Skin & Subcutaneous Tissue

Mpox: recognition, diagnosis, and management

Clinical Overview and When to Suspect Mpox

— Clade I (Central African, historically higher mortality, recent 2024 outbreak in DRC including clade Ib)

— Clade II (West African, responsible for the 2022 global outbreak, case-fatality <1% in well-resourced settings)

— New anogenital, perioral, or acral rash with vesicles/pustules — even a single lesion

— Proctitis, tonsillitis, or penile/vulvar ulcer in a sexually active adult

— Lesions in different stages historically, though the current outbreak often shows synchronous, monomorphic lesions

— Recent sexual contact with a new/anonymous partner, attendance at sex-on-premises venues, or travel to outbreak regions

— Contact with a confirmed case in the prior 21 days

Board pearl: Prominent lymphadenopathy (cervical, submandibular, or inguinal) is a classic discriminator favoring mpox over varicella or HSV. In a Step 3 ambulatory stem, a sexually active adult with a few umbilicated pustules plus tender inguinal nodes should prompt mpox PCR before empiric acyclovir.

Mpox (formerly monkeypox) is a zoonotic Orthopoxvirus in the same genus as variola and vaccinia, with two clades:

Transmission is primarily direct skin-to-skin contact with lesions, mucosal contact, respiratory droplets during prolonged close contact, fomites (linens, sex toys), and vertical transmission. The 2022–2024 outbreak is overwhelmingly driven by sexual networks, especially among men who have sex with men (MSM), but mpox is not exclusively an STI — anyone with skin/mucosal contact is at risk.

Incubation: 5–21 days (typically 7–14). Patients are infectious from symptom onset until all lesions have crusted, fallen off, and a fresh layer of skin has formed (often 2–4 weeks).

When to suspect in the outpatient/urgent care setting:

Prodrome (fever, lymphadenopathy, malaise, myalgia) may precede or follow the rash, or be absent entirely in the current outbreak — do not let a missing prodrome dissuade testing.

Presentation Patterns and Key History

— Often begins at the site of inoculation (anogenital, perianal, oral, perioral)

— Few lesions (sometimes a single ulcer or pustule) rather than diffuse rash

— Prodrome may follow rash or be absent

— Proctitis with severe rectal pain, tenesmus, bloody discharge — extremely characteristic

— Tonsillopharyngitis with odynophagia, sometimes a solitary tonsillar pustule

— Penile edema, paraphimosis, urethritis

— Sexual history (gender of partners, number, anonymous encounters, last 21 days)

— Travel and venue exposure (international travel, festivals, sex-on-premises)

— Known contacts with rash illness or confirmed mpox

— HIV status and last CD4 — advanced HIV (CD4 <200, especially <100) predicts severe, necrotizing disease and higher mortality

— STI screening status, vaccination history (smallpox/JYNNEOS, prior mpox)

— Immunosuppressive medications, pregnancy status, breastfeeding

Key distinction: In an MSM patient presenting with severe rectal pain out of proportion to exam, the differential is mpox proctitis, LGV (Chlamydia L1–L3), HSV proctitis, gonococcal proctitis, and syphilis. Step 3 expects you to send mpox PCR alongside a full STI panel rather than choosing between them — coinfection is common, and treating only the "obvious" diagnosis misses dual pathology.

Classic (pre-2022) presentation: 1–4 day febrile prodrome → centrifugal rash starting on face → spreading to trunk/extremities, palms and soles involved, lesions evolving synchronously through macule → papule → vesicle → pustule → umbilicated → crust.

Current outbreak (clade IIb and clade Ib) presentation:

Key history to obtain in a suspected case:

Counsel that prior smallpox vaccination (those born before ~1972 in the US) confers partial protection but is not fully reliable decades later.

Physical Exam Findings and Severity Assessment

— Lesions are firm, deep-seated, well-circumscribed, often umbilicated (central dimple), 2–10 mm

— Evolution: macule → papule → vesicle → pustule (often the dominant stage seen) → umbilicated → crust → desquamation

— Synchronous stage within a given anatomic region is typical in current outbreak (contrast with varicella's classic "crops")

— Count and map lesions: a "lesion burden" of >100 or any necrotic/confluent lesions signals severe disease

— Look for palmar/plantar lesions — supports mpox over varicella

— Hemodynamic instability suggesting bacterial superinfection/sepsis

— Tachypnea, hypoxia → possible pneumonitis

— Altered mental status → encephalitis

— Dehydration from proctitis/pharyngitis preventing oral intake

Step 3 management: For any suspected mpox patient in clinic, isolate immediately in a single room with the door closed, mask the patient, and have staff don gown/gloves/N95/eye protection. Defer non-essential exam maneuvers. If lesions cannot be covered (e.g., facial), the patient should wear a well-fitted mask and avoid public transit home — arrange private transport. Document a lesion count, distribution map, and photographs (with consent) to track progression and to support tecovirimat eligibility if criteria evolve.

Skin/mucosal exam (use gown, gloves, eye protection, N95):

Lymphadenopathy: tender, firm, often regional to inoculation site (inguinal in anogenital disease, cervical in oropharyngeal disease). Highly suggestive.

Anogenital exam: perianal ulcers, rectal mucosal ulceration on anoscopy (if tolerated), penile lesions, vulvar/vaginal lesions, urethral meatus involvement.

Oropharyngeal exam: tonsillar pustules/ulcers, palatal lesions, lingual ulcers — risk for airway compromise if epiglottic involvement.

Ocular exam: lid lesions, conjunctivitis, keratitis — vision-threatening, urgent ophthalmology referral.

Systemic signs of severity:

Diagnostic Workup — Initial Testing

— Swab 2–3 lesions from different body sites with a sterile dry polyester or Dacron swab (no viral transport medium needed for most CDC-validated assays — check your lab)

— Vigorously swab the lesion surface; unroofing is not required and is discouraged for current outbreak protocols (CDC updated 2022)

— Crusts can also be collected if no fresh lesions remain

— Send to a LRN (Laboratory Response Network) lab, CDC, or commercial lab (Labcorp/Quest now offer mpox PCR)

— HIV (4th-gen Ag/Ab plus RNA if recent exposure suspected)

— Syphilis (RPR or treponemal)

— Gonorrhea and chlamydia NAAT at all exposed sites (pharyngeal, rectal, urogenital) — include LGV reflex on rectal CT NAAT

— HSV PCR from lesion (can be sent on the same swab in some labs)

— Hepatitis B and C screening

— CBC (lymphopenia, thrombocytopenia possible)

— CMP (LFTs, renal function — informs tecovirimat dosing)

— CRP if superinfection suspected

— Pregnancy test in patients who can become pregnant

Board pearl: A common Step 3 distractor is ordering Tzanck smear or electron microscopy — these are historical and not used clinically. The right answer is PCR of lesion swab. Also remember: do not perform routine bloodwork PCR — viral DNA in blood is transient and lesion PCR is far more sensitive.

Confirmatory test: lesion PCR for Orthopoxvirus / Monkeypox virus DNA

Do not rely on serology — antibody testing cross-reacts across orthopoxviruses and does not distinguish infection from vaccination.

Concurrent testing every suspected case should receive:

Basic labs in moderate/severe disease:

Imaging: generally not needed; obtain CXR if respiratory symptoms; CT/MRI brain if neurologic signs (encephalitis is rare but devastating).

Diagnostic Workup — Advanced and Confirmatory Studies

Key distinction: A negative oropharyngeal or anal NAAT swab cannot rule out mpox if there is no visible lesion at that site — mpox PCR must be obtained directly from a visible lesion. Conversely, a positive STI NAAT (e.g., gonorrhea) does not rule out concurrent mpox; co-infection is the rule, not the exception, in current outbreak cohorts.

Clade differentiation: CDC and some reference labs now offer clade-specific PCR distinguishing clade I from clade II — important for public health surveillance and may inform isolation duration and contact tracing intensity. Always notify your local health department of any positive result; mpox is a nationally notifiable condition.

Genomic sequencing: reserved for outbreak investigation, performed at state public health labs or CDC. Not needed for individual clinical care.

Anoscopy/proctoscopy: consider in patients with severe proctitis to assess mucosal involvement, exclude alternative pathology, and obtain rectal swabs. Defer if pain is prohibitive — empirically test and treat.

Ophthalmologic slit-lamp exam: mandatory for any periocular lesion or eye symptoms; fluorescein staining identifies corneal ulceration.

Lumbar puncture: if encephalitis is suspected (altered mentation, seizures, focal deficits). Send CSF for orthopoxvirus PCR, opening pressure, cell count, glucose, protein, plus broad meningoencephalitis workup (HSV, VZV, enterovirus, bacterial cultures).

Bronchoscopy/BAL: consider in immunocompromised patients with pulmonary infiltrates to confirm mpox pneumonitis and exclude opportunistic infections (PJP, CMV, fungal).

Skin biopsy: rarely needed; histology shows ballooning degeneration, eosinophilic cytoplasmic inclusions (Guarnieri-like bodies), and acantholysis. Reserved for atypical presentations where PCR is negative but suspicion remains.

Repeat PCR: if initial test is negative but clinical suspicion is high, resample additional lesions or a newly developed lesion 24–48 h later. Sampling technique is the most common cause of false negatives.

Risk Stratification and Management Framework

— Few lesions, manageable pain with oral analgesics, no mucosal compromise, immunocompetent, tolerating PO

— Outpatient supportive care + isolation

— Extensive lesions (>100), severe proctitis, pharyngitis limiting intake, secondary bacterial cellulitis, ocular involvement, penile edema with urinary obstruction risk

— Consider tecovirimat, outpatient with close follow-up vs. short admission for pain/hydration

— Hemorrhagic, confluent, or necrotizing lesions

— Sepsis, pneumonitis, encephalitis, sight-threatening ocular disease

— Severe immunosuppression (advanced HIV with CD4 <200, transplant, chemotherapy, high-dose steroids)

— Pregnancy with significant disease, neonates

— Inability to maintain hydration, severe pain uncontrolled with PO regimens

— Advanced/uncontrolled HIV

— Solid-organ or stem-cell transplant

— Active hematologic malignancy or cytotoxic chemotherapy

— Pregnancy/breastfeeding

— Pediatric patients, especially <8 years and infants

— Atopic dermatitis or other active exfoliative skin disease (risk of eczema vacciniforme-like dissemination)

— Pain control: scheduled acetaminophen + NSAIDs, topical lidocaine, sitz baths, stool softeners (docusate, polyethylene glycol) for proctitis, gabapentin for neuropathic anorectal pain, avoid opioids when possible but use when needed for severe proctitis

— Skin care: keep lesions clean and dry, cover when possible, avoid shaving over lesions (risk of autoinoculation)

— Hydration and nutrition

— Sexual abstinence until full re-epithelialization, then condom use for 12 weeks after recovery (viral DNA persists in semen)

Step 3 management: When a stem describes a patient with advanced HIV (CD4 <100) and necrotic mpox lesions, the correct next step is hospital admission, ID consultation, and initiation of tecovirimat — not outpatient management, even if the patient appears stable.

Stratify every confirmed case into mild, moderate, or severe categories — this drives antiviral decisions and disposition.

Mild disease (most patients):

Moderate disease:

Severe disease — admit and treat:

High-risk hosts who warrant lower threshold for antiviral therapy even with mild-appearing disease:

Supportive care anchors of management:

Pharmacotherapy — Tecovirimat and Adjunctive Agents

— FDA-approved for smallpox; for mpox it is used under CDC's Expanded Access IND or via the STOMP trial (NIH placebo-controlled RCT, ongoing)

— PALOMA trial (NEJM 2024) in clade I disease in DRC: tecovirimat did not significantly shorten lesion resolution vs placebo (~7 vs 8 days) in mostly mild disease, though mortality was low in both arms — reinforces that tecovirimat is not a cure-all and should be prioritized for severe disease and high-risk hosts

— ≥40 kg and ≥13 yr: 600 mg PO BID with a fat-containing meal × 14 days

— Weight-based dosing for pediatrics and lower weights

— IV formulation available for those unable to tolerate PO

Board pearl: Tecovirimat must be taken with a high-fat meal to achieve therapeutic levels — counseling failure is a Step 3 trap. Also, although enrollment in STOMP or other clinical trials is preferred, treatment should never be withheld from a severely ill or high-risk patient awaiting trial logistics.

Tecovirimat (TPOXX, ST-246): the principal mpox antiviral, an inhibitor of the orthopoxvirus VP37 envelope protein preventing virion egress.

Dosing (oral):

Renal/hepatic: IV tecovirimat avoided in CrCl <30 due to vehicle (hydroxypropyl-β-cyclodextrin) accumulation; oral preferred. Hepatic dose adjustment generally not required.

Adverse effects: headache, nausea, abdominal pain; CYP3A4 inducer (mild) — may reduce levels of midazolam, some HIV ART, hormonal contraception; counsel on backup contraception.

Brincidofovir: oral lipid-conjugated cidofovir, FDA-approved for smallpox; second-line for mpox if tecovirimat fails or contraindicated. Hepatotoxicity is a key concern.

Cidofovir IV: active in vitro; nephrotoxic, requires probenecid and saline pre-hydration; reserved for refractory severe disease.

Vaccinia immune globulin (VIG-IV): consider in severe disease, especially in immunocompromised hosts or with eye involvement; obtained through CDC.

Adjunctive antibiotics: for secondary bacterial superinfection (cellulitis, abscess) — cover Staph aureus (including MRSA) and Strep pyogenes; cephalexin or TMP-SMX outpatient, vancomycin inpatient.

Vaccination, Post-Exposure Prophylaxis, and Prevention

— Safe in immunocompromised, pregnancy, and atopic dermatitis because it does not replicate

— Considered fully protective ~14 days after the second dose

— MSM and transgender persons with multiple partners or recent STI

— Sex workers

— Laboratory workers handling orthopoxviruses

— Healthcare workers performing high-risk procedures on mpox patients

— Within 4 days of exposure: vaccinate to prevent disease

— Days 4–14: vaccinate to attenuate disease severity (PEP++)

— High-risk exposure = unprotected skin/mucosal contact, sexual contact, household contact with a confirmed case

— Isolate at home until all lesions have crusted, scabs have fallen off, and a fresh layer of intact skin has formed

— Cover lesions, wear a mask around others, avoid sharing linens/utensils, no sexual contact

— Avoid contact with pets and other animals (rodents, lagomorphs especially) — reverse zoonosis is documented

Step 3 management: A patient presents 2 days after sexual contact with a confirmed mpox case and has no symptoms. The correct action is offer JYNNEOS vaccination now (PEP within 4 days), counsel on symptom monitoring for 21 days, and advise abstinence until past the incubation period — not "wait for symptoms to develop."

JYNNEOS (Modified Vaccinia Ankara-Bavarian Nordic, MVA-BN): non-replicating live attenuated vaccinia virus, two-dose series 28 days apart, subcutaneous (0.5 mL) or intradermal (0.1 mL, dose-sparing strategy authorized during shortage).

ACAM2000: replication-competent vaccinia; contraindicated in immunocompromised, pregnancy, atopic dermatitis, cardiac disease — rarely used now.

Pre-exposure prophylaxis (PrEP) indications (ACIP 2023):

Post-exposure prophylaxis (PEP):

Isolation guidance for confirmed cases:

Healthcare worker protection: gown, gloves, eye protection, N95 for direct patient contact; airborne isolation room preferred for aerosol-generating procedures.

Special Populations — Elderly and Renal/Hepatic Impairment

— Higher risk of dehydration from proctitis/pharyngitis

— Greater risk of pressure injury from lesions in immobile patients

— Polypharmacy increases drug-interaction risk with tecovirimat (CYP3A4)

— Oral tecovirimat: no dose adjustment needed; preferred route

— IV tecovirimat: the vehicle hydroxypropyl-β-cyclodextrin (HPBCD) accumulates in CrCl <30 mL/min → avoid IV; if absolutely necessary, use with caution and monitor renal function

— Cidofovir: nephrotoxic; avoid in CrCl <55, requires saline hydration and probenecid; not used outside refractory severe disease

— Brincidofovir: no renal adjustment (advantage over cidofovir), but hepatotoxic

— Adjust analgesics: avoid NSAIDs in CKD, dose-reduce gabapentin (gabapentin elimination is renal — reduce to 100–300 mg daily if CrCl <30)

— Tecovirimat: no specific adjustment; monitor LFTs in baseline hepatic disease

— Brincidofovir is contraindicated/used with extreme caution in significant hepatic dysfunction — it causes dose-dependent transaminase elevations and has been associated with hepatic failure

— Acetaminophen dose ceiling 2 g/day in advanced cirrhosis; avoid NSAIDs in decompensated liver disease (risk of AKI, variceal bleeding)

Key distinction: The renal concern with tecovirimat is only with the IV formulation because of the cyclodextrin vehicle — the active drug itself is not nephrotoxic. A Step 3 stem asking "best antiviral choice in an mpox patient with CKD stage 4" should still select oral tecovirimat, not avoid it altogether.

Older adults (>65): Limited outbreak data, but comorbidity-driven risk for severe disease is presumed. Many were vaccinated against smallpox in childhood (before 1972 in the US), conferring partial residual immunity — but waning over decades. Do not assume protection; offer JYNNEOS if indicated.

Renal impairment:

Hepatic impairment:

Dialysis patients: prefer oral tecovirimat; coordinate with nephrology for any IV formulation.

Special Populations — Pregnancy, Pediatrics, and Immunocompromised

— Mpox in pregnancy carries elevated risk of fetal loss, preterm birth, and congenital mpox with stillbirth or neonatal disease — documented vertical transmission via placenta

— JYNNEOS is not contraindicated in pregnancy (non-replicating); offer for PEP or PrEP when indicated — pregnancy is itself a risk factor for severe disease

— ACAM2000 is contraindicated (live replicating vaccinia → fetal vaccinia)

— Tecovirimat: limited human data, but reproductive animal studies reassuring; CDC and ACOG recommend offering tecovirimat to pregnant patients with mpox — benefits outweigh theoretical risks

— Monitor for preterm labor, perform fetal surveillance; coordinate delivery planning with MFM and neonatology; C-section considered if active genital lesions at term (analogous to HSV approach)

— Direct breastfeeding contraindicated while infectious — virus has been detected in breast milk; risk of skin-to-skin transmission to infant

— Pump and discard if any breast lesions; resume breastfeeding after full resolution

— Children <8 years, and especially <1 year, have higher rates of severe disease historically

— Tecovirimat is weight-based dosed down to 3 kg

— JYNNEOS authorized for children under EUA/expanded access for at-risk exposures

— Consider child abuse evaluation when genital lesions are present in a child — but recognize non-sexual household transmission is possible

— Highest risk for necrotizing, disseminated mpox with mortality up to 15% in CD4 <100

— Threshold for hospitalization, tecovirimat ± brincidofovir ± VIG, and ID consultation is low

— ART initiation/optimization is critical in HIV; do not delay ART for fear of IRIS — early ART improves outcomes

— Avoid ACAM2000; JYNNEOS is the preferred vaccine

Board pearl: In an HIV patient with a new mpox diagnosis, always check viral load, CD4 count, and ensure ART is started or optimized — and screen for the full STI panel including syphilis, which has a strong epidemiologic overlap.

Pregnancy:

Breastfeeding:

Pediatrics:

Immunocompromised (advanced HIV CD4 <200, transplant, chemotherapy, biologics):

Complications and Adverse Outcomes

— Secondary bacterial infection (Staph aureus, Strep pyogenes) — cellulitis, abscess, necrotizing fasciitis in severe cases

— Scarring and post-inflammatory hyperpigmentation — particularly on the face; counsel patients on sun protection during healing

— Keratitis, corneal ulceration, vision loss — urgent ophthalmology consult; topical trifluridine has been used; tecovirimat plus VIG considered

— Severe proctitis with tenesmus, hematochezia, urinary retention from reflex spasm

— Rectal perforation, perirectal abscess, anal stenosis as late complications

— Penile lesions → paraphimosis, urethral stricture, urinary retention requiring catheterization

— Vulvar lesions → painful urination, urinary retention

— Tonsillar, epiglottic, or laryngeal lesions → airway obstruction — threshold for ENT and ICU evaluation should be low

— Encephalitis, myelitis, seizures — rare but devastating; treat with tecovirimat plus VIG and supportive care

— Acute disseminated encephalomyelitis (ADEM) has been described post-mpox

— Stigma, anxiety, depression, isolation distress — particularly in MSM populations already navigating HIV stigma

— Job/housing disruption from prolonged isolation

CCS pearl: In a CCS-style inpatient case of severe mpox, advance the clock with: IV fluids, scheduled multimodal analgesia, ID consult, tecovirimat initiation, daily lesion mapping, ophthalmology if any eye involvement, surgery consult for perirectal abscess, and DVT prophylaxis — anchored by contact + droplet + airborne (for aerosolizing) precautions the entire admission.

Skin and soft tissue:

Ophthalmologic:

Anorectal:

Urogenital:

Oropharyngeal/airway:

Pulmonary: mpox pneumonitis (especially in immunocompromised) — hypoxia, infiltrates, ARDS

Neurologic:

Cardiac: myocarditis and pericarditis reported, including in young men; obtain ECG and troponin if chest pain, dyspnea, or arrhythmia

Psychosocial:

Mortality: clade II <1% in resourced settings; clade I historically 1–10%; sharply higher in advanced HIV, neonates, and pregnancy.

When to Escalate Care — Inpatient, ICU, and Consultations

— Mild-to-moderate disease, intact mucosa, controlled pain, can hydrate and toilet at home, has a safe isolation environment, and reliable follow-up within 24–72 hours

— Inability to control pain orally (especially severe proctitis or pharyngitis)

— Inability to maintain hydration/nutrition

— Secondary bacterial infection requiring IV antibiotics

— Significant ocular involvement

— Severe immunosuppression with active disease

— Pregnancy with moderate-severe disease

— Neonate or young infant with mpox

— Unstable housing or inability to isolate safely (public health partnership for isolation housing may be available)

— Hemodynamic instability/sepsis

— Airway compromise (epiglottic/laryngeal lesions, severe pharyngeal edema)

— Mpox pneumonitis with hypoxia or respiratory failure

— Encephalitis with reduced consciousness or seizures

— Myocarditis with hemodynamic compromise or arrhythmia

— Infectious Diseases: for tecovirimat sourcing, severe/refractory disease, immunocompromised host management

— Ophthalmology: any ocular symptom or periocular lesion

— Dermatology: atypical presentations, biopsy decisions

— Colorectal surgery: perirectal abscess, severe proctitis, suspected perforation

— Obstetrics/MFM: pregnant patients

— Pediatrics: all pediatric cases

— Public health: mandatory reporting to local/state health department for every confirmed case; coordinate contact tracing

— HIV/Ryan White services: for newly diagnosed HIV or care linkage

Step 3 management: When a stem describes mpox with stridor, drooling, or muffled voice, the next step is secure the airway in a controlled setting (OR or ICU with ENT and anesthesia present) — not awaiting further workup. Severe oropharyngeal mpox is a true airway emergency.

Outpatient is appropriate when the patient has:

Hospital admission indications:

ICU criteria:

Consultations to mobilize:

Transfer considerations: community hospitals should transfer severe/immunocompromised cases to tertiary centers with ID expertise and tecovirimat access.

Key Differentials — Vesiculopustular and STI Lesions

— Lesions in multiple stages simultaneously ("crops") — classic distinguishing feature

— More superficial, "dewdrop on a rose petal" vesicles

— Centripetal distribution (trunk > extremities), spares palms and soles

— Mild or absent lymphadenopathy

— Confirm with VZV PCR if uncertain

— Grouped vesicles on erythematous base, recurrent at the same site

— Painful, often preceded by prodrome of tingling

— Coinfection with mpox is common — test for both

Key distinction: Mpox lesions are firm, deep-seated, painful, evolve over days, and accompanied by lymphadenopathy and often fever. Molluscum is soft, painless, persists for weeks-to-months unchanged, no systemic symptoms. When uncertain, mpox PCR is rapid and definitive.

Varicella (chickenpox):

Disseminated herpes zoster: in immunocompromised — starts dermatomal then disseminates; VZV PCR confirms.

HSV (genital or oral):

Primary syphilis: painless indurated chancre with clean base — contrast with painful mpox ulcer

Secondary syphilis: copper-colored papules on palms and soles, condylomata lata, mucous patches — can mimic mpox; RPR + treponemal testing required

Chancroid (Haemophilus ducreyi): painful, soft, ragged-edge ulcers with suppurative inguinal buboes — rare in US

LGV (Chlamydia L1–L3): small painless papule → tender inguinal buboes, groove sign; severe proctitis in MSM — strongly mimics mpox proctitis. Test rectal CT NAAT with LGV reflex.

Granuloma inguinale (Klebsiella granulomatis): beefy red painless ulcers; rare in US

Molluscum contagiosum: pearly, umbilicated papules — most likely to confuse on physical exam because mpox is also umbilicated. Molluscum is painless, non-tender, no lymphadenopathy, and grows slowly over weeks.

Key Differentials — Other-Category Mimics

— Vesicles on palms, soles, and oral mucosa

— Atypical adult HFMD with Coxsackie A6 can be widespread and severe — increasingly reported

— Usually shorter course, no prominent lymphadenopathy

— Tenosynovitis, migratory polyarthralgia, pustular skin lesions with hemorrhagic base on extremities

— Positive blood/joint/mucosal cultures; treat with ceftriaxone

— SJS/TEN — mucocutaneous, sloughing, Nikolsky positive, drug exposure history

— AGEP — diffuse non-follicular pustules on erythematous base, fever, neutrophilia, drug trigger

Board pearl: When a stem features palmar and plantar lesions in a sexually active adult, think secondary syphilis vs. mpox vs. HFMD — order RPR + treponemal AND mpox PCR simultaneously. Don't fall for the trap of treating only the first diagnosis that fits.

Hand-foot-mouth disease (Coxsackie A6/A16, enterovirus 71):

Disseminated gonococcal infection:

Smallpox (variola): eradicated since 1980 — only relevant in bioterrorism scenarios. Lesions are all in the same stage (unlike varicella), centrifugal, deep, painful — looks nearly identical to mpox. Notify public health immediately if suspected; CDC bioterrorism response activates.

Orf and milker's nodule: parapoxvirus zoonoses from sheep/goats/cattle — solitary nodular lesion on hand, self-limited.

Eczema herpeticum: disseminated HSV in atopic dermatitis patients — punched-out monomorphic erosions; HSV PCR positive; treat with IV acyclovir.

Drug eruptions:

Bullous impetigo: Staph aureus exfoliative toxin; honey-colored crust; bacterial culture positive.

Scabies (especially crusted/Norwegian): intense pruritus, burrows in web spaces and genitals; mineral oil prep shows mites.

Folliculitis/HS: follicular distribution, recurrent.

Syphilis with HIV can cause atypical "lues maligna" with pustular and ulcerative lesions — RPR and biopsy distinguish.

Secondary Prevention, Counseling, and Long-Term Plan

— Natural infection is presumed to confer durable immunity, but the magnitude/duration is incompletely characterized; CDC does not currently recommend JYNNEOS for those with confirmed prior mpox

— Continue routine vaccinations as scheduled

— Treat any concurrent STIs per CDC guidelines (ceftriaxone for GC, doxycycline for CT/LGV [21-day course for LGV], penicillin G for syphilis)

— Doxycycline post-exposure prophylaxis (doxy-PEP) 200 mg within 72 hours of condomless sex is now recommended (CDC 2024) for MSM/transgender women with a bacterial STI in the past year — reduces syphilis, chlamydia, and gonorrhea recurrence

— Abstain from sex until all lesions are healed and a fresh skin layer has formed

— Use condoms for 12 weeks after recovery (viral DNA in semen persists)

— Avoid sharing sex toys; clean thoroughly

— Reduce partner numbers and use harm-reduction strategies during outbreaks

Step 3 management: A 32-year-old MSM resolves mpox and asks "can I have sex again?" The complete answer is: wait until all lesions have crusted, fallen off, and new skin has formed; use condoms for 12 weeks; start HIV PrEP; consider doxy-PEP; and ensure JYNNEOS vaccination of any unvaccinated regular partners.

Post-illness vaccination:

HIV PrEP: for sexually active patients without HIV who are diagnosed with mpox, strongly counsel HIV PrEP (oral TDF/FTC or TAF/FTC, or injectable cabotegravir) — mpox is a marker of high HIV acquisition risk

HIV care linkage: if new HIV diagnosis made during mpox workup, initiate rapid ART (within days) and link to longitudinal care; address insurance/Ryan White

STI co-management:

Sexual health counseling:

Vaccination of contacts: ensure household and intimate contacts receive JYNNEOS PEP within 4–14 days

Mental health and stigma: screen for depression, anxiety, and substance use; refer to community-based LGBTQ+ services where appropriate

Skin care: sunscreen and gentle skincare during scar maturation to reduce hyperpigmentation

Notification of partners: assist with anonymous partner notification through public health partner services

Follow-Up, Monitoring, and Counseling Cadence

— Confirm public health notification completed

— Telephone or telehealth check-in at 48–72 hours to assess pain control, hydration, and lesion progression

— Reinforce isolation and household precautions

— In-person or telehealth visit

— Reassess lesion count, evolution to crusting, signs of secondary infection

— Check on mental health, employment/financial impact (FMLA paperwork, sick leave letters)

— Review STI panel results and treat as needed

— Lesion crusting/desquamation phase

— Confirm completion of tecovirimat course if prescribed

— Schedule end-of-isolation assessment once all crusts are off and new skin has formed

— Skin examination for scarring, hyperpigmentation, residual ulcers

— Anoscopy if persistent proctitis symptoms

— Ophthalmology follow-up if any eye involvement

— Initiate or confirm HIV PrEP, doxy-PEP candidacy, vaccination updates (HPV, hepatitis A/B, meningococcal as indicated for MSM populations)

— Symptom diary; counsel to take with high-fat meal

— LFTs not routinely required in short courses but consider in prolonged or repeat courses

— Drug-interaction review (hormonal contraception, midazolam, some statins, certain ART)

— Reassess sexual health goals, STI rescreen, HIV testing if PrEP started

— Address any persistent skin sequelae, neuropathic pain, or anorectal dysfunction

— Mental health follow-up

CCS pearl: On a CCS case ending in discharge, advance the simulated clock and order: "Follow-up appointment in 1 week," "HIV PrEP counseling," "JYNNEOS vaccination for partners," "STI rescreen at 3 months," and "Mental health screening." These transition-of-care orders are explicitly Step 3-flavored and often differentiate a passing case from a perfect one.

Day 0–3 post-diagnosis (outpatient):

Day 7–10:

Day 14–21:

Post-isolation visit:

Monitoring while on tecovirimat:

3-month follow-up:

Public health/contact tracing: continues through health department; clinician's role is to support patient through the process and protect confidentiality.

Ethical, Legal, and Patient Safety Considerations

— Document only clinically necessary sexual history in the chart; avoid extraneous identifying information about partners

— Use opt-out language rather than presumptive labels (e.g., "men who have sex with men" is a behavioral descriptor, not an identity)

— Be vigilant about EHR access by family members on shared portals — sexual health information may inadvertently disclose orientation

— Patients must sign an expanded access IND consent acknowledging tecovirimat is FDA-approved for smallpox but used off-label/under EA-IND for mpox, with limited efficacy data

— Document discussion of alternatives including supportive care alone and clinical trial enrollment (STOMP)

— Patients may need clinician letters for isolation leave; advocate for paid sick leave and ADA/FMLA accommodations

— Schools and childcare exclusion until lesions resolved

Board pearl: A pregnant patient with mpox declines tecovirimat citing fetal safety concerns. The correct ethical posture is: explore her concerns, share that ACOG and CDC support its use in pregnancy due to higher maternal/fetal risk of untreated disease, document shared decision-making, and respect her decision — autonomy is preserved while informed consent is robustly documented.

Mandatory reporting: Mpox is a nationally notifiable disease. Report every confirmed and probable case to the local/state health department promptly — typically within 24 hours. Reporting does not require patient consent and is not a HIPAA violation; it is a public health legal obligation.

Confidentiality and stigma:

Informed consent for tecovirimat under EA-IND:

Occupational exposure: Healthcare workers with exposure should report to occupational health, receive JYNNEOS PEP, and be evaluated for return-to-work clearance per institutional and CDC guidance.

Workplace and school:

Partner notification: Public health partner services can perform anonymous notification — encourage participation; respect patient autonomy if they decline, but document counseling.

Pediatric mpox and child protection: Genital lesions in a child must trigger a thoughtful, non-presumptive evaluation for sexual abuse with social work and child protective services involvement when indicated — but understand that non-sexual household transmission does occur.

Transition-of-care risk: Patients discharged from ED with presumptive mpox often face fragmented follow-up; ensure a confirmed appointment within 72 hours, contact information for ID, and clear return precautions in writing before they leave.

High-Yield Associations and Rapid-Fire Facts

Key distinction: If a stem mentions "prior smallpox vaccination in childhood," assume partial residual protection — but not full immunity. Offer JYNNEOS if otherwise indicated.

Family/genus: Poxviridae, Orthopoxvirus — same genus as variola, vaccinia, cowpox

Genome: double-stranded DNA, largest viruses by genome size, replicate in cytoplasm (unique among DNA viruses)

Incubation: 5–21 days (avg 7–14)

Infectious period: symptom onset until all crusts off + new skin

Hallmark exam finding: lymphadenopathy (distinguishes from varicella/smallpox)

Lesion character: firm, deep-seated, umbilicated, synchronous within a region

Classic at-risk site of inoculation in 2022–2024 outbreak: anogenital, perioral, hands

Confirmatory test: lesion PCR (not serology, not Tzanck, not EM)

First-line antiviral: tecovirimat (VP37 inhibitor), 600 mg PO BID × 14 days with fatty meal

Vaccine of choice: JYNNEOS (MVA-BN) — 2 doses 28 days apart, safe in immunocompromised and pregnancy

PEP window: ≤4 days (prevention), 4–14 days (attenuation)

High-mortality host: advanced HIV with CD4 <100 — up to 15% mortality

Mpox proctitis differential includes: LGV, HSV, GC, syphilis — co-test always

Notifiable disease: report to public health within 24 hours

Bioterrorism mimic: smallpox — same Orthopoxvirus genus, same morphology

Vertical transmission: documented, causes congenital mpox, fetal loss

Breastfeeding: contraindicated during active infection

Post-recovery condom use: 12 weeks (viral DNA in semen)

Doxy-PEP: 200 mg within 72 h post-sex — reduces bacterial STIs in high-risk MSM

JYNNEOS replication: non-replicating (safe in HIV, atopy, pregnancy); ACAM2000 replicates (contraindicated in those groups)

PALOMA trial: tecovirimat did not significantly shorten clade I mpox lesion resolution — reserve for severe/high-risk disease

Board Question Stem Patterns

A 29-year-old MSM presents with a 3-day history of fever, malaise, and tender inguinal lymphadenopathy. Exam shows three umbilicated pustules in the perianal region. Best next step? → Lesion PCR for orthopoxvirus + full STI panel including HIV, syphilis, GC/CT NAAT with LGV reflex.

A 35-year-old man had condomless receptive anal sex 2 days ago with a partner who now has confirmed mpox. He is asymptomatic. Next step? → JYNNEOS vaccination now (within 4-day window), counsel on 21-day symptom monitoring, and offer HIV PrEP/doxy-PEP.

A 41-year-old man with HIV (CD4 78, not on ART) presents with confluent necrotic lesions on the face and genitals, fever, and hypotension. Best management? → Admit, ID consult, start tecovirimat, IV fluids, broad-spectrum antibiotics for superinfection, initiate/optimize ART, consider VIG.

A 7-year-old presents with vesicles in multiple stages scattered over the trunk and face, no lymphadenopathy. Diagnosis? → Varicella, not mpox (multiple stages and no lymphadenopathy).

A 26-year-old MSM has severe rectal pain, tenesmus, and a single perianal ulcer. Manage? → Lesion PCR + rectal CT NAAT with LGV reflex + GC NAAT + syphilis + HIV; empiric pain management; treat positives.

A 28-year-old at 24 weeks gestation has confirmed mpox with extensive lesions. Best therapy? → Offer tecovirimat (CDC/ACOG support); MFM consult; fetal surveillance; plan for C-section if active genital lesions at term.

A 34-year-old man with atopic dermatitis and HIV (CD4 480, undetectable) needs mpox vaccination. Which? → JYNNEOS (non-replicating). ACAM2000 contraindicated.

When can a recovered patient resume sex? → After all lesions crusted, fallen off, and new skin formed; condom use for 12 weeks afterward.

Step 3 management: Stems will often hide the answer in transition-of-care details — recognize that "schedule 1-week follow-up, initiate HIV PrEP, vaccinate partners" is a single composite right answer, not multiple separable choices.

Stem 1 — Classic recognition:

Stem 2 — Post-exposure prophylaxis:

Stem 3 — Severe disease in HIV:

Stem 4 — Differential discrimination:

Stem 5 — Proctitis decision:

Stem 6 — Pregnancy:

Stem 7 — Vaccine selection:

Stem 8 — Discharge counseling:

One-Line Recap

Mpox is an Orthopoxvirus characterized by firm, deep-seated, umbilicated lesions with prominent lymphadenopathy that, in the current outbreak, presents predominantly with anogenital or oropharyngeal disease in sexually active adults — diagnosed by lesion PCR, treated with supportive care and tecovirimat in severe or high-risk patients, and prevented with JYNNEOS vaccination as PrEP or PEP within 4–14 days of exposure.

Board pearl: When in doubt on Step 3, the right answer for a sexually active adult with new umbilicated anogenital lesions is almost always "lesion PCR plus comprehensive STI/HIV testing plus public health notification plus JYNNEOS for contacts" — never a single isolated intervention.

Recognize: umbilicated lesions + regional lymphadenopathy + sexual/contact exposure → swab lesions for PCR; co-test for HIV and full STI panel (including LGV reflex) every time.

Treat: supportive care for most (pain control, hydration, sitz baths, stool softeners); tecovirimat 600 mg PO BID × 14 days with a fatty meal for severe disease, immunocompromised, pregnancy, pediatrics, or sight-/airway-threatening disease — ideally via STOMP trial enrollment or CDC EA-IND.

Prevent: JYNNEOS (2 doses, 28 days apart, non-replicating, safe in HIV/pregnancy/atopy) as PrEP for high-risk populations and as PEP within 4 days of exposure (or 4–14 days for attenuation); counsel abstinence until full re-epithelialization and condoms for 12 weeks after recovery; offer HIV PrEP and doxy-PEP as part of comprehensive sexual health care.

Report and protect: mpox is nationally notifiable — call public health within 24 hours; protect patient confidentiality, support partner notification through public health services, advocate for paid isolation leave and stigma-free care, and arrange 48–72 hour follow-up to bridge the transition from ED or clinic diagnosis to longitudinal management with primary care, infectious diseases, and mental health support.