Factors associated with geographic variations in the 2022 monkeypox outbreak; A systematic review

Abstract

Background

The review aimed at examining patient factors that were associated with the worldwide geographic variation in number of monkeypox cases during the 2022 outbreak.

Methods

A systematic search was conducted using Scopus, Google Scholar, and PubMed/MEDLINE, to identify studies published in the year 2022 until 30 September on the 2022 monkeypox outbreak. Studies that described demographics and patient characteristics of the affected populations were eligible. Only countries/regions with the highest and lowest globally reported numbers were included.

Results

A total of 24 eligible studies reported data from the most affected countries in Europe [Spain and UK]; Americas [USA and Brazil]; and the least affected region [South East Asia]. There were no eligible studies reporting data from the Eastern Mediterranean which was allegedly the least affected region. Cases from Europe and the Americas were mostly men having sex with men [MSM], in fourth and fifth decades of life, with a substantial proportion of HIV and sexually transmitted diseases. Sporadic cases among women [sexual, household] and children [household] were identified. Sexual orientation and/or mode of transmission were not clearly stated in most studies from South East Asia.

Conclusions

The 2022 monkeypox outbreak was most obvious in the western part of the globe due mainly to sexual activities among MSM. Low numbers in the east may indicate the influence of the conservative social behaviors. Co-morbidities in the form of HIV and sexually transmitted diseases were identified. Detection of the disease among women and children highlights the importance of adopting appropriate preventive public health measures.

Introduction

Human monkeypox virus is a double stranded DNA zoonotic virus [1]. Originally identified in animals, this orthopoxvirus was first isolated in 1958 in monkeys transported from Singapore to Denmark for research purposes. However, the first confirmed human case was identified in 1970 in a child from the Democratic Republic of Congo [2]. While monkeypox is transmitted incidentally to humans from infected animals, reports have shown that the virus can also be transmitted through direct physical contact during sexual intercourse or skin-to-skin contact, respiratory droplets, and via fomites such as towels and bed sheets [3]. Clinically the disease may resemble other viral infections such as smallpox, chickenpox, herpes simplex infections, or other diseases such as dermatitis herpetiformis and drug eruptions [4]. A key distinguishing feature of human monkeypox from smallpox and chickenpox is the obvious lymphadenopathy that develops in 90% of patients a few days before the onset of a vesicular rash [5]. This characteristic rash is also preceded by mild prodromal symptoms of fever and flu-like symptoms [6]. Serious complications may develop in the form of pneumonitis, encephalitis, keratitis, and secondary bacterial infections [[7], [8], [9]]. Patients are considered infectious once the prodrome or rash begins, until the crusting lesions fall off. Identification of the viral DNA in swabs taken from crusts of vesicles or ulcers represent the preferred strategy for diagnosing active monkeypox cases [10].

Most cases of monkeypox occur in rural Africa, therefore, suspected underreporting may translate to an underestimation of the potential threat of this pathogen [2]. Outside Africa some outbreaks have emerged in the twenty first century such as the outbreak that occurred in the USA in 2003, and at that time the potential use of monkeypox in bioterrorism was highly considered and warned against in published literature [4]. More recently, monkeypox cases have been reported in early May 2022 from countries where the disease is not endemic. This is the first time that many monkeypox cases and clusters have been reported concurrently in non-endemic and endemic countries in widely separated geographical areas. Although cases were reported to the WHO [World Health Organization] from 1 January 2022, a sharp rise of cases was reported from 13 May 2022 in countries not previously known to report such infection.

Another distinguishing feature of this outbreak is concerned with gender and sexual orientation of more than 90% of patients. Most reported cases so far have involved mainly, but not exclusively, men who have sex with men [MSM] [11]. These patients consistently reported recent sexual activities with single or multiple partners. On the other hand, the WHO has recently confirmed that sustained transmission beyond these networks in not likely [12]. Close monitoring of the outbreak is undertaken by different authorities such as the WHO, CDC [Centers for Disease Control and Prevention] and ECDC [European Center for Disease Control and Prevention]. Up to December 23, 2022, there were 83,497 laboratory confirmed cases, 1694 probable cases, and 72 deaths reported from 110 countries [12]. At the beginning of this outbreak, the WHO assessed the risk as high in the European and the Americas regions, and as moderate in the African, Eastern Mediterranean and the South-East Asia regions. On a country level according to the WHO report released on October 7 2022, the top five most affected countries were USA [n = 26,723], Brazil [n = 8147], Spain [n = 7209], France [n = 4043], UK [n = 3654], while the least two affected geographic regions were the Eastern Mediterranean and the South-East Asia regions which reported a total of 80 and 35 cases respectively so far [13]. Eight months after the emergence of this outbreak the region of the Americas remains assessed as high risk, however the European region joins the African, Eastern Mediterranean, and the South-East Asia Regions in the moderate risk assessment [12].

The wide variability in geographic distribution of cases entails a closer look at the possible patient factors that may influence the pattern of spread and number of cases in the affected countries. Therefore, this study aimed at reviewing the literature published from the most and least epidemiologically affected countries to analyze the factors that may contribute to geographic variations in the reported number of monkeypox cases of the 2022 outbreak.

2. Methods

2.1. Eligibility criteria

Studies were considered eligible for inclusion in this review if they had the following inclusion criteria.

• 1.Studies on human monkeypox infections.
• 2.Case reports/case series, cross-sectional, cohort studies describing epidemiological characteristics of monkeypox cases in the 2022 outbreak.
• 3.Studies from the following countries/geographic regions: USA, Brazil, Spain, UK, Eastern Mediterranean region, South-East Asia region.
• 4.Studies published in English language.
• 5.Publication date: 1, January 2022 to 30, September 2022.

Studies were excluded if they were.

• 1.Clinical trials, opinion, commentary, letter to the editor, editorial, review
• 2.Reporting other than the countries/regions mentioned in the inclusion criteria

2.2. Information sources

Literature of the following databases were searched: PubMed/Medline, Scopus, and Google Scholar. References of retrieved articles were searched where applicable. Further, the websites of the WHO, ECDC, and CDC were searched for relevant data. Search was conducted for literature published within the period: 1 January 2022 till 30 September 2022.

2.3. Search strategy

The included databases were initially searched for the keywords: “Monkeypox” and “2022”, using the following filters: Case Reports, Case Series, Cross-sectional studies, from 1/1/2022- 30/9/2022, Human studies and English language. The WHO website was consulted to obtain data on the most and least affected geographic areas by the MPX outbreak. The retrieved articles were then searched for the following keywords: “USA”, “Brazil”, “Spain”, “UK”, “Eastern Mediterranean”, and “Asia”. Names of the countries that constitute the Eastern Mediterranean region and south East Asia were inserted in the included databases in combination with the term “Monkeypox” to ensure retrieving all relevant articles.

2.4. Selection process

Two reviewers [N. D-O. and O. A-H.] worked independently to select eligible articles. This was done by initial screening of titles and abstracts of retrieved articles. Only relevant articles were screened for full text.

2.5. Data collection process

Three reviewers [A.Raheem. J.: USA studies; A. Rahman. J: Asia and East Mediterranean and A.A-H: Europe] independently collected data from selected articles.

All collected data were further revised by a fourth reviewer [N.D-O.] to confirm accuracy of retrieved data.

2.6. Data items

Collected data included: Author[s] name; Study type; Country; Number of monkeypox cases reported by the study; sociodemographic characteristics of patients including: age, gender, sexual orientation; disease factors including: history of HIV, history of sexual transmitted diseases [STDS] [concurrent or past], and possible transmission route.

2.7. Study risk of bias assessment

Risk of bias [methodological quality] in included articles was determined using Joanna Briggs institute critical appraisal tools for case series [14], cohort studies, case reports, and cross-sectional studies [15]. Two reviewers [[N. D-O. and A. A-H.] worked independently to assess all studies.

2.8. Data synthesis

Quantitative synthesis in this study was not possible due to the type of included studies. These were in the main case reports and series. Further, the studies were clinically heterogeneous, therefore, narrative synthesis was considered the most appropriate approach for this study.

2.9. Reporting bias assessment

Missing results were mainly related to the “sexual orientation” of patients and “possible route of transmission”. This was primarily detected in studies originating from Asia. This data was determined to be influenced by self-reported patient history. Therefore, the subjective nature of reporting cannot be excluded, particularly in certain cultures where sexual practices may be considered socially sensitive information.

3. Results

3.1. Study selection

A total of 24 articles [seven cross-sectional, 12 case reports, four case series and one cohort study] were determined to be appropriate for inclusion in this review. The flowchart that describes the selection process is presented in Fig. 1.

Fig. 1.

Preferred Reporting Items for Systematic reviews and Meta-analyses [PRISMA] flowchart showing the identification process of studies obtained via: MEDLINE/PubMed, Scopus, and Google Scholar databases.

3.2. Included studies and their findings

Included studies originated from Spain and UK [n = 12]; USA [n = 5]; Brazil [n = 3]; and Asia [n = 4]. There were no studies originating from the Eastern Mediterranean region within the specified time frame of the study.

Included studies and their findings are presented in table 1.

Table 1.

Studies included in the review with data on country, type of study, number of described cases, gender, age, history of HIV, history of concurrent or past STDs, sexual orientation and possible transmission routes

Author	Study type	Country	No of cases	Gender	Age	HIV [ %]	STDs [concurrent or past] [%]	Sexual orientation	Transmission route
Catala et al., [2022] [16]	Cross-sectional	Spain	185	Male	Mean = 38.7 years	[42%]	[76% ][concurrent]	MSM: 99%	Sexual
Orviz et al., [2022] [17]	Cross-sectional	Spain	48	Male	M = 35 years	[39.5%]	[25%] [concurrent]	MSM: [97.9%]	Sexual
Tarín-Vicente et al. [18]	cohort	Spain	181	Male: 175 [97%] Female: 6 [3%]	M = 37 years]	[40%]	[17%] concurrent	MSM: 92% Heterosexual men: 9 [5%] Heterosexual women: 6 [3%]	Household: [3%] Sexual: 97%
Gomez-Garberi [19]	Case series	Spain	14	Male	M = 42 years	[57%]	43% concurrent	MSM: 71%	12 patients: sexual
Pérez-Martín [20]	Case report	Spain	1	Male	40 years	0%	Not mentioned	MSM	Sexual
Patel et al. [21]	Case series	UK	197	Male	M = 38 years	[35.9%]70 out of 195 screened	56 [31.5%] of those screened [concurrent]	MSM: [99.5%]	170/177 [96.0%] reported sexual contact with a male partner
Girometti et al. [22]	Cross-sectional	UK	54	Male	M = 41 years	[24%]	25%] concurrent	MSM:100%	Sexual
Vivancos et al. [23]	Cross-sectional	UK	79	Male.	M = 38 years	Not mentioned	N/A	MSM: 83.5%	Sexual
Vusirikala et al. [24]	Cross-sectional	UK	45	Male	M = 40 years	26%	[60%] Past history	MSM: 44 [98%]	Sexual
Lima et al. [25]	Case report	Brazil	1	Male	41	Not available	Not mentioned	MSM	Sexual
Brites et al. [26]	Case report	Brazil	2	Male	37 31	50%	Not mentioned	MSM	Not indicated
Menezes et al. [27]	Case report	Brazil	1	Male	41	100%	Not mentioned	MSM	Sexual
Karan A et al. [28]	Case report	USA	1	Male	20s	0%	Past history Syphilis	MSM	close, nonsexual contact with numerous unknown persons at a crowded outdoor event.
Hernandez LE et al. [29]	Case report	USA	1	Male	37	100%	Past history Syphilis	Not mentioned	Unknown
Philpott D et al. [30]	Case series	USA	1194	99% males	M = 35 years	Among 334 persons with available HIV data, 136 [41%] had HIV infection	Not mentioned	Not clear	Among 358 [30%] men with information on sexual encounters, 337 [94%] reported sex or close intimate contact with a man
Saunders KE et al. [31]	Case report	USA	1	Male	Less than 2 months	0%	Not mentioned	Not relevant	Contact with one of his caregivers who reported activities that placed him at high risk for monkeypox exposure during the 2 months preceding the infant's illness Possible routes of transmission included shared bed linens and skin-to-skin contact through holding and daily care activities.
Pastula DM et al. [32]	Case report	USA	2	Male	30s	0%	one: a past syphilis infection	MSM	Not mentioned
Jang et al. [33]	Case report	South Korea	1	Male	34	0%	0%	MSM	Patient denied sexual intercourse however he had a genital lesion
Koh et al. [34]	Case series	Singapore	15	Male	M = 36 years	Not mentioned	Not mentioned	Most were MSM	5 only reported sexual contact 9 had genital lesions
Yang et al. [35]	Case report	Taiwan	1	Male	20	Not mentioned	Not mentioned	Not mentioned	A travel history was only mentioned
Yadav et al. [36]	Case report	India	2	Male	35, 31 years	0%	0%	Not mentioned	Both denied previous sexual contacts, however they had genital lesions

M: median; HIV: Human acquired immunodeficiency virus; STD: Sexually transmitted diseases; MSM: Men who have sex with men.

3.3. Risk of bias assessment

All studies included in this review, except two, were assessed as having low risk of bias according to The JBI critical appraisal criteria for case reports [20,[25], [26], [27], [28], [29],31,32,36,37]; cohort studies [18]; cross-sectional studies [16,17,[22], [23], [24],38,39] and case series [19,21,30,34]. Two case reports [33,35] were assessed to have a high and moderate risk of bias due to reasons mentioned in Table- 2.

Table 2.

Studies that showed a moderate-high risk of bias in methodological quality, and the reasons for this assessment

Study	Level of risk	Reasons: The following items were not clearly described in the case report:
Yang et al. [35]	High risk of bias	1Lack of diagnostic tests or assessment methods 2Lack of intervention[s] or treatment procedure[s] 3Lack of post-intervention clinical condition 4Unreported adverse events [harms] or unanticipated events
Jang et al. [33]	Moderate risk of bias	1Lack of intervention[s] or treatment procedure[s] 2Lack of post-intervention clinical condition 3Unreported adverse events [harms] or unanticipated events

4. Discussion

Early reports on the monkeypox outbreak pointed to certain social behaviors as possible risk factors in the global spread of the infection, therefore this review explored patient risk factors associated with the global variation in the burden of the 2022 monkeypox outbreak. According to the worldwide situation in the WHO regions, it can be concluded that the most affected regions are the Americas and Europe, while the least affected regions are the Eastern Mediterranean and South East Asia [13]. The two remaining regions [African and Western Pacific regions] lie in between. As of 30th September 2022, the most affected countries in Europe and the Americas were Spain, UK, USA and Brazil. This review included only these four countries in Europe and the Americas because of the epidemiological similarities identified among these countries in the current outbreak. Global geographic variation was obvious in the wide variation in reported numbers of cases. Reports that were published during the early days of this outbreak highlighted the possible role of certain demographic and social factors that prevailed in most cases such as gender [males], fourth decade of life and sexual relations among men [homosexual and bisexual] as the possible route of transmission. Other comorbidities that were identified by these reports included HIV infection and STDs as many patients were initially seen in sexual health facilities complaining of genital lesions.

Due to the importance and characteristic presentations in this outbreak many studies were published, however, we could not include them because they were in the form of letters/commentaries, a research that is most probably not peer reviewed. The methodological quality of all studies included in this review, except two studies from Asia, were assessed to have a low risk of bias, which certainly reflect on the importance of reported data.

Historically, Human monkeypox was linked to Africa since it was discovered there in 1970s. During the 21st century, cases occurred elsewhere, however, they did not attract much epidemiological attention because they were sporadic and small in numbers. This disease has attracted attention in the year 2003 when a cluster of 53 patients were affected in the USA, however, the source of infection was identified to be animals imported to the country [40]. In the last few years [2018-2021], only four cases were reported, all of them affecting men who travelled from Nigeria to areas outside Africa [40]. Reports that documented these cases did not identify the source of infection or highlight the sexual orientation of patients [41], even in cases where genital areas were affected by the characteristic rash [42]. Sexual route of transmission was not explored previously probably because of the small numbers of cases that did not attract epidemiological attention. The first report of cases identified in the 2022 outbreak originated from the UK and it described that in May, three members of the same household that returned to the UK from Nigeria became infected with the monkeypox virus within one month period. In this report, the term “household” was used to describe this patient group, however, it did not give any further description, nor described the sexual orientation or source of infection. The following batch of affected four patients also detected in the UK were self-identified as MSM [43]. Later, the surge in case numbers was indeed linked to mass gatherings and social activities of the LGBT communities [24]. As of 26 September 2022 there were 3485 confirmed and 150 highly probable monkeypox cases in the UK with 95.2% being in England and [98.6%] being men. Although Western Europe served as the epicenter of the outbreak, the region of the Americas now report the highest numbers of cases. As of 23 December 2022, there were a total of [56,259] and [25,699] cases reported in the Americas region and Europe respectively.

In the East specifically in the Eastern Mediterranean region the epidemiological picture was different due to the very low numbers of cases. Further, epidemiological and clinical data on cases were lacking from primary literature. The Eastern Mediterranean region comprises a population of nearly 679 million people, however, cases constitute less than 1% of the globally reported cases [47]. Further, there was a mild increase in cases noticed in reports published from 30 September till 23 December 2022 whereby case numbers have increased from 42 to 80 cases only.

Most studies reported in this review originated from Spain followed by the UK in the form of cross-sectional studies and case series indicating the large numbers of cases to be reported. This is probably due to the initial emergence of large numbers of cases from these two countries [43]. On the other hand, studies reported from Brazil, USA and Asia were mainly case reports.

Most cases were identified as males, in their late thirties or early forties and a small proportion of infections have been reported in women and children [44]. Among male cases, more than 90% self-identified as MSM. A large proportion of cases [94%] reported sexual transmission, often at gatherings and events which provided the opportunity for amplification through sexual networks [44]. Even those cases identified among healthcare workers were reported as MSM cases [44],and the setting of infection was determined to be the community not nosocomial in origin [12].

In this review studies reporting infection among females originated from Spain. According to the most recent data female patients constitute a proportion of 3.4% of all cases and they are mostly reported from the Americas and Europe [12]. In concordance with this review, the route of transmission was identified to be heterosexual transmission [12] in a household setting [18,39]. Studies in this review did not report any pregnant patients, however, there were 53 pregnant women reported among cases worldwide constituting approximately 2% of the total female patient population [12]. Interestingly, reports indicate mild disease outcomes among pregnant patients with no deaths or admissions to intensive care being reported [12].

This review described monkeypox infection among children ≤17 years. As of 23 December 2022 a total of 779 patients aged ≤17 years were reported with 80% of them being reported from the Americas [12]. None of these patients reported exposure in a school setting [12]. However, the sexual route of transmission among the 13-17 age group cannot be excluded [20]. Approximately one in four pediatric patients is ≤ 4 years [12]. This review included two case reports that described two infant patients. The first one was identified in Spain and the source of infection was determined to be a breast feeding mother [37]. Transmission of monkeypox virus through breast milk is not yet determined [37], therefore, the likely infection route is thought to be close skin contact with the mother. The second infant case was reported from the USA and the infection was thought to be household due to contact with a care giver who reported “activities that place him at high risk for MPX exposure” [31]. One relevant study on MPX infection among children was reported by Aguilera-Alonso et al. [20], however, it was not included in this review because it was a correspondence. The study described a group of 16 patients in Spain: 10 males and six females. Four patients were <4 years and 12 were between 13-17 years. The reported transmission route among the 13-17-year age group was determined to be sexual [3], or related to a tattoo and piercing studio outbreak [9]. On the other hand, contact with contaminated objects or household was the possible route of transmission for the younger age group of children. In a characteristic case series on monkeypox transmission among clients of a tattoo establishment, the finding of monkeypox virus DNA on fomites and surfaces for more than two weeks after the probable index case attended the establishment suggest an extended infectivity period of the virus [45]. Moreover, transmission of monkeypox requires prolonged close interaction with a symptomatic or asymptomatic individual in the form of unprotected contact between skin, mucous membranes, bodily fluids through sexual contact, inadvertent splashes of patient saliva to the eyes or oral cavity, or contaminated materials such as linen and clothing [46].

Another atypical characteristic of the current outbreak is the clinical presentation involving an atypical rash-illness, with a relatively low, but still notable proportion of patients hospitalized. It is estimated that approximately 7% of patients were hospitalized for isolation or medical treatment [12]. Hospitalization for the purpose of isolation may be necessary to prevent spread into populations with increased risk of severe disease, including those with untreated HIV or who are otherwise immunosuppressed. Furthermore, severe complications such as encephalitis have been reported in a small number of cases which necessitates hospitalization.

Minimal numbers were reported from the Eastern Mediterranean region according to the WHO, however, within the time frame of this study, no eligible studies were identified from this region. Several factors behind this epidemiological picture may be considered. This geographic area is mostly inhabited by a Muslim Arab population, where societies there only recognize male-female marriage as the only socially acceptable means for sexual relations and making families [47]. Further, the local conservative background of Arabic societies often does not welcome homosexuality, and according to Islamic teachings, this is morally unacceptable. This may have contributed to the underreporting of MPX cases by merely mentioning case numbers without going into further relevant details such as age, gender and possible routes of transmission. On the contrary to the good amount of data reporting the epidemiological status in the western areas of the globe, there were no published studies on the cases identified in Arabic countries. Until 30 September 2022, only four studies were reported from Asian countries, however, official sites of the WHO and national ministries of health were the only source for number of cases in Arabic countries. Lebanon [n = 24], Sudan [n = 18] and the United Arab Emirates [n = 16] reported the highest numbers of cases in this region. In Sudan the first case was reported to be a 16-year-old student from West Darfur state in the western part of the country, but no further details were provided [48]. In Jordan, the only case reported was explained to be for a national returning home without mentioning further details. In Morocco the first case was reported in a traveler coming from Europe [49]. The same trend was observed in cases detected in the UAE, where it was reported that the first case was a 29-year-old woman visiting the country from West Africa [50]. It was interesting to notice no appearance of new monkeypox cases in Qatar. This Arabic country hosted the FIFA World Cup during November and December 2022, and it did not record any new cases apart from the 5 cases reported previously with the last case being reported in September 2022 [12], that is two months before the commencement of the tournament. This may indicate effectiveness of public health measures done to mitigate the rate of spread of infections known to appear in mass gatherings seen in sport events and social gatherings in general.

More details were provided by studies originating from south East Asia such as India. Yadav et al., [2022] reported two cases of monkeypox for two men in their thirties who returned from the UAE to India. Although both men denied sexual or physical contact with monkeypox cases, the pattern of lesions affecting the genital area may suggest a sexual route of transmission [36]. The remaining studies reporting cases from South East Asia originated from South Korea, Taiwan and Singapore. All patients reported were men, however transmission route was not confirmed except in some patients of the Singapore case series. Lack of important details contributed to the assessment of two of these studies as having low-moderate risk of bias.

It is noted that the number of cases is decreasing globally and this is particularly noticed in heavily affected countries such as the USA [12]. This is probably due to increased awareness of preventive measures among susceptible populations. The ECDC attributes the declining numbers to successful efforts in community engagement, reduced numbers of large social events attended by patients at risk, and boosting immunity of patients by natural immunity and vaccination, [51].

Finally, the occurrence of co-morbidities in the form of HIV and STDs such as syphilis among the reported cases may indicate increased transmission rate of several infections that may excessively burden the sexual health facilities in affected countries.

Conclusions: The 2022 monkeypox outbreak was most obvious in the western part of the globe due to human-to-human transmission during sexual activities of mainly men having sex with men. The much lower numbers that were detected in the east may indicate the influence of the conservative culture on shaping sexual behaviors. In conservative countries that encourage heterosexual relations under the umbrella of marriage, under-reporting was represented by lack of sufficient case histories that describe clinical manifestations and possible routes of transmission. This is probably due to patients’ embarrassment and fear of being judged. A substantial proportion of co-morbidities in the form of HIV and sexually transmitted diseases were identified among affected patients. Identification of the disease among women and children highlights the importance of adopting appropriate public health measures that protect such vulnerable populations. Public health authorities in conservative countries should adopt policies that guarantee patient confidentiality, combat stigmatization, and encourage transparency in reporting.

CRediT authorship contribution statement

Osama Abu-Hammad: Conceptualization, Methodology, Project administration, Writing – review & editing. Abdalla Abu-Hammad: Conceptualization, Methodology, Writing – original draft. Abdul-Raheem Jaber: Methodology, Writing – original draft. Abdel Rahman Jaber: Methodology, Writing – original draft. Najla Dar-Odeh: Conceptualization, Methodology, Resources, Supervision, Writing – review & editing.

Declaration of competing interest

Authors declare no conflict of interest.