• Information
  1. Introduction
  2. Clinical Manifestations
  3. Pathogenesis
  4. Differential Diagnosis
  5. Treatment
  6. Vaccination

A. Introduction

1. Variola Virus was eradicated from all natural sources in 1980
2. No known cases since ~1978
3. Five Types of Smallpox
   1. Ordinary (variola major) - 90% of cases, fatality rate 30%
   2. Modified type - 2% of natural cases, 25% in previously vaccinated patients
   3. Flat lesions - 7%, 97% fatality rate in unvaccinated persons
   4. Hemorrhagic smallpox - <3% of cases
   5. Variola sine eruptions - in vaccinated persons or infants with maternal antibodies; minimal symptoms, no rash, good outcome

B. Clinical Manifestations

1. Median incubation 10-12 (range 7-17) days from inoculation to febrile prodrome
   1. Temperature spikes initially
   2. Rash appears 2-3 days later, usually as macules
2. Progression to papules and then pustules -- all at same stage in one area
   1. Rash begins as small, reddish macules
   2. These become papules 2-3 mm after 1-2 days
   3. Papules become vesicles with diameter 2-5 mm over next 1-2 days
   4. Pustules 4-6 mm develop 3-7 days after onset of rash
   5. Secondary bacterial infection may contribute to pustules
   6. Crusts often begin separating from skin in second week of eruption
3. Lesions occur first on face and extremities
   1. Then spread to other parts of body
   2. Lesions on plams and soles persist the longest
4. Highly Contageous [6]
   1. Easily transmitted within 10-12 feet via aerosol
   2. May be transmitted by persons recently vaccinated
   3. Increased risk may be present in immunocompromised patients
5. Temperature spikes 5-8 days after rash often accompanies secondary bacterial infection
6. After severe smallpox, pockmarks (pitted lesions) occur in 65-80% of survivors
7. Death from Smallpox
   1. Immune complex mediated disease
   2. Hypotension

C. Pathogenesis

1. Virus seeds mucous membranes of respiratory tract
2. Pass rapidly into local lymph nodes
3. Viremia occurs initially, then virus is latent
4. Latent period lasts 4-14 days
5. Virus multiples in reticuloendothelial system during latent period
6. Another period of viremia follows
7. Virus then invades capillary epithelium of dermal layer of skin
   1. This leads to vesicular lesions
   2. Oropharyngeal dermis is also highly targeted by virus
8. Virus levels are very high during active, symptomatic phase
9. Spleen, lymph nodes, liver, bone marrow, kidneys, others may contain high viral loads
10. Migration of infected macrophages to lymph nodes stimulates immune system
    1. Cytotoxic T cells
    2. B cells which mature to antibody production
    3. Neutralizing antibodies usually appear during first week of illness
    4. Neutralizing antibodies present for many years

D. Differential Diagnosis

1. Presence of vesicles and/or pustules
2. Maculopapular rashes much more common than papulovesicular
3. Maculopapular Eruptions
   1. Measles
   2. Rubella
   3. Drug Eruptions
   4. Secondary syphilis
   5. Erythema multiforme
   6. Scabies
   7. insect bites
   8. Acne
   9. Scarlet fever
4. Papulovesicular Eruptions [1,2]
   1. Atypical measles (rubeola)
   2. Severe acne
   3. Chickenpox (varicella-zoster virus, VZV)
   4. Coxsackievirus (hand foot and mouth disease)
   5. Dermatitis herpetiformis
   6. Drug eruptions
   7. Eczema herpeticum (herpes simplex virus)
   8. Generalized vaccinia and eczema vaccinatum (vaccinia)
   9. Impetigo
   10. Insect bites
   11. Molluscum contagiosum
   12. Papular urticaria
   13. Pemphigus
   14. Ricettsialpox
   15. Shingles (VZV)
   16. Yaws (syphilis)
   17. Smallpox

E. Treatment [2,3]

1. Mortality rate of untreated, unvaccinated persons is ~30%
2. Cidofovir (Vistide®) has been effective in vitro and in animal pox models
3. Ribavirin aerosol (Virazole®) may have some efficacy
4. Immune globulin is also available
5. Vaccination during early incubation period can also reduce symptoms, mortality rates

F. Vaccination [7,8]

1. Current vaccine is suspension of live vaccinia virus (derived from cowpox)
2. Dryvax® is current vaccine - lyophilized preparation from lymph nodes of calves
3. Newer vaccine derived from monkey kidney and human fibroblast cells in preparation
4. Efficacy
   1. Highly effective vaccine is available when given 3-4 days after exposure
   2. Vaccine prevents disease in many people and death in most
   3. Family transmission studies suggest efficacy >90%
5. Utility
   1. Vaccination recommended in high risk situations such as biological warfare
   2. Routline vaccination in USA was stopped in 1972
   3. Risk of biological warfare suggests revaccination should be considered
   4. May be given to persons exposed to smallpox (with good efficacy)
6. Contraindications
   1. Not recommended for children <18 years old except in emergency
   2. Live virus vaccines should not be given to immunocompromised patients
   3. Persons receiving chronic prednisone >20mg/day are at increased risk of dissemination
   4. Exczema - strong contradication with increased risk of eczema vaccinatum
   5. Not recommended in infants or pregnant women
7. Side Effects [8,11.12]
   1. Many adverse effects of live virus reported but generally mild
   2. <3.0% of military smallpox vaccinees required sick leave
   3. Historically, ~1 death per 1 million vaccinations
   4. Recent data showed 100 severe adverse events including 3 deaths in 38,885 vaccinees [11]
   5. In 450,000 military vacinees, 1 case of encaphilitis and 37 acute myopericarditis
   6. Rates of neurological adverse events are similar to non-vaccinated persons [12]
   7. Local reactions include satellite lesions, lymphadenopathy, local inflammation oin ~2% [11]
   8. Folliculitis (local and general) also occurs and is a benign side effect [10]
   9. Viral illness occurs briefly in many patients
   10. No cases of worker to patient transmission, eczema vaccinatum or progressive vaccinia
   11. Progressive vaccinia can occur in patients with impaired cell-mediated immunity
8. Vaccine Myopericarditis [9]
   1. Incidence ~7.8 per 100,000 military vaccinees within 4-30 days of primary vaccination
   2. No cases reported in persons receiving booster vaccination
   3. All cases occurred in men (with women underrepresented in military cohorts)
9. Vaccine Dosage [4,5]
   1. Vaccine should be given with bifurcated needle
   2. Vaccine dose of 10,000 plaque forming units (pfu) per dose usually sufficient
   3. Goal is formation of vesicle which leads residual scar
   4. Vesicles indiate that viral replication is followed by vigorous interferon gamma and T lymphocyte responses
10. Management of Vaccine Complications
    1. For patients with severe reactions and/or progressive vaccinia
    2. Vaccinia immune globulin (see below)
    3. Cidofovir (Vistide®) - approved for cytomegolovirus; effective in vitro and in animals
    4. Ribavirin (Virazole® and others) - intravenous may be useful in immunocompromised
11. Vaccinia Immune globulin [7]
    1. May be given with vaccine >7 days post-exposure
    2. No evidence that immune globulin + vaccine better than vaccine alone
    3. Especially effective for progressive vaccinia infection

References

1. Moore ZS, Seward JF, Lane JM. 2006. Lancet. 367(9508):425
2. Breman JG and Henderson DA. 2002. NEJM. 346(17):1300
3. Drugs and Vaccines Against Biological Weapons. 2001. Med Let. 43(1115):87
4. Frey SE, Couch RB, Tacket CO, et al. 2002. NEJM. 346(17):1254
5. Frey SE, Newman FK, Cruz J, et al. 2002. NEJM. 346(17):1275
6. Sepkowitz KA. 2003. NEJM. 348(5):439
7. Smallpox Vaccine. 2003. Med Let. 45(1147):1
8. Grabenstein JD and Winkenwerder W Jr. 2003. JAMA. 289(24):3278
9. Halsell JS, Riddle JR, Atwood JE, et al. 2003. JAMA. 289(24):3283
10. Talbot TR, Bredenberg HK, Smith M, et al. 2003. JAMA. 289(24):3290
11. Casey CG, Iskander JK, Roper MH, et al. 2005. JAMA. 294(21):2734
12. Sejvar JJ, Labutta RJ, Chapman LE, et al. 2005. JAMA. 294(21):2744