2.1 Literature search strategy

Literature was mined without time filters or language restrictions. More specifically, two major scholarly, electronic databases, PubMed/MEDLINE and Scopus, were searched. “Medical subject headings” terms were utilized. In particular, we focused on the period from the inception of the ongoing outbreak and we compared current epidemiological trends and clinical features with those of previous outbreaks. Google Scholar was also searched to increase the chance of getting all relevant studies, not still indexed in the previously mentioned databases and to retrieve gray literature. The following keywords were utilized: “monkeypox,” “monkey pox,” “monkeypox virus”, “monkey pox virus,” “MPX,” “MPXV,” “variole du singe” (in French), “variole simienne” (in French), “viruela del mono” (in Spanish), “Affenpocken” (in German), “Affenpockenkrankheit” (in German), “Affenpockenvirus” (in German), and “varíola dos macacos” (in Portuguese).

The literature search was supplemented by extensive mining of websites from the major health authorities, including the World Health Organization, the US “Centers for Disease Control and Prevention,” the “UK Health Security Agency,” and the “European Centre for Disease Prevention and Control.”

2.2 Inclusion and exclusion criteria

Any relevant study design (case report, case series, cohort population study, clusters/outbreaks investigation, epidemiological or surveillance studies) reporting epidemiological and/or clinical data on the currently ongoing monkeypox epidemic in nonendemic countries (i.e., to say, countries outside of Africa) was considered eligible.

2.3 Monkeypox case definition

The Portuguese Directorate-General of Health (https://www.dgs.pt/normas-orientacoes-e-informacoes/orientacoes-e-circulares-informativas/orientacao-n-0042022-de-31052022-pdf.aspx) has proposed the following working definition for suspected, probable, and confirmed monkeypox cases. A suspected case is an individual of any age, clinically presenting with a localized or generalized rash (at any stage, macular, papular, vesicular, or pustular phase) and/or anogenital complaints (such as ulcers), with sudden symptom onset since March 15, 2022, after ruling out other differential diagnoses (including other sexually transmitted infections [STIs]). Moreover, this person presents one or more of the following signs/symptoms: namely, (i) sudden onset fever (≥38.0°C), (ii) asthenia, (iii) myalgia, (iv) backache, (v) headache, and (vi) lymphadenopathy. A probable case is defined when a subject, besides meeting the previous criteria, presents also one or more of the following signs/symptoms: namely, (i) contact with a suspected, probable, or confirmed monkeypox case within 21 days before the onset of symptoms, (ii) sexual intercourse with multiple or anonymous random sexual partners within 21 days before the symptom onset, (iii) hospitalization due to a clinical condition consistent with a suspected case, and (iv) travel history to monkeypox-endemic countries within 21 days before the symptom onset. Finally, a confirmed case is an individual with a laboratory-proven monkeypox infection (in a clinical sample, using reliable and validated techniques, such as real-time polymerase chain reaction [PCR] and/or nucleotide sequencing). Similar working definitions have been proposed in other countries.

A slightly different working definition has been formulated by Bunge et al.²: a case is defined as suspected in presence of sudden onset of high fever, with a (vesicular or pustular) rash affecting the face, the palms of the hands, and the soles of the feet, or if at least five smallpox-like scabs are present. A case is defined as possible when it exhibits a typical rash (vesicular, pustular, or crusty), for which the primary healthcare or family provider has ruled out a diagnosis of chickenpox, if it reports a history of rash and fever, if one of the epidemiological criteria is met or raised concentrations of Orthopoxvirus-specific antibodies (immunoglobulin M [IgM]) have been proven, with unexplained rash and fever and two other signs/symptoms from the clinical criteria.^4-6 A case is probable if it meets the criteria of a suspected case but there is no possibility to have a laboratory confirmation, however, a robust epidemiological link to a confirmed case exists. Finally, a confirmed case is a laboratory-proven suspected case (positivity of IgM antibodies, positive PCR testing result, and/or virus isolation). The feasibility of the working definition by Bunge et al.² will be discussed in the following sections.

2.4 Statistical analysis

Relevant data (surname of the first author, journal, study country, study period, monkeypox case working definition, sample size, sex/gender and sexual orientation, age, human immunodeficiency virus (HIV) status and sexual health, epidemiological exposures, smallpox vaccination status, signs/symptoms at clinical presentation, clinical course/evolution, hospital admission, treatment/management, diagnosis, and outcome) were extracted, and when possible and appropriate, were pooled together, conducting a descriptive statistical analysis.

3.1 Sex, gender, and sexual orientation

The subjects retained in the pooled data analysis were all males, with most reporting sexual intercourse with same-gender individuals (97.14%). Only one of the Portuguese cases¹¹ was a man having sex with a woman. Pooling this data together with information provided by Vivancos et al.,¹² an overall rate of 87.72% of MSM was computed.

3.2 Age

A total of 54.29% of the individuals were in their 30s, with 8.57% and 2.86% of cases in their 40s and 50s, respectively; 20.00% of subjects were in their 20s. In a few cases (14.29%), age was unknown. The Portuguese sample¹¹ had a median age of 33 years, ranging from 22 to 51 years with the majority (n = 13, 48.15%) aged 30–39 years. Similarly, the English sample¹² had a median age of 38 years, ranging from 32 to 43 years.

3.3 HIV status

A total of 54.29% were HIV-positive, whereas the remaining were HIV-negative generally on HIV pre-exposure prophylaxis (PrEP), either daily or event-driven/on-demand.

3.4 Smallpox vaccination status

Two cases documented being vaccinated against smallpox: a young individual in his 30s from the Italian cluster⁷ and one middle-aged from the Portuguese cluster.¹¹

3.5 Signs/symptoms at clinical presentation

The most prevalent sign/symptom reported was fever (in 54.29% of cases) followed by inguinal lymphadenopathy (45.71%) and exanthema (40.00%). Asthenia, fatigue, and headache were described in 22.86% and 25.71% of the subjects, respectively. Myalgia was present in 17.14% of the cases. Both genital and anal lesions (ulcers and vesicles) were reported in 31.43% of the cases. Finally, cervical lymphadenopathy was described in 11.43% of the sample, while the least commonly reported symptom was axillary lymphadenopathy (5.71% of the case series). The English cluster cases (5.71%) presented diarrhea.⁹

3.6 Infection evolution

In all cases, the evolution of the lesions was asynchronous, developing in multiple stages, with some of them forming scabs and crusts while others were still in the early papular (umbilicated papulae with progressive central ulceration), vesicular, and pustular phases. Of note, most cases reported a story of previous STIs, including syphilis, hepatitis A, B, and C. Syphilis was the most commonly reported STI. Interestingly, there was a case of likely coinfection of syphilis and monkeypox.⁸

3.7 Transmission route

Sexual exposure could be documented in 91.67% of the cases. Sexual intercourse was unprotected (condomless) with multiple, random/anonymous sexual partners. Of note, 14/16 of the Portuguese cases¹¹ reported sexual exposure, and in seven cases sexual encounters occurred in saunas and other venues. All four Italian cases⁷ reported sexual encounters: three cases during festivals and gathering events, and one case during sex work. The Czech case⁸ reported random sexual encounters during the festival/gathering event in Maspalomas (Spain).

Concerning other potential transmission routes and epidemiological exposures, three cases from the Portuguese cluster¹¹ had contact with animals (two cases with cats and one case with pigs), while only one case from the same cluster reported contact with another case.

3.8 Outcomes

No deaths were so far reported.

4.1 Sex, gender, and sexual orientation

All cases included in our review were males, having unprotected sex with men, mostly in their thirties. This is in line with other studies: Vivancos et al.¹² reported that (at least) 83% of the cases they analyzed were known to be gay or bisexual. In previous outbreaks of at least two cases as well in single clusters that occurred in African countries, males represented ≥50% of the confirmed cases. In nonendemic countries, males were most affected.²

4.2 Age

Generally, subjects included in the present review were in their 30s. Similarly, Vivancos et al.¹² computed a median age of their cases of 38 years (interquartile range, 32–43 years). Moreover, young individuals were more likely to be sexually active and engaged in mass gathering events/festivals. This represents a significant shift in the epidemiological trend of monkeypox: in countries where monkeypox is endemic, and in the early years (1970–1989), monkeypox was primarily a disease affecting young children, with a median age at the clinical presentation of 4–5 years. Mean age has increased to 10 years in 2000–2009 and 21 years in 2010–2019, suggesting a major role of smallpox vaccination discontinuation and waning of immunity. In the 2003 US outbreak, 10 out of 34 (29.41%) were less than 18 years.²

4.3 Smallpox vaccination status

Subjects reviewed, as expected, were young because older individuals were protected against monkeypox by the smallpox vaccination. Of note, one of the four Italian monkeypox cases (25.0%), who was in his 30s, reported being vaccinated against smallpox.⁷ The proportion of vaccinated subjects affected by monkeypox in both endemic African and nonendemic countries in previous outbreaks ranges from 4% to 21%, with the highest percentage reported during the US 2003 outbreak.²

4.4 Transmission route

Despite the sexual transmission route is not generally associated with monkeypox infection, being skin-to-skin, or respiratory, most cases reported genital and/or (peri-)anal lesions, suggesting that sexual intercourse is likely to play a key role. Indeed, the lesions mirror the point of skin-to-skin sexual contact and the type of sexual intercourse and there is a significant temporal association of symptoms to sexual intercourse.⁹ On the other hand, the Israeli case of the 2018 cluster¹⁷ reported a lesion affecting his penile shaft and the epidemiological assessment was able to link the case to exposure to Africant infected rodent carcasses.

Concerning risk factors, the Australian case¹⁰ reported unprotected sexual intercourse with four random sexual partners during his travel to Europe. Seven of the Portuguese cases¹¹ had attended a sauna. Interestingly, one of the four Italian cases was a sex worker. This occupational risk factor warrants further investigations. From a biological perspective, the seminal fluid obtained from some of the cases reviewed was found to be positive for the monkeypox virus, with quantification cycle (Cq) values comparable to those obtained for nasopharyngeal swabs. However, correlations between viral seeding in the male reproductive tract, viremia, and viral shedding/transmissibility are not obvious and still unknown. The presence of the monkeypox virus in the semen could be just a consequence of the systemic dissemination of the virus itself and the viremia, due to the imperfection of the blood–testis barrier and the immune-privileged nature of the testes (“the sanctuary site theory”).

Concerning other potential transmission routes, three of the Portuguese cases reported contact with animals (a pig in one case, and cats in two cases), and one from the same cluster reported contact with another monkeypox case. Contact with other cases was reported also for three of the English cluster,¹² documenting a household outbreak, as previously mentioned.

4.5 Infection course

Generally, the infection course was mild, with no severe symptoms (such as dyspnea) being reported and with complications being described only in a few cases. For instance, the Australian case¹⁰ experienced a superinfection (a superimposed bacterial cellulitis of his penile shaft and lower central abdomen). Laboratory exams (full blood-work, and biochemistry liver function tests) were in the normal ranges, with mildly increased C-reactive protein levels. Usually, in monkeypox, evolution and dissemination of the rash is monomorphic and centrifugal, with lesions concentrated on the face and peripheral extremities, but unusual presentations, with initial genital rashes and face and extremities relatively spared by the virus, are possible and have been particularly observed during the ongoing monkeypox epidemic. Of note, one of the Italian cases⁷ and one of the English cases¹² presented a rash limited to the genital and pubic areas. In a few cases, there were no prodromal symptoms, atypically followed by systemic symptoms/signs.⁹

4.6 Monkeypox virus and HIV

Another point that merits further studies is the interplay between HIV and the monkeypox virus. This topic has been relatively underlooked in the existing scholarly literature, with a few exceptions. For instance, in a study conducted in Nigeria,²⁰ where the monkeypox is endemic, the authors found that HIV status impacted the clinical course of the infection. Clinical variables associated with HIV positivity were genital ulcers (odds ratio [OR]: 1.94 [95% confidence interval {95% CI}: 1.38–2.72], p = 0.015), secondary infections and complications (OR: 3.1 [95% CI: 1.86–5.16], p < 0.0001), rash size, equal to or greater than 2 cm (OR: 12.7 [95% CI: 1.4–114.4], p = 0.020), and duration of illness, equal to or longer than 28 days (OR: 9.3 [95% CI: 1.36–63.9], p = 0.029). However, other variables, including age group, sex, hospital day, and outcome, had no statistically significant correlation. Mobility and rash distribution resulted in a borderline significant association (p = 0.09 and p = 0.06, respectively).

4.7 Outcome

No fatalities were reported so far for the case series reviewed in the present study. According to Bunge et al.,² the case fatality rate (CFR) of monkeypox is computed at 8.7% (95% CI: 7.0–10.8), being higher for the central African clade (10.6% [95% CI: 8.4–13.3]) compared to the Western clade (3.6% [95% CI: 1.7–6.8]). When restricting the analysis to endemic countries only, Bunge et al.² computed a value of 4.6% (95% CI: 2.1–8.6) for the CFR of the Western clade. CFR of the US 2003 outbreak was 0% (no deaths reported for the 47 cases).

4.8 Implications for public health

The ongoing monkeypox epidemic represents a true challenge in terms of global/public health.^21-24 Contact tracing is rather difficult and unfeasible given that most cases were engaged in risky behaviors with multiple anonymous partners. Only 28% of sexual contacts of the English cases had details that could be fully disclosed and reported.¹² For this reason, the involvement of all relevant actors and stakeholders—professional agencies, third sector organizations, LGBTQI+ associations, organizers of Pride festivals and related events, and developers of geospatial dating apps—is absolutely necessary. Furthermore, a stigmatizing approach should be avoided.¹⁸ Besides tracing close contacts as much as it is possible, the implementation of an integrated and concerted package of public health interventions such as home isolation/quarantine, pre- (PrEP), and postexposure prophylaxis with smallpox vaccine when indicated, along with sexual health promotion should be considered. Since willingness of immunizing against smallpox seems to be rather low among at-risk groups (approximately 14%),¹² awareness campaigns should be conducted. So far, Belgium has been the first to introduce a 21-day monkeypox-induced mandatory quarantine. Finally, a standardized definition of monkeypox should be formulated, potentially updating previous working definitions and including unusual/atypical clinical presentations of monkeypox lesions.

4.9 Study limitations

The present study has several shortcomings, that should be properly acknowledged. Data are not complete and still preliminary, drawn from a relatively small cohort/population, and the epidemic is still ongoing, with cases expected to significantly increase. On the other hand, understanding the main determinants of the monkeypox infection is of paramount importance and extremely urgent and could effectively assist the public health response to the outbreak.

4.10 Future directions and prospects

This review should be considered a “living review” and will be updated when new data emerge.