Differentiation of Poxviruses

1. Classification by Genus

2. Orthopoxviruses - Detailed Comparison

A. Smallpox (Variola)

• Virus: Orthopoxvirus variola
• Reservoir: Humans only (eradicated 1980; the only poxvirus reportable under International Health Regulations)
• Transmission: Inhalation of respiratory droplets; fomites; direct contact with rash lesions
• Incubation: 10-17 days (mean 12 days)
• Prodrome: High fever (38-40°C), headache, backache, vomiting, prostration
• Rash:
  • Centrifugal distribution - lesions more numerous on face and extremities than trunk
  • Lesions appear on palms and soles
  • All lesions in the same stage of development in any one area (synchronous)
  • Progresses: macule → papule → vesicle (day 4-5) → pustule (day 7) → crust (day 14)
  • Deep-seated, hard, raised lesions
• Lymphadenopathy: Absent (key differentiator from monkeypox)
• Clinical subtypes: Ordinary (90%), Modified (5%, vaccinated), Flat (5%, nearly fatal), Hemorrhagic (<1%, always fatal)
• Mortality: Varied; ordinary type ~30% in unvaccinated
• Secondary attack rate: ~60% in unvaccinated contacts; ~4% in vaccinated

B. Monkeypox (Mpox)

• Virus: Orthopoxvirus monkeypox (two clades: Central African/Congo Basin and West African)
• Reservoir: Central/West African rodents (squirrels, Cricetomys); NOT monkeys despite name
• Transmission: Zoonotic (direct contact with animals); human-to-human via respiratory droplets, direct lesion contact, sexual contact
• Incubation: 7-17 days (mean 12 days)
• Prodrome: Fever, headache, backache, fatigue
• Rash: Very similar to smallpox - centrifugal, synchronous, macule → papule → vesicle → pustule → crust; involves palms and soles
• Key differentiator from smallpox: Pronounced lymphadenopathy (cervical, postauricular, submandibular, inguinal) - this is the hallmark clinical distinction
• Other features: Hypopigmentation followed by hyperpigmentation post-healing; pharyngitis, anorectal pain in recent outbreaks; 25-30% subclinical infection in contacts
• Clades: Congo Basin clade = more severe, higher mortality; West African clade = milder, no documented human-to-human transmission in 2003 US outbreak
• Mortality: Congo Basin clade >10%; West African clade <1%
• Smallpox vaccination: ~85% protective against monkeypox

Monkeypox rash showing centrifugal distribution on face (A) and lesions involving the palms and extremities (B) - Goldman-Cecil Medicine

C. Vaccinia

• Origin: Uncertain; likely hybrid of smallpox and cowpox, possibly derived from horsepox
• Reservoir: Used as live vaccine; variants include buffalopox (India) and dairy cattle variants (Brazil, Colombia)
• Transmission: Inoculation (vaccine); contact with vaccinees; zoonotic (buffalopox variant)
• Clinical use: The live virus in the smallpox vaccine; cross-protective against all orthopoxviruses (~33% sequence homology shared)
• Local reaction: Papule → vesicle (Jennerian vesicle) → pustule (days 7-9) → crust/scab (days 10-14) → scar
• Complications: Eczema vaccinatum, progressive vaccinia (in immunocompromised), generalized vaccinia, post-vaccinial encephalitis
• Immunity duration: Full protection 3-5 years; waning but significant immunity for decades

D. Cowpox

• Reservoir: Wild rodents (primary); cattle and cats are incidental hosts
• Transmission: Direct contact with infected animals (cat scratches are the most common source in Europe)
• Lesion: Usually restricted to hands and face; 70% have only ONE lesion; passes through macular → papular → vesicular → pustular → hard black crust (characteristic)
• Features: Very painful; significant erythema and edema; fever, malaise, lymphadenitis
• Severity: ~30% may require hospitalization; recovery takes 6-12 weeks; permanent scarring common
• Geography: Europe and western Asia

3. Parapoxviruses

E. Orf (Ecthyma Contagiosum)

• Virus: Orf virus
• Reservoir: Sheep and goats (occupational/contact zoonosis)
• Transmission: Direct contact with infected animals or their products; farmers, veterinarians, abattoir workers
• Lesion morphology (6 stages):
  1. Erythematous papule
  2. Target lesion - red center + white halo + outer inflamed halo
  3. Acute weeping nodule
  4. Nodular/papillomatous stage with "weeping" surface
  5. Regenerative/dry stage
  6. Papillomatous regression
• Number of lesions: Usually ONE (occasionally multiple with multiple inoculations)
• Systemic features: Relatively uncommon; lymphadenopathy in some
• Special complication: Erythema multiforme in up to one third of patients
• Self-limiting: Resolves in 4-6 weeks

F. Pseudocowpox (Milker's Nodule)

• Very similar to orf clinically
• Source: Cattle (milking contact)
• Occupational: Dairy farmers

4. Molluscipoxvirus

G. Molluscum Contagiosum (MCV)

• Virus: MCV types 1-4; the most common poxvirus affecting humans since smallpox eradication
• Reservoir: Humans only (like variola, but benign)
• Transmission: Skin-to-skin contact; fomites (towels, pools); sexual transmission in adults; autoinoculation/Koebnerization
• Population: Children (median age 5 years; most common <14 years); sexually active adults (genital lesions); HIV patients (severe, widespread disease)
• Lesion: 2-5 mm, discrete, dome-shaped, smooth, flesh-colored papule with central umbilication (pathognomonic)
• Histology: Henderson-Paterson bodies = large intracytoplasmic inclusion bodies (molluscum bodies) - diagnostic on biopsy
• Distribution: In children: exposed areas; in adults: genital area (STI)
• Complications: Eczematous reaction (molluscum dermatitis) around lesions; in HIV: giant molluscum (>1 cm), widespread hundreds of lesions; Gianotti-Crosti type reactions
• Treatment: Usually self-limiting (6-12 months); cryotherapy, curettage, topical agents

5. Yatapoxviruses

H. Tanapox / Yabapox

• Reservoir: Subhuman primates (Africa)
• Transmission: Direct contact; possibly insect vectors
• Lesion: 1-2 lesions, nodular, generally mild and self-limiting
• Geography: Restricted to Africa (Kenya, DR Congo)
• Key point: G+C ~32%; geographically restricted by reservoir distribution

6. Quick-Reference Comparison Table

7. Key Diagnostic Differentiators

• Smallpox vs. Monkeypox: Lymphadenopathy distinguishes monkeypox (present) from smallpox (absent). Epidemiologic context (zoonotic exposure, geographic origin) is also key.
• Smallpox/Monkeypox vs. Chickenpox (varicella): Poxvirus lesions are synchronous (all same stage); varicella lesions are asynchronous (different stages simultaneously). Pox lesions are deep-seated; varicella lesions are superficial. Electron microscopy can distinguish poxvirus particles from herpesviruses in ~1 hour. - Jawetz Medical Microbiology
• Cowpox vs. Orf: Cowpox forms a hard black eschar; orf forms a target lesion with weeping surface. Both are occupational zoonoses.
• Molluscum: Pathognomonic central umbilication + Henderson-Paterson inclusion bodies; no systemic illness.
• Laboratory: PCR - non-variola orthopoxvirus (NVO) assay, generic orthopoxvirus PCR, mpox-specific PCR; G+C ratio by sequencing helps genus-level classification.

8. Treatment Summary

• Goldman-Cecil Medicine, Chapter 343
• Harrison's Principles of Internal Medicine 22E, p. 1652
• Sherris & Ryan's Medical Microbiology, 8th Ed, p. 439
• Fitzpatrick's Dermatology, p. 3116