%) involvement were less common according to our meta-analysis. In contrast, the most common rash locations in post-2022 patients were the genitalia (55.6%, 95% CI 51.7–59.4, I2: 88.11), trunk (45.2%, 95% CI 38.6–52.0, I2: 96.19), upper limb (41.8%, 95% CI 36.4–47.4, I2: 94.37), and anal/perianal area (39.8%, 95% CI 30.4–49.9, I2: 98.10). Anal/perianal involvement was not reported in pre-2022 included studies. The pooled frequency of oropharyngeal lesions in post-2022 outbreaks was 18.3% (95% CI 13.2–24.9, I2: 95.95%), which was lower than the previous frequency (Table 6). Figure 3 and Figure 4 indicate the pooled frequency of genitalia involvement in pre- and post-2022 included studies. As shown, genitalia involvement was more common during the 2022 outbreak and was reported from much more studies with a greater population (Table 6)
Figure 3. Pooled frequency of genitalia involvement in pre-2022 studies. Osadebe, 2017 [17], Ogoina, 2019 [21], Whitehouse, 2021 [23], Besombes, 2022 [24], Adler, 2022 [26], Yinka-Ogunleye, 2019 [51].
Figure 4. Pooled frequency of genitalia involvement in post-2022 studies. Tarín-Vicente, 2022 [27], Angelo, 2022 [28], Betancort-Plata, 2022 [29], Caria, 2022 [30], Vanhamel 2022 [31], Girometti, 2022 [33], Orviz, 2022 [34], Hoffmann1, 2022 [35], Cobos, 2022 [36], Hoffmann2, 2022 [37], Van Ewijk, 2022 [38], Mailhe, 2022 [39], Nunez, 2022 [40], Catala, 2022 [41], Cassir, 2022 [42], Pascom, 2022 [70], Suner, 2022 [43], Maldonado, 2023 [44].
The most commonly involved lymph nodes in patients with LAP were cervical (79.7%, 95% CI 61.6–90.6, I2: 97.09) and inguinal lymph nodes (44.1%, 95% CI 30.2–59.1, I2: 95.57) in pre- and post-2022 cases, respectively (Table 6).
Several studies reported the disease severity of mpox cases based on the WHO clinical severity score [22] and divided patients into mild (<25 skin lesions), moderate (25–99 skin lesions), severe (100–250 skin lesions), and grave (>250 skin lesions). According to our analysis, most of the pre-2022 patients had moderate skin rash severity (53.6%, 95% CI 46.6–60.5, I2: 88.72%). In contrast, most of the post-2022 mpox patients experienced mild skin rash severity (84.9%, 95% CI 71.9–92.5, I2: 96.28) (Table 6).
Figure 5 summarizes the clinical features of confirmed mpox cases before and after the 2022 outbreak.
Figure 5. Clinical characteristics of mpox-confirmed patients adjusted with the pooled frequency.
Insufficient data were available on VZV coinfection in mpox-confirmed patients. Four studies investigated the probability of MPOX/VZV coinfection in their patients and only two of them reported the exact coinfected cases [16,22]. Based on these studies, we calculated the frequency of MPOX/VZV coinfection as 21.86% (Table 5 and Table 6).
The pooled frequency of HIV in mpox-confirmed patients was 11.4% (95% CI 0.2–91.3, I2: 88.75) and 41.1% (95% CI 35.5–47.0, I2: 94.91) among pre- and post-2022 cases, respectively, indicating higher prevalence of HIV in post-2022 mpox patients.
The smallpox vaccination status of mpox patients was considered because of the potential preventive role of the smallpox vaccine in controlling recent outbreaks of mpox infection. Of the pre-2022 confirmed cases with a known smallpox vaccination status, 94.4% (CI 89.4–97.2, I2: 86.92%) had no history of smallpox vaccination and 5.6% (CI 2.8–10.6, I2: 86.92%) had been previously vaccinated. The pooled frequency of smallpox vaccination in post-2022 cases was much greater than the previous ones (11.0%, 95% CI 8.9–13.6, I2: 67.70 vs. 5.6%, 95% CI 2.8–10.6, I2: 86.92); however, there was evidence of publication bias in post-2022 studies regarding the vaccination status (Begg’s test p-value < 0.05) (Table 6).
Significant complications of the disease were bacterial superinfections and abscesses, keloids, hyperpigmented atrophic scars, hypertrophic scars, alopecia, severe ulcerative proctitis, sepsis, cellulitis, epiglottitis, bronchopneumonia, lymphangitis, balanitis, urinary complications and obstructions, orchiepididymitis, myocarditis, ocular opacities, keratitis, and unilateral or bilateral ocular complications (Table 5).
Only 21 articles reported the incubation period of the disease in their cases (Table 5). However, according to our calculations, the mean incubation period was 7.9 days (1–21, SD: 4.0). Moreover, the disease duration was reported only in 17 studies, and according to our analysis, the mean disease duration was 17.33 days (7–35, SD: 8.40) (Table 5).
The majority of the pre-2022 cases were treated as inpatients (76.2%, 95% CI (30.1–96.0, I2: 52.72), while most of the post-2022 cases were managed as outpatients (95.1%, 95% CI 92.9–96.6, I2: 87.49) (Table 6).
Regarding patient outcome, our meta-analysis showed a mortality rate of 4.2% (95% CI 1.6–11.0, I2: 83.22) in pre-2022 outbreaks and a mortality rate of 0.2% (95% CI 0.1–0.3, I2: 19.18) during the 2022 outbreak (Table 6). It is important to note that the outcome of the majority of reported cases before 2022 was unknown. Therefore, it is probable that the pooled mortality rate of pre-2022 cases calculated in our study is higher than the actual rate.

4. Discussion

While the COVID-19 pandemic has not yet ended, the world has been confronted with a new health emergency due to the monkeypox virus [86]. Since the eradication of smallpox in 1980, mpox has been the most widespread and, in terms of morbidity and mortality, the most important orthopoxvirus infection in humans [17,20,87,88,89,90,91]. The gradual increase in the number of cases in endemic areas and the increasing reports of mpox outside endemic areas in recent years have raised concern about the epidemic potential of the virus [7,17]. Two major clades of the virus have been identified: the West African clade, which is associated with a mild disease course and lower human-to-human transmission, and the Congo Basin clade, which is associated with severe disease, higher mortality, and greater human-to-human transmission [89,92,93]. According to our study, more than half of the cases reported in the past 10 years were primary cases involving animal exposure. Human-to-human transmission through skin contact or droplet infection in households or among healthcare workers was also included in 38.35% of cases in the studies reviewed. This low frequency of human-to-human transmission can be explained by the dominance of the West African clade in the articles we reviewed.
To date, there is no conclusive evidence of biological or genetic changes in the virus leading to the current resurgence. Moreover, the West African clade has been isolated from some of the cases in the current outbreak [7,94]. However, an analysis by Kugelman et al. indicated gene loss in 17% of the samples from the Democratic Republic of Congo (DRC), which appeared to be associated with an increase in human-to-human transmission [6,95]. There is increasing evidence of a possible new zoonotic reservoir for the virus and human-to-animal transmission outside of endemic areas [96]. In addition, there is the possibility of undetected transmission in the community via an unusual route, possibly sexual transmission, as indicated by the high incidence of the disease in the community of men who have sex with men (MSM) [8,93,96]. Sexual transmission of mpox virus is not a new possibility. Ogoina et al. reported the likelihood of sexual transmission of the virus through close skin-to-skin contact in their young adult patients with genital ulcers in the 2017 Nigerian outbreak [21]. Based on our meta-analysis, the pooled frequency of genital lesions has increased during the 2022 outbreak (55.6% vs. 53.5%). In the current outbreak, the transmission rate among sexually active participants, especially MSM or bisexual individuals, is surprising. For example, Vivancos et al. reported that 83% of confirmed mpox patients in their study were MSM or bisexual [97]. In addition, we found a pooled frequency of 93.5% for MSM individuals in the post-2022 included studies. Therefore, it is very plausible that sexual activity is a possible route of transmission for the disease. An analysis of seminal fluid from some patients has demonstrated the existence of the mpox virus [98]. Bragazzi et al. suggested that the presence of mpox virus in seminal fluid may be due to the systemic spread of the virus, called viremia, as well as defects in the blood–testicular barrier and immune privilege of the testis [98]. However, the question remains about the infectivity of the virus in semen. Further studies are needed to clarify this issue.
The clinical manifestations of mpox are another problem in distinguishing mpox from other similar diseases, such as varicella-zoster virus (VZV) infection, in the current outbreak. According to our analysis, rash and fever were the most common symptoms of mpox, with pooled frequencies of 96.6% and 62.3% in the post-2022 cases, respectively. The timing of fever and rash is one of the most important points in distinguishing varicella zoster from mpox, as in mpox, a high-grade fever usually occurs before the rash, whereas in VZV infection, a mild fever usually occurs simultaneously with the rash [22]. Most patients in the studies we examined had experienced a febrile prodromal stage with or without chills, headache, sore throat, malaise, and myalgia lasting for 1 to 4 days. As with the improvement of prodromal symptoms, the rash progressed slowly, with centrifugal distribution and concentration on the face and extremities. According to our results, before the 2022 outbreak, the rashes occurred most frequently on the head and neck, followed by the trunk, upper limbs, and lower limbs. Our analysis showed that the palms were more frequently affected (85.9%) than the soles, for which a pooled frequency of 73.8% was calculated. However, involvement of the palms (15.4%) and soles (10.6%) was less common in post-2022 studies compared with that in the previous outbreaks. The pooled frequencies we calculated are both lower than those in the study by Osadebe et al., who found involvement of the palms and soles in 91.2% of cases [17]. Involvement of the palms and soles has been noted in other orthopoxvirus infections, such as smallpox. This has also been noted in VZV cases, with a prevalence of 81.3% [17,99]. However, palms and soles are more commonly affected in mpox cases, and Osadebe et al. suggested this sign as one of the 12 signs/symptoms for mpox-specific case investigations [17]. One of the most important differences between mpox and VZV is that in mpox, all lesions are at the same stage and develop slowly in the order of macule, papule, vesicle, pustule, crust, and finally desquamation over 1–2 days [90,100]. In contrast, VZV lesions usually occur in multiple stages on different parts of the body and rapidly develop from a macule to a crust within a day or sooner [22]. The appearance of mpox lesions is another important consideration. According to the studies we reviewed, mpox lesions are firm, deep-seated, monomorphic, and well-circumscribed, with central punctate nodules. In contrast, VZV lesions are superficial and have an irregular border [22].
Lymphadenopathy (LAP) is another common manifestation that can be used as a distinguishing feature for mpox. The pooled frequency of LAP in our study was 80.6% and 55.5% during the pre- and post-2022 outbreak, respectively. LAP is typically not prominent in VZV patients and unlike smallpox, it may occur before or at the onset of rash [7,17,101].
The pooled frequency of genital involvement in our study was 55.6% during the 2022 outbreak which is higher than that in previous reports. Genital ulcer has also been observed in VZV cases, as reported by Osadebe et al., in 14.9% of their patients [17]. However, it occurs more frequently in mpox cases and has a high specificity for mpox [17].
It appears that the disease pattern has changed slightly in the current 2022 outbreak. The CDC states that mpox rashes can begin in the mouth and spread to the face and extremities, including the palms and soles of the feet [93]. Atypical disease courses have also been reported, such as the absence of or minimal prodromal symptoms, isolated lesions confined to the genital/anal area, and initial genital rashes followed by facial and extremity involvement [67,97,98,102,103,104]. Further population-based studies are needed to determine possible changes in the clinical manifestations of mpox disease.
There is conflicting information on the onset of transmissibility in patients. Patients are thought to be infectious from the onset of the rash and during the four-week desquamation phase because of high viral shedding [93]. However, Nolen et al. point out that patients may be infectious even before the onset of the rash [15].
VZV/MPOX coinfection was reported in some of the studies we reviewed. However, the exact mechanism behind this is not yet fully understood. It is not clear whether the existence of two viruses in a host occurs independently or whether one virus influences the pathogenesis of the other [16,105]. Some studies suggest that mpox can directly trigger VZV reactivation [16,22,106]. Evidence for this hypothesis comes from historical case reports of herpes zoster reactivation after smallpox vaccination [107]. Hughes et al. suggested that primary infection with VZV or mpox weakens the patient’s immune system and leads to susceptibility to secondary infections [22]. In endemic areas with a high prevalence of mpox and VZV, the patients are more susceptible to these pathogens as secondary infections. Another hypothesis is that VZV lesions disrupt skin integration, making it easier for mpox virus to invade [22]. We have estimated the prevalence of MPOX/VZV coinfection to be about 22%. However, in reality, it could be higher or lower due to a biased selection of studies or inadequate investigations, respectively. VZV/MPOX coinfected patients are more likely to report symptoms, and their number of lesions is significantly higher compared with those in only VZV patients [22]. On the other hand, the disease is more severe in patients with only mpox virus than in VZV/MPOX-coinfected patients. This may lead to a bias in the selection of reported cases [22]. In the 1980 laboratory protocols of the surveillance program of the WHO, dual testing of VZV and mpox in suspected individuals was not supported unless mpox tests were negative [16,108]. Therefore, it is likely that a larger percentage of mpox-confirmed patients have undiagnosed VZV coinfection and that the calculated incidence is lower than the true rate.
Coinfection of mpox and HIV is another point of challenge that requires further research. The incidence of MPOX/HIV coinfection was 41.1% in our study, according to the available data on post-2022 cases, which is greater than the pre-2022 calculated frequency (11.4%). Most of the pre-2022 cases we studied were reported from the Democratic Republic of Congo and Nigeria, where HIV is endemic. HIV prevalence in Nigeria was reported to be 3.4% in 2018 [21]. Given that HIV testing was not performed in the majority of cases studied, it is highly plausible that the prevalence of MPOX/HIV coinfection is higher than that calculated in our analysis. It appears that HIV-positive mpox patients have more severe disease with higher morbidity and mortality [21]. In the 2017–2018 outbreak in Nigeria, four of seven patients who died were HIV-positive [20]. Ogoina et al. reported that the incidence of genital ulcers, secondary infections, and complications, as well as the greater rash size and longer disease duration, were significantly associated with HIV positivity in mpox cases. In addition, this study showed that the age, sex, hospitalization, and outcome of these patients did not differ significantly from those of HIV-negative mpox-positive patients [56,98]. In the current outbreak, preliminary data suggest that HIV seropositivity and a previous history of sexually transmitted infections may be risk factors for mpox infection [109]. Therefore, we suggest that mpox vaccination should be a priority prevention measure for this population.
The mean age of mpox cases in our study was calculated to be 29.9 years, which is greater than the previous data from the 2010–2019 outbreak investigations, where the median age at disease onset was 21 years [6]. Available demographics from previous outbreaks show a clear shift in the mean age of mpox cases over time. The mean age has increased from 4 years in the 1970s to 10 years in the 2000s and 21 years in the 2010s [6]. Concerning the outbreak in 2022, the current literature gives an average age of 30 years for those affected, which is consistent with our study [98]. This increasing age trend in patients over time appears to be due to decreased immunity to smallpox following the cessation of smallpox vaccination in the 1980s [23,110,111,112]. According to our meta-analysis, only 5.6% and 11% of pre- and post-2022 mpox patients had been previously vaccinated, respectively. In a study by Whitehouse et al., it was suggested that 10% of mpox cases had been vaccinated before mpox infection [23]. There is evidence that historical smallpox vaccination provides cross-protective immunity against other poxviridae family members including cowpox and monkeypox [113,114,115]. The effectiveness of the vaccinia vaccine against mpox is reported in various studies to be 81–85% [90,91,96,113]. However, some studies suggest that smallpox vaccination-induced immunity declines over time, particularly after 20 years of vaccination, but it appears to reduce the morbidity and mortality from mpox disease [18,100,116]. As with the investigation into the 2017 outbreak in the Democratic Republic of the Congo, the mortality rate among unvaccinated mpox-confirmed cases was approximately 9.5% [115]. Vaccination of close contacts has also reduced transmission of the disease in previous outbreaks [93].
The majority of cases reported in our study were male, consistent with previous studies. This may be due to the gender-specific roles in previous outbreaks in endemic areas, as males had greater exposure to animal reservoirs when hunting [117,118,119]. Young men in particular were also affected by the current outbreak [98]. This could be due to their increased sexual activity and participation in festivals such as Pride [98]. However, we found a significant publication bias regarding the gender of the individuals in post-2022 studies. We assume that during the 2022 outbreak, most of the attention has been assigned to screening the MSM community and this has resulted in the mentioned bias and a stigma. Both genders can be infected with mpox. To date, several studies have reported mpox cases in women including old women [120,121]. CDC reported a total of 769 cases of mpox among cisgender women, including 23 (3%) who were pregnant, by 42 public health jurisdictions from 11 May to 7 November 2022 [122]. The clinical features of mpox in females were similar to those described in males, including the presence of anal and genital lesions with marked mucosal involvement. Anatomically, anogenital lesions reflected sexual practices: vulvovaginal lesions predominated in cis women, with anorectal features in trans women [64,123,124,125].
The mortality rate from mpox cases has been reported to be 1–11% in previous outbreaks [7,20,23,101]. However, the mortality rate is highly dependent on medical care, the endemic nature of the disease, the viral clade, and the characteristics of the individuals affected. Bunge et al. analyzed an all-cause mortality rate of 8.7% with a range of 10.6% for the Central African and 3.6% for the West African clade of the virus. This value was 4.6% for the West African clade exclusively in endemic areas [6]. The mortality rate is very low in areas with good medical care, since there were no reported deaths when the disease broke out in the US in 2003 [93,98]. According to patient characteristics, the majority of deaths have been reported in infants, children under 10 years of age, pregnant women, immunocompromised patients (e.g., HIV), unvaccinated individuals, and those who have developed complications [7,87]. As the age at diagnosis increases, an increasing trend in the age at death has also been demonstrated [6]. In our analysis, there was little data on patient treatment status and outcomes in pre-2022 studies. Using the available data, we calculated a pooled mortality rate of 4.2% and 0.2% in pre- and post-2022 mpox cases, respectively. However, we believe that a large amount of missing data and a bias in the selection of reported cases in pre-2022 studies has resulted in the higher calculated mortality rate of previously described cases.
One of the rare but significant mpox complications is ocular involvement. These injuries are divided into (a) more common and benign lesions and (b) less common and vision-threatening sequelae. Conjunctivitis, blepharitis, and photophobia are the most commonly reported uncomplicated manifestations. There are also mpox-related symptoms, such as eye redness, frontal headache, periocular and orbital rash, lacrimation and ocular discharge, subconjunctival nodules, and less frequently, keratitis, corneal ulceration, opacification, and perforation [126]. Ocular manifestations were less common and probably less severe in the current outbreak. The pooled frequencies of ocular involvement, mostly conjunctivitis, were 23.3% and 1.6% in pre- and post-2022 studies, respectively. Observational studies suggest rates of about 1% ocular involvement in the current outbreak, compared with 9–23% in previous outbreaks in endemic countries, which is consistent with our calculated rates [127]. Smallpox vaccination in the past is a protective factor against these complications. Although there is no clear and established treatment, simple therapies, such as regular lubrication and the prophylactic use of topical antibiotics, can be considered for ocular complications of mpox. The timely administration of specific antiviral agents may also be effective in severe cases. Mpox usually has mild-to-moderate severity and a self-limited course. The risk of permanent ocular sequelae and disease morbidity could be reduced if the disease is identified early and appropriately treated [128,129].

5. Limitations and Suggestions

One of the major limitations of our study was the insufficient and missing data from the pre-2022 articles reviewed. All of our analyses have been performed based on the available data, and due to the significant amount of unavailable information, especially regarding the pre-2022 included studies, our final statistics may be overstated or understated. Insufficient data on the characteristics of the reported deaths resulted in an inability to stratify the mortality rate by age, sex, immunization status, comorbidities, etc. Further investigation is needed to clarify this issue. We strongly encourage future investigators to provide complete data on the cases that they report. Especially, comprehensive information about dead individuals is urgently needed to reveal high-risk patients. These data are required to prioritize the high-risk individuals for inclusion in preventive measures, such as vaccination, as well as increased medical care after being affected. We propose to screen mpox cases for VZV or HIV coinfection. Future data are needed to determine a possible correlation between these infections and to take necessary measures in these patient groups.

6. Conclusions

Our meta-analysis study highlights important differences in the epidemiologic, demographic, and clinical features of mpox cases before and after the 2022 outbreak. In the current outbreak, the possibility of changes in the pathogenic properties of the virus has been speculated because of the sudden increase in patients, especially in non-endemic areas. Therefore, our study could serve as a basis for current investigations to identify the different aspects of previous mpox outbreaks and compare them with the current ones. According to our analysis, it seems that post-2022 mpox cases experience a milder disease with fewer rashes and lower mortality rates. In addition, more than 95% of post-2022 cases have required outpatient management.
In the current global emergency, first-line medical practitioners, as well as public health policy-makers, should be aware of the previous, and recently identified, characteristics of the disease, especially clinical manifestations and epidemiological features, to make appropriate decisions and actions to control the outbreak.

Author Contributions

H.H. and P.J. designed the study. P.J. conducted the search. M.A., P.F., G.I.-J. and P.J. collaborated in the screening process. Data extraction was performed by M.A., P.F., B.M., G.I.-J. and S.A.A.S.-N. P.J. performed the meta-analysis and prepared the results and tables. S.A.A.S.-N. prepared the figures. P.J., M.A., B.M., M.Z. and S.A.A.S.-N. wrote the first draft of the manuscript. M.J.N., L.A.S., M.Z. and A.N. revised the manuscript. All authors made considerable contributions to the present study. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Data Availability Statement

All data were included in the manuscript.

Acknowledgments

This study is related to the MD-MPH project from the Department of Public Health, School of Public Health and Safety, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Conflicts of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare no conflict of interest.

Abbreviations

MPOX: human monkeypox disease; DRC: Democratic Republic of Congo; WHO: World Health Organization; RT-PCR: reverse transcriptase polymerase chain reaction; LAP: lymphadenopathy; VZV: varicella-zoster virus; STI: sexually transmitted infection.

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