5/9/01

1. Biological Terrorism Smallpox 5/9/01

2. History • Caused by variola virus • Most deaths of any infectious disease • ~500 million deaths in 20th Century • ~2 million deaths in 1967 • Known in ancient times • Described by Ramses • Natural disease eradicated • Last U.S. case – 1949 (imported) • Last international case – 1978 • Declared eradicated in 1979 Photo: National Archives

3. Bioweapon Potential • Features making smallpox a likely agent • Can be produced in large quantities • Stable for storage and transportation • Known to produce stable aerosol • High mortality • Highly infectious • Person-to-person spread • Most of the world has little or no immunity

4. Bioweapon Potential • Prior attempted use as bioweapon • French and Indian Wars (1754-1767) • British gave Native Americans infected blankets • Outbreaks ensued, some tribes lost 50% • Allegations of use in U.S. Civil War • Alleged use by Japanese in China in WWII

5. Bioweapon Potential • Current concerns • Former Soviet Union scientists have confirmed that smallpox was successfully weaponized for use in bombs and missiles • Active research was undertaken to engineer more virulent strains • Possibility of former Soviet Union virus stock in unauthorized hands

6. Bioweapon Potential • Nonimmune population • <20% of U.S. with substantial immunity • Availability of virus • Officially only 2 stocks (CDC and Russia) • Potential for more potent attack • Combined with other agent (e.g. VHF) • Engineered resistance to vaccine

7. Bioweapon Potential • Delivery mechanisms • Aerosol • Easiest to disperse • Highest number of people exposed • Most contagious route of infection • Most likely to be used in bioterrorist attack • Fomites • Theoretically possible but inefficient

8. Epidemiology • All ages and genders affected • Incubation period • From infection to onset of prodrome • Range 7-17 days • Typical 12-14 days

9. Epidemiology • Transmission • Airborne route known effective mode • Initially via aerosol in BT attack • Then person-to-person • Hospital outbreaks from coughing patients • Highly infectious • <10 virions sufficient to cause infection • Aerosol exposure <15 minutes sufficient

10. Epidemiology • Person-to-person transmission • Secondary Attack Rate (SAR) • 25-40% in unvaccinated contacts • Relatively slow spread in populations (compared to measles, etc.) • Higher during cool, dry conditions • Historically 3-4 contacts infected • May be 10-20 in unvaccinated population • Very high potential for nosocomial spread • Usually requires face-to-face contact

11. Epidemiology • Transmission via fomites • Contaminated hospital linens/laundry • May have been successfully used as weapon in French-Indian War

12. Epidemiology • Infectiousness – Rash is marker • Onset approx one day before rash • Peaks during first week of rash • ? Carrier state possible • Some data show virus detectable in saliva of contacts who never become infected • Unclear if they can transmit infection, but theoretically possible

13. Epidemiology • Infectious Materials • Saliva • Vesicular fluid • Scabs • Urine • Conjunctival fluid • Possibly blood

14. Epidemiology • Role of index case severity • Does not predict transmissibility • Does not predict severity of 2° cases • Role of prior vaccination • Immunity wanes with time • Maintain partial immunity for many years • Partial immunity reduces disease severity • Reduces transmissibility (less virus shed)

15. Epidemiology • Mortality • 25-30% overall in unvaccinated population • Infants, elderly greatest risk (>40%) • Higher in immunocompromised • May be dependent on ICU facilities • Dependent on virus strain • Dependent on disease variant

16. Epidemiology • Factors that allowed smallpox eradication • Slow spread • Effective, relatively safe vaccine • No animal/insect vectors • No sig. carrier state (infected die or recover) • Infectious only with symptoms • Prior infection gives lifelong immunity • International cooperation

17. Microbiology • Variola virus – the agent of smallpox • Orthopoxviridae family • 2 strains of variola • Variola major • Variola minor • Vaccinia • Used for current vaccine • Namesake of “vaccine” • Cowpox – used by Jenner in first vaccine • Monkeypox – rare but serious disease from monkeys in Africa

18. Microbiology • Variola major • Classic smallpox • Predominant form in Asian epidemics • Highest mortality (~30%)

19. Microbiology • Variola minor • Same incubation period, mode of transmission, clinical presentation • Causes milder disease • Less severe prodrome and rash • Mortality ~1% • Discovered in 20th century • Started in S. Africa • Was most predominant form in N. America

20. Microbiology • Environmental survival • Longest (>24hr) in low temp/low humidity • Inactive within few hours in hi temp/humidity • Dispersed aerosol • completely inactivated within 2 days of release

21. Pathogenesis • Virus lands on respiratory/oral mucosa • Macrophages carry to regional nodes • Primary viremia on Day 3 • Invades reticuloendothelial organs • Secondary viremia on Day 8

22. Pathogenesis • White Blood Cells infected • WBCs migrate capillaries, invade dermis • Infects dermal cells • Influx of WBCs, mediators cause vesicle • Systemic inflammatory response • Triggered by viremia • Sepsis, multiorgan failure, often DIC

23. Pathogenesis • Severity of disease • Not influenced by severity of source case • Probably related to degree of viremia • Inoculation dose • Longer exposure, higher concentration at release • Virulence of variola • strain, engineered resistance • Host immune status • Type of rash predictive of outcome • More severe rashes = poorer outcomes

24. Clinical Features • Three stages of disease • Incubation • Asymptomatic • Prodromal • Nonspecific febrile illness, flu-like • Eruptive • Characteristic rash

25. Clinical Features • Incubation Stage • From time of infection to onset of symptoms • Average 12-14 days (range 7-17) • Important for epidemiologic investigation • Considered non-infectious during this stage • Virus sometimes culturable

26. Clinical Features • Prodromal Stage • Common symptoms • High fever, prostration, low back myalgias, HA • Occasional symptoms • Vomiting, abdominal pain, delirium • Duration typically 3-5 days • End of stage heralded by mucosal lesions • Mucosal lesions onset of infectiousness

27. Clinical Features • Eruptive Stage (Rash) • May start with transient defervescence • Characteristic rash • Centrifugal (in order of appearance & severity) • Initially oral mucosa– borders pre-eruptive stage • Head, face • Forearms, hands, palms • Legs, soles, +/- trunk

28. Classic Centrifugal Rash of Smallpox Involving Face and Extremities, Including the Soles. Photo: National Archives

29. Classic Centrifugal Rash of Smallpox Involving Face and Extremities. Photo: National Archives

30. Clinical Features • Rash stages of development • All lesions in one region at same stage • Starts macular, then papular • Deep, tense vesicles by Day 2 of rash • Turns to round, tense, deep pustules • Pustules dry to scabs by Day 9 • Scabs separate

31. Classic Smallpox Rash, Demonstrating Same Development Stage (Pustular) of All Lesions in a Region Photo: National Archives

32. Clinical Features • Scarring • From separated scabs • Fibrosis, granulation in sebaceous glands • Pink, depressed pock marks • Prominent on face, usually >5 lesions • Permanent

33. Clinical Features • Rash variations • Sine eruptione variant • Prodrome without rash • Clinically less severe

34. Clinical Features • Modified variant • Previously vaccinated with partial immunity • Milder rash, better outcome, faster resolution Photo: National Archives

35. Clinical Features • Rash variations • Ordinary (Classic presentation) variant • >90% all cases • Subdivided based on confluence of lesions • Discrete (<10% mortality) • Semiconfluent (25-50% mortality), most common • Confluent (50-75% mortality)

36. Discrete Type of Classical Smallpox Rash Photo: National Archives

37. Confluent Type of Classical Smallpox Rash Photo: National Archives

38. Clinical Features • Rash variations • Flat (Malignant) variant • Uncommon • Prodrome more sudden, severe • More likely severe abdominal pain • Rash never forms pustules/scabs • Leathery in appearance • Sometimes hemorrhagic or exfoliating • DDX – acute abdomen, hemorrhagic varicella • >90% mortality

39. Clinical Features • Rash variations • Hemorrhagic • Rare • Prodrome more acute and severe • Bleeding diathesis before onset of rash • Rash is also hemorrhagic • Pregnant women at highest risk (?immune state) • Higher risk of transmission (more fluid shedding) • DDX – meningococcemia, DIC • Mortality 100%

40. Clinical Features • In an outbreak setting atypical or variant rashes must be considered smallpox until proven otherwise

41. Clinical Features • Complications • Sepsis/toxemia • Usual cause of death • Associated with multiorgan failure • Usually occurs during 2nd week of illness • Encephalitis • Occasional • Similar to demylination of measles, varicella

42. Clinical Features • Complications • Secondary bacterial infections uncommon • Staphylococcus aureus cellulitis • Responds to appropriate antibiotics • Corneal ulcers • A leading cause of blindness before 20th Century • Conjunctivitis rare • During 1st week of illness

43. Diagnosis • Clinical diagnosis • Sufficient in outbreak setting • >90% have classical syndrome • Prodrome followed by rash • Rarely, variants can be difficult to recognize • Hemorrhagic – mimics meningococcemia • Malignant – more rapidly fatal • Sine eruptione – prodrome without rash • Partially immune – milder, often atypical

44. Diagnosis • Traditional confirmatory methods • Electron microscopy of vesicle fluid • Rapidly confirms if orthopoxvirus • Culture on chick membrane or cell culture • Slow, specific for variola • Newer rapid tests • Available only at reference labs (e.g. CDC) • PCR, RFLP

45. Diagnosis • Specimen procurement/handling • By recently successfully immunized person • Open vesicle with blunt end of blade • Collect with cotton swab • Place swab into sealed vacuum blood tube • Place tube in larger jar, tape lid

46. Diagnosis • Differential Diagnosis • Chickenpox (varicella) • Vesicles shallow, in crops, varied stages • Centripetal, spares palms/soles • Other orthopox viruses • Monkeypox – only in Africa, monkey contact • Vaccinia – after exposure to vaccine • Cowpox – rare, only in UK

47. Treatment • Management of cases • Supportive • Post-exposure prophylaxis • Vaccine • Vaccinia immunoglobulin • Primary prophylaxis • Vaccine

48. Treatment • Managing confirmed or suspected cases • No specific effective antiviral treatment • Supportive care is critical • Electrolytes / Volume / Ventilation / Pressors • Antibiotics only for secondary infections • e.g. S. aureus cellulitis • Isolation • Vaccinate (in case diagnosis is wrong)

49. Post-Exposure Prophylaxis • Vaccine • Protective if given within 3-4 days exposure • Reduces incidence 2-3 fold • Decreases mortality by ~50% • Vaccinia immune globulin (VIG) • 3 fold decrease in incidence and mortality • Passive immunity for 2 weeks • Very limited supply (at CDC)

50. Post-Exposure Prophylaxis • Antivirals • Cidofovir • Limited experimental data • May be beneficial in first 2 days post-exposure • Available IV only • Significant renal toxicity