Before April 2022, human monkeypox was a rare viral zoonotic disease endemic to West and Central Africa [1,2]. The disease, first recognized in 1970, resembled smallpox clinically but differed epidemiologically. It was recognized that smallpox vaccination protected against monkeypox virus infection, as the majority of reported cases were unvaccinated children younger than 10 years of age. Secondary spread among susceptible close contacts was distinctly uncommon (5%), much lower than that reported from smallpox (25% to 40%) [3]. Human monkeypox occurred infrequently, and the spread of disease among susceptible close contacts was limited, suggesting the virus was not sufficiently transmissible to permit sustained propagation of infection in humans. Thus, monkeypox disease was not considered to be an important public health problem [3].

Monkeypox virus is a member of the orthopoxvirus family of viruses, the same family as variola virus, the cause of smallpox. Symptoms and signs are similar to smallpox but milder, and case fatalities are rare. The characteristic clinical syndrome begins with systemic symptoms, fever, and lymphadenopathy followed by the onset of a striking papulovesicular skin eruption of varying severity. Absent complications (e.g., pneumonitis, encephalitis, secondary bacterial skin and soft tissue infection), the illness tends to resolve in two to four weeks. In the decades before smallpox eradication in 1980, prevailing natural and vaccine immunity to variola within population groups provided immune cross-protection against related orthopoxvirus infections, including monkeypox [2,3]. During this period of widespread attention to variola, clinical recognition of other pox-like infections was obscured, and occasional intercurrent cases of monkeypox were likely attributed to mild smallpox [1].

Several factors of public health importance are thought to be driving the current global monkeypox outbreak: biologic changes in the virus that affect transmission; waning of herd immunity to smallpox; changes in human behavior, such as relaxation of COVID-19 preventive measures and resumption of international travel; and sexual interactions associated with large gatherings, suggesting an amplification of transmission through sexual networks [11]. Women and children account for a small (~2%) subset of cases, indicating the potential for wider spread and the propensity for anyone to become infected who has been in close contact with someone who has monkeypox.

Unlike endemic case clusters of monkeypox previously reported, human-to-human transmission is common in the 2022 outbreak and accounts for the scope and rapidity of spread. As indicated, human spread of monkeypox occurs through close, sustained physical contact that permits direct exposure to body fluids or material from open skin and mucosal lesions. Examples of intermediate- and high-risk exposures associated with the 2022 monkeypox outbreak include [10]:

The incubation period of monkeypox is 5 to 21 days [1]. As noted, illness usually begins with a prodromal phase of fever, malaise, headache, myalgias, and lymphadenopathy. This is followed in one to five days by the onset of a maculopapular skin eruption and/or mucosal lesions, most pronounced on the face and extremities. According to WHO 2022 outbreak data, the most common sites for skin and mucosal lesions are face (95%), palms and soles (75%), oral mucus membranes (70%), genitalia (30%), and conjunctivae (20%) [1]. Typically, the skin lesions progress in stages from maculopapular to papulovesicular to umbilicated pustules before crusting over and desquamating within a period of two to four weeks. Unusual features of the rash associated with the current outbreak include the following: mucosal lesions more numerous than previously described; lesions confined to atypical locations, such as the genital or perineal/perianal area, as well as the mouth and eyes; and development of rash or mucosal lesions prior to onset of constitutional symptoms [1].

The incubation period of monkeypox is 5 to 21 days [1]. As noted, illness usually begins with a prodromal phase of fever, malaise, headache, myalgias, and lymphadenopathy. This is followed in one to five days by the onset of a maculopapular skin eruption and/or mucosal lesions, most pronounced on the face and extremities. According to WHO 2022 outbreak data, the most common sites for skin and mucosal lesions are face (95%), palms and soles (75%), oral mucus membranes (70%), genitalia (30%), and conjunctivae (20%) [1]. Typically, the skin lesions progress in stages from maculopapular to papulovesicular to umbilicated pustules before crusting over and desquamating within a period of two to four weeks. Unusual features of the rash associated with the current outbreak include the following: mucosal lesions more numerous than previously described; lesions confined to atypical locations, such as the genital or perineal/perianal area, as well as the mouth and eyes; and development of rash or mucosal lesions prior to onset of constitutional symptoms [1].

The possibility of monkeypox should be considered in any patient with compatible clinical syndrome (e.g., any combination of fever, rash, lymphadenopathy) and epidemiologic risk factors, such as travel or animal exposure connected to endemic areas of virus circulation or recent history of sexual activity involving persons known or suspected of monkeypox disease. The differential diagnosis includes other infections that present with generalized or focal skin lesions (e.g., herpes, varicella zoster, secondary syphilis, acute streptococcal or meningococcal infection). The presence of lymphadenopathy helps distinguish monkeypox from other, similar viral exanthems (e.g., varicella zoster, chickenpox). The laboratory diagnosis of monkeypox relies on DNA PCR testing of specimens (scrapings) obtained from skin or mucosal lesions. PCR testing of blood samples are usually inconclusive because of the short duration of viremia relative to the timing of specimen collection [1]. Serologic testing is unreliable for monkeypox-specific confirmation because of common cross-reactivity with other orthopoxviruses and vaccination.

The characteristic skin eruption of monkeypox disease exhibits the following features: deep-seated and well-circumscribed lesions, often with central umbilication (Image 1), and lesion progression through specific sequential stages—macules, papules, vesicles, pustules, and scabs. It is sometimes confused with other diseases that are more commonly encountered in clinical practice (e.g., secondary syphilis, herpes, varicella zoster). Historically, sporadic accounts of patients co-infected with monkeypox virus and other infectious agents (e.g., varicella zoster, syphilis) have been reported, so patients with skin lesions typical for monkeypox should be considered for testing, even if other tests are already positive [13]. Key characteristics for identifying monkeypox rash, including instructive photographic images of skin lesions in sequential stages, are provided at the CDC website, accessible at https://www.cdc.gov/poxvirus/monkeypox/clinicians/clinical-recognition.html [14].

VIG can be considered for prophylaxis against monkeypox in an exposed person with severe immunodeficiency in T-cell function for which smallpox vaccination following exposure to monkeypox virus is contraindicated [12].

In the context of the current national Public Health Emergency (PHE), an alternative regimen to subcutaneous JYNNEOS vaccine administration may be used. The authorized alternative regimen involves an intradermal route of administration with an injection volume of 0.1 mL. This approach could increase the number of available JYNNEOS vaccine doses by up to five-fold. Results from a clinical study showed that the lower intradermal dose was immunologically non-inferior to the standard subcutaneous dose [20].