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Often enough, monkeypox can present as anorectal pain or as a single genital lesion and easily be misdiagnosed as a sexually transmitted infection (STI), according to authors of the largest case series yet of the current international outbreak.

Of more than 500 infections diagnosed, predominantly in men who have sex with men (MSM), 95% presented with a rash, 73% had anogenital lesions, and 41% had mucosal lesions, reported Chloe Orkin, MD, of Queen Mary University of London, and colleagues.

Additionally, 15% of the patients had anorectal pain and 10% presented with only a single skin lesion in the genital area, according to the findings in the .

"The current international case definitions need to be expanded to add symptoms that are not currently included, such as sores in the mouth, on the anal mucosa, and single ulcers," Orkin said in a statement. "These particular symptoms can be severe and have led to hospital admissions so it is important to make a diagnosis."

Different presentations such as solitary genital skin lesions and lesions on the palms and soles can lead to misdiagnosis as syphilis and other STIs such as herpes, which may in turn delay detection, the researchers noted.

"Expanding the case definition will help doctors more easily recognize the infection and so prevent people from passing it on," Orkin continued. "Given the global constraints on vaccine and antiviral supply for this chronically underfunded, neglected tropical infection, prevention remains a key tool in limiting the global spread."

The analysis included 528 people diagnosed between April 27 and June 24 across 16 countries. Overall, 98% of the individuals were MSM -- the study sample included nine heterosexual men with monkeypox. Median age was 38, three-fourths were white, and 41% had HIV, which in the vast majority was well controlled. Clinically, the presence of HIV infection did not significantly affect the presentation of monkeypox, the researchers said.

Anorectal lesions associated with anorectal pain, proctitis, tenesmus, diarrhea, or a combination of these were seen in 61 persons, the researchers noted, while 26 persons presented with oropharyngeal symptoms including pharyngitis, odynophagia, epiglottitis, and oral or tonsillar lesions. In three individuals, the initial symptoms were conjunctival mucosa lesions.

The team noted a wide range of skin lesions presenting in several phases simultaneously, with 58% of those studied described as vesiculopustular. Regarding the number of lesions, although 39% of the patients had fewer than five lesions, the number increased over time and occurred with or without systemic features. Rash was accompanied or preceded by systemic symptoms including fever (62%), lethargy (41%), myalgia (31%), and headache (27%); lymphadenopathy was also common, affecting 56%.

Monkeypox transmission was suspected to have occurred through sexual activity in 95% of the cases -- a theory supported by "the findings of primary genital, anal, and oral mucosal lesions, which may represent the inoculation site," the authors noted. Potential risk factors included numerous sex partners, recent international travel, and attendance of large gatherings or sex-on-site venues.

Notably, concomitant STIs were reported in 29% of those tested. The researchers urged clinicians to consider monkeypox in at-risk persons presenting with traditional STI symptoms.

"It is important to stress that monkeypox is not a sexually transmitted infection in the traditional sense," said co-author John Thornhill, MD, PhD, also of Queen Mary University. "It can be acquired through any kind of close physical contact. However, our work suggests that most transmissions so far have been related to sexual activity -- mainly, but not exclusively, amongst men who have sex with men."

While the virus DNA was present in semen samples for 29 of 32 persons tested, "this may be incidental as we do not know that it is present at high enough levels to facilitate sexual transmission," Thornhill added. "More work is needed to understand this better."

How long the virus remains infectious after lesions have cleared also remains unclear, the investigators said, adding that U.K. Health Security Agency guidelines have advised condom use for 8 weeks after infection.

Overall, 5% of the persons in the study received antiviral treatment, most often with cidofovir or tecovirimat (Tpoxx); 13% were hospitalized, primarily for severe anorectal pain and soft-tissue superinfection. Overall, "clinical outcomes in this case series were reassuring," the researchers wrote. "Most cases were mild and self-limited, and there were no deaths."

The team noted that 9% of patients reported having received smallpox vaccination, but data were too limited to comment on its potential effect.

Study limitations, the researchers said, included that the symptom-driven enrollment may have missed people who were asymptomatic or had mild symptoms, while those with HIV may have been over-represented due to referrals from HIV clinics.

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