Mpox: skin lesions, differential diagnosis and isolation

In a sexually transmitted infections outpatient clinic, a man in his early twenties arrives with painful sores in the anal region for five days and pain when passing stool. He reports having had a low fever and "swollen glands" in the groin before the lesions, and that a recent partner had something similar. On examination there are some umbilicated, firm lesions with a whitish center, along with enlarged and painful inguinal lymph nodes. The first hypothesis of the person attending may be herpes, and the second, syphilis. The scene is fictional and was written for teaching. This text uses this picture as a clinical reasoning scenario: how to think about mpox when faced with a skin lesion, how to tell it apart from herpes, syphilis, varicella and other causes, when and how to test, and why isolation and testing for other infections are part of the same consultation.

NEXO is a daily medical diagnosis game: one clinical case a day, up to six progressive clues, and ICD-10 proximity feedback across five levels.

The text is not a protocol. Notification, isolation flows, vaccination and access to antivirals follow national guidelines and the training of each service. The interest here is reasoning: why mpox misleads when the lesion is single, why lymphadenopathy is a valuable clue and why one diagnosis does not exclude another. If you play the case of the day on NEXO, you will recognize the move: two similar hypotheses call for the clue that separates them.

Key points

• Since 2022, mpox has often presented with few lesions, concentrated in the anogenital and oral regions, and not always in sequential stages.
• Lymphadenopathy is an important clue that helps separate mpox from varicella.
• The diagnosis is confirmed by PCR of material from the lesion, collected as soon as possible.
• Herpes, syphilis and other sexually transmitted infections can coexist with mpox, so testing should be broad.
• Most cases are mild and can be followed at home, with lesions covered and guidance on warning signs.

Why mpox is a reasoning scenario

Mpox is an infection caused by the mpox virus, an orthopoxvirus. For decades it was described mainly in countries of Central and West Africa, with cases linked to contact with animals and household transmission. In 2022, an outbreak on several continents changed the clinical picture of the disease, with transmission predominantly through close contact, including sexual contact. In 2024, the World Health Organization declared a new public health emergency of international concern, given the expansion of clade I in Africa, and ended that emergency in 2025, keeping permanent recommendations (World Health Organization, 2024).

The end of an emergency does not mean the end of the disease. Cases continue to appear, and mpox has entered the differential diagnosis of skin lesions in many services. The clinical challenge is no longer just recognizing an exotic disease; it has become distinguishing mpox from common diseases that look like it.

Different clades and contexts

The World Health Organization guideline describes two main clades, with subclades: Ia, Ib, IIa and IIb (World Health Organization, 2025). The 2022 outbreak was caused mainly by clade IIb, with transmission mostly through sexual contact between adults. Clade I, historically associated with more severe disease, drew attention again with the expansion of subclade Ib, which also spreads in households and affects children.

For the person attending, this difference changes the list of people to think about. In one context, the central question is about sexual partners. In another, it is about household contact, travel and cases in the family. The clinical reasoning is the same, but the history that leads to suspicion changes.

What the scene teaches

The scene has three clues. The first is the sequence: fever and lymph nodes before the lesions, a pattern common in mpox and less typical in herpes. The second is the appearance of the lesions, firm and umbilicated, with pain out of proportion. The third is the exposure history, with a partner who had a similar picture. None of the three is exclusive to mpox. Together, they make mpox a hypothesis that needs to be tested, without ruling out herpes and syphilis.

The post about differential diagnosis shows how each new clue reorders the hypotheses instead of eliminating all the others.

The clinical picture after 2022

The series by Thornhill and colleagues, with cases from several countries, described the profile of the 2022 outbreak (Thornhill and colleagues, 2022). The median incubation period was about one week. Most people had anogenital lesions, often few, and systemic symptoms such as fever, fatigue and muscle pain were frequent. A relevant share had another sexually transmitted infection at the same time.

The prospective cohort by Tarín-Vicente and colleagues added important details: proctitis and tonsillitis were frequent presentations, viral load was higher in samples from skin lesions than in throat samples, and the time until crusts dried was about ten days (Tarín-Vicente and colleagues, 2022). The authors argued for a low threshold of suspicion when faced with anogenital or oral lesions.

Presentations that confuse

The series by Patel and colleagues showed presentations that depart from the expected: intense rectal pain, penile edema, isolated tonsillar lesions and solitary lesions (Patel and colleagues, 2022). Some patients needed hospitalization, mainly for pain, not for systemic severity. This variety explains why mpox is confused with more common diseases.

The World Health Organization living guideline on clinical management and infection prevention and control, whose most recent version is from 2025, describes an incubation period of about three to seventeen days and acknowledges that, since 2022, lesions do not always evolve sequentially, can appear at different stages and often concentrate in anogenital regions (World Health Organization, 2025).

The skin lesion: what to observe

The classic mpox lesion goes through phases: macule, papule, vesicle, pustule and crust. The pustules are usually firm, deep and umbilicated, with a depressed center. They are often painful, sometimes very painful, and may itch during the healing phase. The wound can ulcerate, especially on mucous membranes.

In practice, the examination should record the number of lesions, where they are, what stage they are in and whether there are lesions on mucous membranes, such as the mouth, anus, urethra and eyes. It should also look for enlarged lymph nodes, which are usually painful. The World Health Organization guideline highlights lymphadenopathy as a characteristic feature of mpox (World Health Organization, 2025).

Skin, mucosa and symptoms that disappear from the examination

Proctitis, pain on defecation, rectal discharge, sore throat and difficulty swallowing can be the main complaints, with few visible skin lesions. In these cases, mpox only enters the differential diagnosis if someone asks and examines the mucous membranes. The post about signs, symptoms and history shows how the history directs the examination, and not the other way around.

The differential diagnosis: herpes, syphilis, varicella and others

The World Health Organization guideline lists a broad differential diagnosis for mpox: varicella, herpes simplex, syphilis, disseminated gonococcal infection, molluscum contagiosum, chancroid, lymphogranuloma venereum, drug reactions and others (World Health Organization, 2025). The table below summarizes clues that help you think, without replacing testing.

Condition	Clues in favor	Clues that resemble mpox
Mpox	Prodrome with fever, painful lymph nodes, firm and umbilicated pustules, lesions on mucous membranes	May have few lesions, at different stages
Herpes simplex	Grouped vesicles on an erythematous base, recurrence in the same place, burning before the lesions	Painful genital ulcers, inguinal lymph nodes
Primary and secondary syphilis	Single painless, indurated ulcer; in the secondary phase, rash on palms and soles	Genital lesions and generalized rash
Varicella	Rapid progression, lesions in several stages at the same time, central distribution, little lymphadenopathy	Vesicles and pustules over the body
Molluscum contagiosum	Pearly, umbilicated, painless papules, no systemic symptoms	Central umbilication
Chancroid and lymphogranuloma venereum	Soft and painful ulcers or lymph nodes that fistulize	Genital ulcer with adenopathy

Varicella deserves special attention. The guideline notes that it tends to progress faster, has a more central than peripheral distribution and does not usually bring marked lymphadenopathy (World Health Organization, 2025). But the same guideline also notes that coinfection with varicella-zoster virus is possible.

One diagnosis does not exclude another

In the series by Thornhill and colleagues, an important share of people with mpox had another sexually transmitted infection at the same time (Thornhill and colleagues, 2022). This has a direct consequence for reasoning: finding syphilis does not exclude mpox, and confirming mpox does not exclude syphilis or herpes. The post about a patient with many complaints discusses how to organize reasoning when there is more than one possible explanation.

When to suspect and how to test

The World Health Organization guideline recommends that people with a skin rash accompanied by fever or lymphadenopathy be screened for mpox and isolated while awaiting assessment (World Health Organization, 2025). Confirmation is done by PCR of material from the lesion, such as a swab of the roof of a vesicle, of the fluid or of the crust. The sooner the sample is collected, the better.

In the cohort by Tarín-Vicente and colleagues, lesion samples had a higher viral load than oropharyngeal samples (Tarín-Vicente and colleagues, 2022). Therefore, when there is a visible lesion, it is the best target. When the presentation is rectal or oral without an evident skin lesion, swabs from those regions can help.

What to do while the result has not arrived

The PCR result can take hours or days. In that interval, management should not stand still. The person should receive guidance on covering the lesions and avoiding close contact, treatment for pain and, when suspicion of another infection is strong, treatment of that infection according to the local protocol, without waiting for the mpox result. An ulcer with strong suspicion of syphilis, for example, does not need to wait for mpox confirmation to be treated. Recording contact details to return the result is also part of the consultation.

Testing for the rest: HIV, syphilis and herpes

The same guideline recommends offering HIV testing right at the start, in addition to testing for syphilis and herpes, and for other sexually transmitted infections according to the history (World Health Organization, 2025). The reason is twofold. First, coinfection is common. Second, untreated HIV changes the prognosis of mpox. The post about pretest probability helps to think about how the exposure history changes the value of each test.

Isolation and prevention of transmission

Transmission happens mainly through direct contact with lesions, body fluids and mucous membranes, and also through contaminated objects and droplets in close and prolonged contact. The 2025 World Health Organization guideline brings practical recommendations for each context (World Health Organization, 2025).

People with mild disease can be followed at home. According to the guideline, they do not need strict isolation if they keep the lesions covered and wear a mask when in contact with other people, until the lesions heal, with crusts fallen off and new skin underneath. They should avoid sexual contact, sharing bed linen, towels and utensils, and close contact with more vulnerable people, such as young children, pregnant women and immunosuppressed people.

Precautions in the health service

Health professionals should use contact and droplet precautions when caring for suspected or confirmed cases: gloves, gown, mask and eye protection, with attention to handling bed linen and waste (World Health Organization, 2025). Procedures that generate aerosols require additional respiratory protection. Separating suspected cases in the waiting room reduces unnecessary exposures.

Contacts

People who had close contact with a case, including sexual partners and people living in the same household, should be advised to watch for the appearance of fever, lymph nodes or lesions for about three weeks, the upper limit of the incubation period. Vaccination after exposure, when available, follows national recommendations. Discussing contacts with respect for the patient's privacy increases the chance that they will notify people who were exposed.

Mpox and advanced HIV

Most people with mpox recover without serious complications. The most important exception is advanced, untreated HIV infection. The global series by Mitjà and colleagues described, in this group, extensive necrotizing lesions, lung involvement, secondary bacterial infections and mortality concentrated in people with severe immunosuppression (Mitjà and colleagues, 2023). The authors proposed that, in this context, mpox be treated as an AIDS-defining condition.

The practical consequence is clear. Every person with mpox should have their HIV status known. People living with HIV who are not on treatment should start antiretroviral therapy promptly, as recommended by the World Health Organization guideline (World Health Organization, 2025). And lesions that become necrotizing, spread or do not improve should lead to an urgent assessment.

Warning signs to teach the patient

The guideline recommends advising patients followed at home about warning signs: severe pain that does not improve, difficulty urinating or having a bowel movement, pain or redness in the eyes, shortness of breath, confusion, lesions that grow or become very red, and inability to eat or drink (World Health Organization, 2025). Knowing when to return is part of the treatment.

Antivirals and vaccines: what the evidence shows

Tecovirimat is an antiviral that acts against orthopoxviruses and was used on a large scale during the 2022 outbreak. Randomized trials, however, did not confirm the expected benefit. The PALM007 trial, conducted with clade I, showed that tecovirimat did not shorten the time to lesion resolution compared with placebo (PALM007 Writing Group, 2025). A virological analysis of the STOMP trial, with clade II, showed that tecovirimat did not reduce virus isolation from lesions and that resistance arising during treatment, rare overall, was more frequent in people with advanced HIV and very low immunity, with slower recovery (Vyshenska and colleagues, 2026).

The World Health Organization guideline states that the section on antivirals is under review (World Health Organization, 2025). Until then, supportive care remains central: pain control, lesion care, hydration, prevention of secondary bacterial infection and attention to the eyes and mucous membranes. The use of antivirals in severe cases follows each country's protocols and studies.

Supportive care in practice

Severe anal or genital pain may require combined analgesia, sitz baths and attention to constipation, which worsens proctitis. Oral lesions can make eating difficult and call for attention to hydration. Lesions near the eyes deserve careful assessment, because eye involvement can leave sequelae. Keeping lesions clean and dry, avoiding scratching and watching for signs of secondary bacterial infection complete the care. These are simple measures, but they are the ones that most relieve the patient while the disease runs its course.

Vaccination

The MVA-BN vaccine, a non-replicating virus vaccine, was used in people at higher risk of exposure. A case-control study by Dalton and colleagues found effectiveness with one dose and greater effectiveness with two doses (Dalton and colleagues, 2023). The vaccination strategy, priority groups and vaccination after exposure follow national recommendations. For clinical reasoning, what matters is asking about prior vaccination and remembering that vaccinated people can still have the disease, usually milder.

Stigma and communication

The 2022 outbreak mainly affected men who have sex with men, and the disease was associated with this group in a stigmatizing way. The name of the disease was changed to mpox partly for this reason. Stigma is not only an ethical issue; it delays diagnosis, because people afraid of judgment take longer to seek care or withhold information. It also delays diagnosis in those outside the group associated with the disease, because the hypothesis is not even considered.

Clinical communication should be objective and without judgment. Asking about sexual partners, practices and exposures is part of the history, just as asking about travel and contact with animals is. The post about implicit bias in diagnosis shows how assumptions about who "fits the profile" for a disease distort the assessment, in both directions.

Outside the expected group

Children, women, older people and people with no reported sexual exposure can also have mpox, especially where there is household transmission of clade I. Remembering this avoids a common type of error: ignoring the hypothesis because the patient does not look like the typical case. The post about base rate in diagnosis discusses how the local frequency of a disease should weigh on suspicion.

Premature closure in the face of a genital lesion

Croskerry described premature closure as the tendency to accept a hypothesis before it has been verified (Croskerry, 2003). Faced with a painful genital lesion, "it is herpes" is a quick and often correct conclusion. The problem arises when it ends the investigation: the swab is not collected, syphilis is not tested, HIV is not offered and isolation is not advised.

The simplest way to avoid this error is to treat the genital lesion as a problem with several possible causes, which can coexist, and test accordingly. The post about diagnostic pause describes how a deliberate question, "what else could it be?", changes the course of the consultation. The post about diagnostic uncertainty shows how to act safely, isolating and advising, while the result is pending.

How NEXO helps train this reasoning

In NEXO, the case of the day is fictional, with a real clinical presentation and up to six progressive clues. You propose a diagnosis by searching for the ICD-10 code and receive proximity feedback at five levels, which shows whether the guess landed on the exact code, the same category, the same group, the same chapter or a different chapter. This format speaks to the theme of this text: herpes, syphilis, varicella and mpox sit at different points in the classification, and the clue that separates one from another is what decides the proximity.

To use the case of the day as training, try three habits. Before each guess, list at least two causes for the skin lesion. When you find one explanation, ask whether another condition could coexist. After the result, note which clue would have separated the hypotheses earlier.

Three exercises with cases

Look for the clue that separates. Faced with two similar hypotheses, ask which finding would be more likely in one than in the other.

Do not stop at the first infection. In cases with a genital lesion, list the other infections that would be worth testing for at the same time.

Think of the atypical patient. Ask how the case would change if the person did not have the profile you expected.

The post about learning based on clinical cases shows how varied cases help recognize presentations that depart from the pattern.

The limits on using the game are described on the NEXO Economy page. If you research the teaching of clinical reasoning, the page for Researchers explains how to get in touch. Professionals who write or review cases find information on Curator and on Creators, and institutions can learn about the proposal on the partnerships page.

Frequently asked questions

Can mpox present with few lesions?

Yes. Cases with few lesions have been common since 2022, sometimes just one, concentrated in the anogenital or oral regions.

Does lymphadenopathy help differentiate mpox from varicella?

Yes. The World Health Organization guideline highlights lymphadenopathy as a characteristic feature of mpox, less common in varicella.

Can mpox coexist with herpes or syphilis?

Yes. Coinfections are frequent, so testing for other sexually transmitted infections is part of the assessment.

Is the lesion sample the best way to confirm the diagnosis?

Yes. PCR of material from the lesion has a higher viral load than oropharyngeal PCR and should be collected as soon as possible.

Can mild cases be followed at home?

Yes. With lesions covered, wearing a mask when in contact with other people and guidance on warning signs, until healing.

Can vaccinated people still have mpox?

Yes. The vaccine reduces the risk but does not eliminate it, and cases in vaccinated people tend to be milder.

Final checklist

• I asked about fever, lymph nodes and the order in which symptoms appeared.
• I examined the skin, mouth, anal region, genitals and eyes.
• I recorded the number, location and stage of the lesions.
• I listed herpes, syphilis, varicella and other causes in the differential.
• I collected PCR of material from the lesion as soon as possible.
• I offered testing for HIV, syphilis and herpes.
• I gave guidance on covering lesions, wearing a mask and avoiding close contact until healing.
• I explained the warning signs and when to return.
• I used contact and droplet precautions during the consultation.

Want to practice the reasoning with progressive clues? Play the case of the day.

References

1. Croskerry P. The importance of cognitive errors in diagnosis and strategies to minimize them. Acad Med. 2003. PMID 12915363.
2. Dalton AF, Diallo AO, Chard AN, et al. Estimated effectiveness of JYNNEOS vaccine in preventing mpox: a multijurisdictional case-control study. MMWR Morb Mortal Wkly Rep. 2023. PMID 37200229.
3. Mitjà O, Alemany A, Marks M, et al. Mpox in people with advanced HIV infection: a global case series. Lancet. 2023. PMID 36828001.
4. World Health Organization. Clinical management and infection prevention and control for mpox: living guideline. 2025. Document.
5. World Health Organization. Mpox IHR Emergency Committee 2024. 2024. Document.
6. PALM007 Writing Group. Tecovirimat for clade I MPXV infection in the Democratic Republic of Congo. N Engl J Med. 2025. PMID 40239067.
7. Patel A, Bilinska J, Tam JCH, et al. Clinical features and novel presentations of human monkeypox in a central London centre during the 2022 outbreak: descriptive case series. BMJ. 2022. PMID 35902115.
8. Tarín-Vicente EJ, Alemany A, Agud-Dios M, et al. Clinical presentation and virological assessment of confirmed human monkeypox virus cases in Spain: a prospective observational cohort study. Lancet. 2022. PMID 35952705.
9. Thornhill JP, Barkati S, Walmsley S, et al. Monkeypox virus infection in humans across 16 countries, April-June 2022. N Engl J Med. 2022. PMID 35866746.
10. Vyshenska D, Reed JC, Roychoudhury P, et al. Tecovirimat treatment of clade II mpox: a virological analysis of a randomised, double-blind, phase 3 trial. Lancet Microbe. 2026. PMID 42526486.