FormalPara Key Points

Genital skin lesions are a dominant symptom in the recently reported mpox cases.

Dermatologists and healthcare professionals should be more cautious and take certain preventive measures since they are usually in close contact with patients infected with the mpox virus.

Clinicians usually recommend symptomatic treatment for mpox patients; however, tecovirimat and brincidofovir, two smallpox drugs, can be recommended off-label for severe mpox infections.

ACAM2000® and JYNNEOSTM, two smallpox vaccines, can be used as prophylaxis against mpox infection, however JYNNEOSTM possesses less adverse effect potential than ACAM2000®.

1 Introduction

The 2022 monkeypox (mpox) outbreak has initially raised fears of another upcoming pandemic following the recent coronavirus disease 2019 (COVID-19) pandemic [1]. The World Health Organization (WHO) declared the current mpox outbreak as a Public Health Emergency of International Concern (PHEIC) on 23 July 2022 [2]. At that time, there were only about 16,000 cases worldwide, reported from 75 countries; many more cases have been reported to date. The mpox virus was first isolated in the State Serum Institute, Copenhagen, Denmark, in 1958 from a captive cynomolgus monkey and was named after the host animal [1]. Notably, the WHO has recently recommended using a new preferred term, ‘mpox’, for monkeypox [3]. In this very first reported instance, the virus did not infect humans working in the research laboratory. However, other hosts, including rope squirrels, tree squirrels, Gambian pouched rats, and dormice, appeared as natural reservoirs of the mpox virus [4]. In 1970, the first human case was identified in the Democratic Republic of the Congo [1, 5]. Thus far, 110 countries, including the US, Canada, and the UK, have reported mpox cases since January 2022, whereas previously, mpox infections were mainly observed in just a few countries located on the African continent [4, 6].

Patients with mpox infection routinely exhibit cutaneous symptoms [7]. Therefore, dermatologists are well-placed to establish this diagnosis. Their knowledge base and experience may allow them to educate and prepare frontline healthcare professionals to presumptively identify new cases [7]. This article reviews differential diagnosis, how symptoms of 2022 mpox infections differ from past cases, its mode of transmission, prevention, and current treatments.

2 Virology of Monkeypox (Mpox) Virus

Genome sequencing to date has identified two mpox variants or clades; clade 1 (formerly known as the Congo Basin or Central African clade) and clade II (formerly known as the West African Clade) [8]. Clade II also has two subclades, clade IIa and IIb [8]. Clade I is reported to be more transmissible and virulent than clade II [9]. Notably, Clade II, more specifically clade IIb, has caused the current 2022 mpox outbreak [10]. Likos and co-workers tried to differentiate between two clades and identified multiple candidate genes that may be responsible for the observed differences [9].

Additionally, mpox variants are continuously evolving. A recent study reported possible microevolution of the mpox virus, which may enhance the virus’s human adaptation [11]. Mutations in APOBEC3 (apolipoprotein B mRNA-editing catalytic polypeptide-like 3), a host genome editing enzyme, may be responsible for this microevolution [11]. Further studies are required to determine whether APOBEC3-mediated genome editing is causing excess mutations observed in the 2022 mpox outbreak [11].

3 Diagnosis, Disease Progression, and Prognosis of Mpox Infection

3.1 Clinical Symptoms and Differential Diagnosis

The clinical features of mpox, chickenpox, and smallpox are relatively similar [12]. Table 1 compares mpox, smallpox and chickenpox, and presents their differential diagnosis [12,13,14,15]. The common symptoms of mpox include high fever, chills, headache, swollen lymph nodes, muscle aches, and a painful cutaneous eruption that usually appears as raised bumps on the skin and tends to distribute on the face, genitals, and extremities (Fig. 1) [12, 15, 16]. The eruption typically progresses rapidly from macules to papules, papules to vesicles, vesicles to pustules, pustules to umbilicated pustules, and finally to a crusted residual [13, 17]. Mpox patients may not have all types of lesions during an eruption, and not all of their lesions may not be in the same stage [13]. However, a study that examined 185 mpox cases in Spain in 2022 found that the first lesions were uniform and papular (pseudo-pustules), not pustules [18].

Table 1 Comparison of mpox, chickenpox, and smallpox and their differential diagnoses [13, 14]
Full size table
Fig. 1
figure 1

Common symptoms of monkeypox infection

Full size image

A recent cohort study conducted on 70 male mpox patients who had sex with men found that over one-third of the patients had proctitis [19]. In two-thirds of those cases, no sign of typical rash was evident, and in one-fifth, there was no visible sign of rash, making it challenging to diagnose. However, a polymerase chain reaction (PCR) of a rectal swab could help diagnose the mpox infection.

Huhn and colleagues studied 34 patients with confirmed mpox infection during the US outbreak in 2003 [20]. The majority of the patients reported rash (97%), followed by fever (85%), chills (71%), adenopathy (71%), headache (65%), and myalgias (56%) [20]. Approximately 68% of patients (n = 31) had a monomorphic rash, whereas 29% exhibited a pleomorphic rash. This is a key differentiating feature from smallpox, where monomorphic pustules or crusting lesions (but not both at the same time) are virtually always seen (Fig. 2). Additionally, generalized centrifugal rash distribution was more common (48.4%) than localized distribution (25.8%) [20].

Fig. 2
figure 2

Polymerase chain reaction-verified pleomorphic monkeypox demonstrates both pustules and crusts.

Full size image

3.2 2022 Mpox Outbreak

As of 25 March 2023, 110 countries have reported 86,646 confirmed and several thousand probable cases of mpox infection, including 112 deaths [6]. Based on the available data, approximately 96.4% of patients were male, with a median age of 34 years. This indicates that the young male population (18–44 years) had a higher incidence of infection in the recent outbreak [6, 21]. In 84.2% of cases, patients identified their sexual orientation as men who have sex with men (MSM) [6, 21]. Approximately 48.4% were HIV-positive among the patients who disclosed their HIV status [6, 21]. Additional epidemiological risk factors identified in retrospective case analysis included recent exposure to multiple, often anonymous, sexual partners and attending pride events [21].

Currently, the number of newly reported mpox cases is trending negative, both globally and in the US [6]. The global number peaked between 8 and 14 August 2022; 7477 new mpox cases were reported.

3.2.1 Anogenital Skin Lesions are a Dominant Symptom in the 2022 Outbreak

An observational study published in The Lancet Infectious Diseases found that mpox infection symptoms in recent cases were different than in past outbreaks [22]. The presence of one or more anogenital skin lesions was a dominant symptom [22]. All 54 patients included in the study had skin lesions, of which 94% (51/54 patients) were anogenital, 89% of patients reported lesions presence in more than one anatomical site, and 7% had oropharyngeal lesions [22]. On the other hand, 67% experienced fatigue, 57% reported fever, and 18% did not present with any prodromal symptoms [22]. In some instances, the genital ulcers were painless with bilateral inguinal lymphadenopathy, mimicking primary syphilis [23].

An international collaborative group of physicians who monitored 528 mpox infections in 2022 also found anogenital lesions as one of the predominant symptoms [21]. While 73% of patients reported anogenital lesions, mucosal lesions appeared in 41% of the patients [21]. Rash appeared in 95% of mpox patients, and other common symptoms were fever (62%), lymphadenopathy (56%), lethargy (41%), myalgia (31%), and headache (27%) [21].

Since clinical symptoms are variable and different in the 2022 outbreak, Tarín-Vicente and colleagues opined that dermatologists and healthcare professionals should maintain a low threshold when examining patients with possible mpox infection [24]. This same research group pointed out that the location of lesions in the present outbreak most often correlated with the type of sexual activity performed [24]. Perianal lesions, for example, would occur in an individual who had receptive anal intercourse (Fig. 3a, b). Oral lesions result from oral sex performed on an already infected individual, while facial lesions may result from performing rimming on an infected partner or simply from kissing (Fig. 4).

Fig. 3
figure 3

a Perigenital PCR-verified mpox lesions in a woman following vaginal intercourse with a bisexual man who was subsequently diagnosed with penile and suprapubic mpox. b PCR-verified umbilicated pustule typical of mpox. PCR polymerase chain reaction, mpox monkeypox

Full size image
Fig. 4
figure 4

Facial monkeypox following ‘rimming’ an infected partner

Full size image

3.3 Laboratory Testing

Timely and accurate testing of mpox infection is vital for breaking the transmission chains and thus stopping the outbreak [25]. Clinicians should recommend appropriate laboratory testing for any patients with suspected mpox infection. The test uses real-time or conventional PCR, alone or in combination with sequencing, to detect unique viral DNA sequence [25]. Laboratory specimens can be lesion surface swabs and/or exudate, roofs collected from more than one lesion, or lesion crusts [25]. It is important that the swab used to collect exudate or lesion base specimens be made of dacron, nylon or polyester, and not of cotton, to ensure proper transfer to testing media. The person who collects the specimen, and the laboratory staff, should handle it carefully and follow a risk-based approach. Depending on the laboratory, one may receive a positive report that reads ‘non-variola orthopox virus detected’. Since no other orthopoxviruses are currently of epidemiologic significance, this is equivalent to a presumptive diagnosis of mpox. WHO recommends notifying all test results, positive or negative, to the national authorities [25].

3.4 Disease Progression and Prognosis

Although mpox infection is often self-limited, generally lasting 2–4 weeks, it may lead to severe complications in some cases [4]. Special populations, such as patients younger than 8 years of age, pregnant women, and immunocompromised individuals (particularly those with untreated or poorly controlled concurrent HIV infection), are more prone to develop mpox-related complications [4]. Such complications may include confluent and necrotic skin lesions, fatigue, sore throat, headache [26], secondary bacterial sepsis, ocular infection leading to keratitis, encephalitis, and myocarditis. The mortality rate of mpox infection has been estimated to be between 0 and 11% in the general population of African countries [27], with the highest mortality rate being observed in young children [27]. As of 25 March 2023, the fatality rate of the current 2022 outbreak was approximately 0.13% (112/86,646) [6]. Moreover, individuals under 40–50 years of age may be more susceptible to mpox infection due to the discontinuation of routine smallpox immunization in the early 1980s following smallpox worldwide eradication [27].

4 Transmission of the Mpox Virus

Mpox does not spread through long-range airborne transmission like COVID-19 [28]. In airborne transmission, small virus particles stay suspended in the air for an extended period and become a potential source of infection [28]. However, mpox may theoretically spread through droplet transmissions (e.g., an infected individual’s respiratory secretions or saliva) [28]. Of note, Peiró-Mestres and co-workers identified mpox in saliva in 12/12 specimens tested; the clinical significance of this finding as it relates to transmission is still uncertain [29].

Mpox spread occurs through both animal-to-human (zoonotic) and human-to-human transmission [30]. Some examples include (1) contact with infected animals (monkeys, wild rats, or rope squirrels); (2) close contact with an mpox patient; (3) transmission through clothes, bedding, or towels used by an infected individual; (4) prolonged exposure to respiratory secretions, droplet or saliva of an mpox patient; (5) direct contact with skin lesions, lesion exudate or crust; and (6) butchering, handling or consuming meats of infected animals [28, 30, 31]. Mpox infection may also transmit from mother to fetus through the placenta [30]. While the zoonotic transmission route remains important in cases seen in Africa, the current global outbreak seems to be primarily spread by intimate human-to-human contact (i.e., sexual contact).

However, walking by an infected individual in a shopping mall or having a casual conversation poses a very low risk of transmission [28]. Although it is still unclear, mpox may spread through sexual routes such as contact with vaginal secretions or semen. Researchers are also actively investigating via infection modeling whether presymptomatic mpox-infected patients can spread the disease, which appears to be both likely and common [28, 32].

5 Prevention of Mpox

5.1 Clinicians and Healthcare Professionals

The prevention of mpox infection in clinicians or healthcare professionals is more challenging since they are usually in close contact with infected patients [4]. To minimize the infection risk, a healthcare professional should follow the recommendations such as (1) avoiding direct contact with skin lesions or materials used by mpox patients; (2) wearing personal protective equipment, including a gown, gloves, eye protection, and a fitted N95 mask when treating a patient with skin rash; (3) masking the patient with suspected or confirmed mpox infection immediately, covering the skin lesions with a gown or cloth, and placing the patient in isolation, preferably in a single-person room; (4) placing the patient in a negative-pressure room in the hospital (if hospital care is required); and (5) wearing gloves while handling the laundry of mpox patients (Fig. 5a) [4].

Fig. 5
figure 5

a Recommendations to minimize the mpox infection in clinicians and healthcare professionals. b Recommendations for individuals to limit the spreading of mpox infection. mpox monkeypox

Full size image

5.2 Individuals

An individual may limit the spread of mpox by paying attention to the following: (1) a patient with suspected or confirmed infection should stay home and limit contact with others; an immunocompetent individual, with mild mpox symptoms, should stay away from others for 3–6 weeks [33]; (2) an individual should avoid intimate contact, including sexual contact, with someone infected or exposed to the mpox virus; (3) individuals should maintain good hand hygiene and respiratory etiquette, such as wearing a fitted mask and covering coughs and sneezes with the bend of arm or a piece of tissue or cloth; and (4) after having visitors at home, proper cleaning and disinfection of high-touch areas are recommended [34]. Additionally, using condoms, practicing safe sex, and having fewer sexual partners may help reduce mpox spread (Fig. 5b) [34]. In the US, a recent Centers for Disease Control and Prevention (CDC) survey study showed that about half of those at the highest risk have in fact already modified their sexual practices and number of sexual partners [35].

5.3 Pre-exposure Prophylaxis

The available data indicate that smallpox vaccination may have 85% cross-protection against mpox [36]. Some experts opined that ending routine smallpox vaccination after the disease was declared eradicated in 1980 could be partly responsible for the recent mpox resurgence [37]. ACAM2000® (smallpox [vaccinia] vaccine, live) [38] and JYNNEOSTM (vaccinia virus modified strain ankara-bavarian nordic non-replicating antigen) [39] are the two licensed vaccines currently available in the US for smallpox prevention (Table 2) [36, 38, 40].

Table 2 Vaccines for monkeypox preventiona
Full size table

A recent study analyzed 2054 men who were eligible to receive a vaccine [41]. During the study period, 50% of the men were vaccinated with JYNNEOSTM and followed up for at least 90 days. During that time, 5 vaccinated and 16 unvaccinated individuals were confirmed to have been infected with the mpox virus. The study estimated the adjusted vaccine effectiveness of JYNNEOSTM to be 86%, with a 95% confidence interval of 59–95% [41]. This indicates that the risk of getting infected with the mpox virus was significantly lower for those who received a single dose of the subcutaneous JYNNEOSTM, which was administered to the high-risk cohort in the study.

Notably, the US FDA has approved only JYNNEOSTM for mpox prevention, which has less adverse effect potential than ACAM2000® [4, 36]. Both ACAM2000® (administered by pricking the skin with a two-pronged or bifurcated needle) and JYNNEOSTM (administered intradermally) vaccines exhibit cutaneous adverse effects. According to the Vaccine Adverse Event Reporting System (VAERS) database, ACAM2000® is mainly associated with skin rash (11.73%), erythema (7.66%), skin lesion (7.07%), pruritus (7.02%), and injection site erythema (6.91%). In comparison, JYNNEOSTM predominantly exhibits injection site erythema (10.16%), injection site swelling (8.64%), injection site pain (6.52%), urticaria (6.27%), erythema (5.84%), injection site pruritus (5.59%) and pruritus (4.06%) [42].

Currently, the CDC does not recommend pre-exposure prophylaxis against mpox for the general population [43]. According to the Advisory Committee and Immunization Practices (ACIP), eligible groups for pre-exposure mpox immunization include (1) individuals who are at risk of occupational exposure (i.e., research laboratory personnel, technicians performing orthopoxvirus diagnostic testing, members of a designated response team, and healthcare professionals administering ACAM2000® or caring for patients with orthopoxvirus infection); (2) gay, bisexual, other MSM, transgender or nonbinary individuals diagnosed with nationally reportable sexually transmitted diseases (i.e., gonorrhea, syphilis, acute HIV, chancroid, or chlamydia) in the past 6 months and have had multiple sex partners; (3) individuals who had sex at a commercial sex place or at large social gatherings in a geographic area where mpox infection is prevalent; and (4) individuals who have sexual partners falling in the category 2 or 3; and individuals who may experience the risks listed in category 2 or 3 [43].

5.4 Post-exposure Prophylaxis

Mpox is transmissible when an individual is exposed to an mpox patient for a prolonged period. Brief exposure, especially if the exposed individual uses appropriate personal protective equipment, may not require post-exposure prophylaxis [44]. An individual may be considered for JYNNEOSTM vaccination depending on the extent of exposure [4]. Table 3 details the CDC’s recommendations for high-, intermediate-, and low-degree exposure. The first dose of the vaccine should be administered within 4 days of exposure [45]. If administered late, within 4–14 days, the vaccination may not prevent disease but will reduce the symptom severity [44].

Table 3 Risk assessment and recommendations for post-exposure prophylaxis in patients exposed to mpox infections
Full size table

6 Treatment of Mpox

Currently, mpox infection has no approved treatments, therefore clinicians mostly recommend symptomatic treatment [4, 44, 46]. However, special cases such as patients with severe mpox infection, immunocompromised individuals, children younger than 8 years of age, and pregnant women may require antiviral treatment [4, 46]. The CDC recommends two antiviral drugs, tecovirimat and brincidofovir, for treating mpox infection (Table 4) [4, 44, 46,47,48,49,50,51,52,53,54,55]. Additionally, Table 4 lists the possible treatments for mpox and chickenpox infections [44, 47,48,49,50,51,52,53,54,55].

Table 4 Treatments for mpox and chickenpox infectionsa
Full size table

6.1 Symptomatic Treatment

6.1.1 Pain Management

Managing pain is important when treating mpox patients because pain is a frequent and often severe symptom (e.g., rectal pain, headache, muscle aches, pain from lesions, and lymphadenopathy pain) [56]. Pain management should be tailored to the individual patient, with a combination of non-pharmacologic and pharmacologic therapies as needed [57]. Clinicians should assess the pain at the beginning and then regularly, and pain management should be adjusted as required [56].

Mild pain can be treated with over-the-counter medications such as acetaminophen or ibuprofen, while short-term management of severe pain (e.g., severe rectal pain due to proctitis) may require opioids such as tramadol or morphine, after assessing the benefits and risks of opioid use [56, 57]. Rinsing with salt water at least four times a day may help patients who have rash inside the mouth [50]. Additionally, local anesthetics (e.g., viscous lidocaine) or prescription mouthwashes can be recommended to relieve the pain [56, 57]. Starting treatment with tecovirimat early on may help alleviate pain in patients with severe proctitis, but more evidence is needed [56]. Long-term follow-up is also important to quickly diagnose prolonged nociceptive syndromes, and consultation with a pain specialist may be required for refractory cases [56].

6.1.2 Rash Relief

Patients must try hard not to touch or scratch the rash [57]. Topical benzocaine or lidocaine gels can provide temporary relief. Oral histamines (e.g., Benadryl), topical preparations (e.g., calamine lotion), or petroleum jelly can help relieve itching. Additionally, a warm bath can help patients with itching sensations. Patients having rash in the anus or genital area may also try sitz baths [57].

6.2 Tecovirimat

The FDA originally approved tecovirimat for treating smallpox infection in 2018 [4]. Table 5 lists pharmacokinetics, contraindications, warnings and precautions, adverse reactions of tecovirimat, and its use in specific populations [48, 51, 58]. The drug hinders viral envelope formation by inhibiting p37 protein, a highly conserved sequence among all orthopoxviruses (Fig. 6) [59,60,61]. Since mpox is an orthopoxvirus, tecovirimat may show antiviral activity against mpox. In the US, patients with mpox infection can access tecovirimat from city, county, or state health authorities via a CDC and FDA-approved expanded access–investigational new drug (EA-IND) protocol [4].

Table 5 Antivirals for mpox treatmenta
Full size table
Fig. 6
figure 6

Mechanism of action of tecovirimat, brincidofovir and cidofovir. The diagram depicts a probable lifecycle of the mpox virus. Tecovirimat hinders viral envelope formation of orthopoxviruses (e.g., mpox and smallpox) by inhibiting p37 protein, a highly conserved sequence among all orthopoxviruses. Brincidofovir, a prodrug and lipid conjugate of cidofovir, can easily pass through the phospholipid bilayer compared with cidofovir. Cidofovir diphosphate competitively inhibits the viral DNA polymerase and thus hinders viral DNA replication. mpox monkey pox

Full size image

6.3 Cidofovir and Brincidofovir

Brincidofovir is the prodrug of cidofovir (Table 5) [48, 51, 58]. The FDA approved cidofovir in 1996 for cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome (AIDS), and brincidofovir in 2021 for smallpox infection. Similar to tecovirimat, patients with mpox infection may get access to brincidofovir from health authorities through a CDC- and FDA-sanctioned EA-IND protocol [4]. Figure 6 illustrates the mechanism of action of brincidofovir and cidofovir [59,60,61]. Brincidofovir may have a better safety profile compared with cidofovir, especially with regard to the potential for renal toxicity [4]. Both of these agents have important drug–drug interactions with various antiretroviral medications, and caution is advised when administering either to an HIV-positive patient who is also taking an antiretroviral therapy (ART) regimen (see Table 5 for details).

6.3.1 Topical Cidofovir

In a prospective study that included 24 mpox patients, half of the patients received only supportive care and the other half received supportive care plus topical cidofovir 1% cream [62]. The patients who used the cream healed faster than the patients who did not. The cidofovir 1% users got rid of the lesions within 12 days (median), while it took the other group 18 days (median). After 2 weeks, only 10% of patients who used topical cidofovir 1% had PCR-positive skin lesions, while 62.5% of patients who did not use cidofovir 1% had PCR-positive skin lesions [62].

6.4 Vaccinia Immune Globulin Intravenous

Although the benefit is uncertain, clinicians may consider intravenous vaccinia immune globulin intravenous (VIGIV) for patients with severe mpox infection, or prophylaxis for patients with T-cell immunodeficiency for whom post-exposure vaccination is prohibited [46, 50]. VIGIV is not pre-positioned in state health departments and must be requested directly from the CDC on a case-by-case basis.

7 Conclusion

Although mpox is remarkably less transmissible than the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, we must act now to stop community transmission and avoid the development of additional animal reservoirs. The public, healthcare professionals, and government should be vigilant and promote preventive measures and appropriate diagnostic testing. By including mpox in the differential diagnosis of (1) papulovesicular or vesiculopustular lesions and (2) genital lesions/ulcers, dermatologists may play an essential role in the timely diagnosis and treatment of new cases, thereby preventing the spread of the disease [7, 23].