بسم الله الرحمن الرحيم

1. بسم الله الرحمن الرحيم BIODEFENSE Epidemiology of Smallpox Shahid Beheshti University of medical sciences, 2008 By: Saghari H. MD. MPH & Hatami H. MD. MPH

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 IRAN case – 1972 (1351) in Shiraz • Last international case – 1978 • Declared eradicated in 1979

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 • Relatively high mortality • Relatively 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 population 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 • Range 7-17 days • Typical 10-14 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 • 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

13. 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

14. Modified Discrete Semi Confluent Confluent Flat Hemorrhagic

15. 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 (and USA 2003)

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

17. 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

18. 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

19. 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

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

21. Clinical Features • Incubation Stage • From time of infection to onset of symptoms • Average 10-14 days (range 7-17) • Important for epidemiologic investigation • Considered non-infectious during this stage • Virus sometimes culturable

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

23. 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

24. روز سوم روز پنجم روز هفتم

25. 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

26. Clinical Features • Modified variant • Previously vaccinated with partial immunity • Milder rash, better outcome, faster resolution

27. 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)

28. Confluent Type of Classical

29. 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%

30. 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

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

32. Diagnosis • Clinical diagnosis • Electron microscopy • Culture on chick membrane • Nucleic Acid Testing • PCR • Multiplex assays • Real time PCR • Histopathology and Immunohistochemistry

33. 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 eruption – prodrome without rash • Partially immune – milder, often atypical

34. 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 • PCR, multiplex assays, real time PCR

35. Diagnosis • Histopathology and Immunohistochemistry • Poxvirus inclusion bodies can be presumptively identified in hematoxylin and eosin (H&E)-stained specimens using light microscopy • B-type inclusion bodies are readily observed in H&E • Histopathologic staining of tissues for evaluating if orthopoxvirus

36. 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

37. Differential Diagnosis Chickenpox (varicella) • Vesicles shallow, in crops, varied stages • Centripetal, spares palms/soles Other orthopox viruses • Monkeypox – only in Africa, monkey contact, USA (2003) • Vaccinia – after exposure to vaccine • Cowpox – rare, only in UK

38. Monkeypox • Enzootic circulation in rainforestsof central and western Africa • Arboreal squirrels and monkeys • Transmissible to humans • Direct contact with infected animals • Airborne transmission possible • Human-to-human transmission rarely can occur

39. Monkeypox in Humans • Smallpox-like syndrome • Generalized rash that progresses to vesicles and pustules

40. Monkeypox in Humans • Direct contact with infected animals • Airborne transmission possible • Human-to-human transmission (Rarely) can occur • Short duration

41. Generalized Vaccinia

42. Differential Diagnosis Varicella (Chickenpox) Chickenpox in an infant. Notice the rose-colored macules, papules, vesicles, pustules, necrotic pustules, and crusted lesions occurring simultaneously. Chickenpox on the hand. Notice the simultaneous occurrence of lesions in different stages of development.

43. Differential Diagnosis

44. Differential Diagnosis Herpes Zoster (Shingles) Varicella zoster on the face. Notice the dermatomal distribution of the papules, vesicles, and pustules. Herpes (varicella) zoster on the arm. Notice the characteristic grouping of vesicles

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

46. 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)

47. 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

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

49. Prevention • Vaccination – History • Variolation • Inoculation with infectious smallpox • Scabs or pustular material • 1% mortality • Immunized were infectious - outbreaks • Provided full immunity • Originated in Eastern countries in ancient times • Started in U.S. by Rev. Cotton Mather 1721

50. Prevention • Vaccination - History • Introduced by Jenner • Inoculated boy with pustular fluid from cowpox • 1st immunization using virus of similar disease • Initially passed arm-to-arm • Also passed syphilis, hepatitis • Eventually passed calf-to-calf on scarified leg • Immunity not lifelong