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Monkeypox (Mpox) in Dermatology

Based on Fitzpatrick's Dermatology (Vol. 1-2), Andrews' Diseases of the Skin, and Goldman-Cecil Medicine, supplemented by recent PubMed reviews.

1. Overview and Classification

Monkeypox virus (MPXV) is a member of the Orthopoxvirus genus - the same genus as variola (smallpox), vaccinia, and cowpox. On electron microscopy, it has the characteristic brick shape of all poxviruses. Its genome is 96% identical to variola virus in the central region (which encodes essential enzymes and structural proteins), but the end regions that determine virulence and host range differ substantially - giving monkeypox a much wider host range than variola.

Since the global eradication of smallpox, monkeypox is now the primary Orthopoxvirus causing disease in humans.

Two clades exist:

Clade I (Central African / Congo Basin clade): More virulent, higher mortality (1-10%), greater human-to-human transmission potential
Clade II (West African clade): Less virulent, lower mortality, responsible for the 2022 global outbreak (specifically Clade IIb)

2. Epidemiology

Endemic to the Congo Basin of Central Africa, particularly the Democratic Republic of Congo, Central African Republic, Republic of Congo, and Sudan
In Africa, the majority of cases are in children under 15, with a fatality rate of ~11% in that group
Reservoir: Wild African rodents (squirrels of genus Funisciurus and Heliosciurus, giant Gambian rats Cricetomys) and secondarily primates
Secondary household attack rate: 10-12%
2003 US outbreak: 72 cases (37 lab-confirmed) linked to pet prairie dogs co-housed with African rodents imported from Ghana - this demonstrated the first Western Hemisphere cases
2022 global outbreak: ~90,000 cases worldwide, >30,000 in the United States; initially concentrated in men who have sex with men (MSM), then spreading to heterosexual contacts and children; caused by Clade IIb

Why is incidence rising? The discontinuation of routine smallpox vaccination programs after 1980 has progressively removed cross-protective immunity in the global population. Prior smallpox vaccination is ~85% protective against monkeypox.

Fitzpatrick's Dermatology, Vol. 1-2, pp. 3108-3110

3. Transmission

Route	Details
Zoonotic (primary)	Bite/scratch from infected animal, contact with body fluids or carcasses
Human-to-human (droplet)	Close contact via respiratory droplets during first week of rash
Direct lesion contact	Contact with skin lesions or body fluids
Fomites	Rare - contaminated bedding, clothing
Sexual transmission	Prominent in 2022 outbreak (anogenital lesions as predominant feature)

The virus enters through abraded skin, multiplies locally at the entry site, then travels to regional lymph nodes (causing the characteristic lymphadenopathy), then invades the bloodstream - producing viremia and dissemination to distant skin sites.

The longest documented chain of human-to-human transmission is 6 individuals, indicating far lower epidemic potential than smallpox.

4. Clinical Features

Incubation Period

7-17 days (Andrews' Diseases of the Skin cites 10-14 days)

Phase 1: Prodrome (1-4 days)

Fever, chills, malaise, headache, myalgias, backache (nearly universal - 82-100%)
Sore throat, cough, shortness of breath
Diarrhea, abdominal pain (less common)
Lymphadenopathy - This appears 1-2 days BEFORE the rash and is the single most distinguishing feature from smallpox

Phase 2: Rash (14-21 days to full evolution)

The rash evolves through characteristic stages in a monomorphic pattern (all lesions at same stage simultaneously - key difference from varicella):

Macules → Papules → Vesicles → Pustules → Umbilication → Crusting → Desquamation → Scarring

Umbilicated pustular lesions on the palm from monkeypox - Fitzpatrick's Dermatology

Fig. 166-15 - Umbilicated pustular lesions on the palm. Note the characteristic deep-seated, well-demarcated, umbilicated lesions. (Fitzpatrick's Dermatology)

Distribution:

Begins on face and/or trunk
Spreads centrifugally (outward) to become generalized - including palms and soles (also differs from varicella)
Can involve oral and genital mucous membranes
In the 2022 outbreak, anogenital lesions were the predominant and sometimes only manifestation

Number of lesions:

African cases: Generalized (hundreds of lesions), 2-5 mm papules
US 2003 cases: More localized, mostly on hands at inoculation sites with 1-50 satellite lesions
80% of patients have largely monomorphic lesions

Late desquamative monkeypox lesions - Fitzpatrick's Dermatology

Fig. 166-16 - Late desquamative monkeypox lesions on the back of a 5-year-old from the DRC. Note widespread, densely distributed lesions with desquamation. (Fitzpatrick's Dermatology)

Lesion characteristics:

Deep-seated
Well-circumscribed
Umbilicated when pustular
Heal with dyspigmented and pitted scars
Hemorrhagic crusts form at resolution

5. Lymphadenopathy - The Hallmark

Lymphadenopathy is the single most clinically important feature distinguishing monkeypox from smallpox and varicella.

Present in 90% of unvaccinated and 53% of previously vaccinated individuals
Precedes the rash by 1-2 days
Typically submandibular, cervical, or inguinal nodes
Andrews' states: "Lymphadenopathy is not a feature of smallpox"

6. Noncutaneous Findings and Complications

Finding	Frequency
Lymphadenopathy	90% (unvaccinated)
Conjunctivitis and keratitis	Variable
Secondary skin/soft-tissue infections	~20%
Pneumonitis	~12%
Encephalitis	<1%
Corneal scarring	Rare but important

African mortality: 1-10%, mainly in children. Death usually occurs in the second week from bacterial superinfection, GI complications, or pulmonary complications - compounded by malnutrition and limited healthcare access.

7. Histopathology

Skin biopsy is NOT specific but shows characteristic poxvirus changes:

Dermal papillary edema
Acute inflammation
Ballooning degeneration of keratinocytes
Cytoplasmic eosinophilic inclusion bodies (Guarnieri bodies) - pathognomonic of poxvirus infection
Focal necrosis

These findings are indistinguishable from smallpox histologically. Special confirmatory testing is required.

8. Diagnosis

Laboratory Testing (non-specific markers)

Leukocytosis (common)
Elevated transaminases
Low blood urea nitrogen
Lymphocytosis and thrombocytopenia (less common)

Confirmatory Testing

Test	Details
PCR (preferred)	Swab of lesion, crust, or fluid - confirms MPXV; can speciate
Electron microscopy	Shows brick-shaped poxvirus; cannot distinguish monkeypox from variola or vaccinia
Serology	Confirms Orthopoxvirus infection; not species-specific
Skin biopsy	Guarnieri bodies; not species-specific

PCR of lesion material is the gold standard for confirming monkeypox specifically.

9. Differential Diagnosis

Condition	Key Distinguishing Features
Smallpox (variola)	No lymphadenopathy; more severe; centrifugal distribution identical to monkeypox
Varicella (chickenpox)	Milder/absent prodrome; centripetal distribution (trunk > extremities); pleomorphic (multiple stages simultaneously); no lymphadenopathy
Orf / Bovine stomatitis	Parapoxvirus; more localized lesions; occupational exposure
Drug eruptions	Drug history; no viral prodrome
Eczema herpeticum	Background atopic dermatitis; HSV positive
Rickettsialpox	Eschar at bite site; rickettsia serology
Molluscum contagiosum	Immunocompromised patients can develop extensive lesions; no systemic features
Syphilis (secondary)	Maculopapular rash on palms/soles; VDRL/RPR positive; no vesiculation

The key clinical triad pointing to monkeypox: Prodrome + lymphadenopathy preceding rash + monomorphic centrifugal vesiculopustular rash progressing to umbilicated lesions.

10. Monkeypox vs. Smallpox vs. Varicella - Comparison Table

Feature	Monkeypox	Smallpox	Varicella
Lymphadenopathy	Yes (90%)	No	No
Distribution	Centrifugal	Centrifugal	Centripetal
Lesion morphology	Monomorphic	Monomorphic	Pleomorphic
Palms/soles involved	Yes	Yes	Rarely
Oral mucosa	Yes	Yes	Yes
Prodrome severity	Moderate	Severe	Mild/none
Mortality (unvaccinated)	1-10%	30%	<0.01%
Contagiousness	Moderate	High	Very high

11. Management

Infection Control

Contact and droplet precautions
Negative-pressure room isolation if possible
Healthcare workers at higher risk from contaminated fomites (examination tables, gowns, gloves)

Antiviral Treatment

Drug	Notes
Tecovirimat (TPOXX)	First-line for severe disease; VP37 envelope protein inhibitor; maintained in US Strategic National Stockpile; used under IND protocol; reduces severity even when given after symptom onset
Cidofovir	DNA polymerase inhibitor; nephrotoxic
Brincidofovir	Oral prodrug of cidofovir; less nephrotoxic

All three are approved for smallpox and used off-label for monkeypox - efficacy in humans remains uncertain but animal models are promising.

Most cases are self-limiting and require only supportive care.

Post-Exposure Prophylaxis (PEP)

Preferred: Vaccinia (smallpox) vaccine within 4 days of exposure (consider up to 14 days)
PEP applies even to: infants <12 months, pregnant women, those with skin conditions
Contraindicated in severe T-cell immunodeficiency (risk from vaccination may equal or exceed risk from monkeypox in this group)

12. Vaccination

Vaccine	Details
JYNNEOS (Imvamune/Imvanex)	Live attenuated, non-replicating modified vaccinia Ankara (MVA); specifically approved for monkeypox; 2 doses; safer profile; can be used for both pre- and post-exposure prophylaxis
ACAM2000	Live replicating vaccinia; effective but more adverse effects (myocarditis, eczema vaccinatum risk); second-line
Dryvax (historical)	85% protective in African studies

Pre-exposure indications: Laboratory workers, monkeypox investigators, healthcare workers caring for monkeypox patients.

Global eradication of monkeypox is more difficult than smallpox eradication because of the wide range of animal reservoir hosts.

13. 2022 Outbreak - Clinical Shift (Clade IIb)

The 2022 global outbreak introduced important clinical differences relevant to dermatologists:

Anogenital skin lesions as the predominant feature - often the only manifestation
Rash limited to 1-5 lesions in some cases (not the classic widespread eruption)
Painful lesions (rectal pain, dysuria prominent)
Transmitted primarily through close sexual contact in MSM initially
Less prominent systemic prodrome before rash in some cases
Same vaccine and treatment strategies apply
Gupta AK et al., Am J Clin Dermatol 2023 [PMID: 37106278]

Summary Mnemonic: MONKEYPOX

Letter	Key point
M	Monomorphic lesions (all at same stage)
O	Orthopoxvirus (brick-shaped on EM)
N	No smallpox vaccine immunity in today's population
K	Key sign = Lymphadenopathy (before rash)
E	Endemic - Congo Basin
Y	JYNNEOS vaccine for prevention
P	Prodrome: fever, chills, myalgias, backache
O	Oropharyngeal and anogenital mucosa involved
X	X-clude variola: lymphadenopathy differentiates

Sources: Fitzpatrick's Dermatology Vol. 1-2, pp. 3108-3112; Andrews' Diseases of the Skin, p. 369; Goldman-Cecil Medicine, p. 3587; Gupta et al. Am J Clin Dermatol 2023 [PMID: 37106278]

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