1. Last Smallpox Victim on Earth
One reason to use the vaccine again is so that this Ethiopian man remains the last case of smallpox on earth, which will save me the trouble of having to change the title of this slide.
In the next 25’ I will discuss the epidemiology and clinical features of smallpox, including how to tell smallpox from chickenpox. I will close with my opinions about the CDC’s interim smallpox response plan, which is available on the internet.
I should thank ron up front for letting me burrow a few of his teaching slides, and Nolan Lee for getting me some good pictures. Those of you who lose your appetite during this lecture have nolan to thank.
Let’s start by making it clear that viruses, such as smallpox, are different from bacteria, such as anthrax.

2. Little Nasty Things Protozoa Bacteria Viruses Prions Amebae
Allow me to grossly simplify the world of very little things.
The largest one-celled organisms, which include much of what we think of as parasites (like the cause of amebic dysentary or malaria) are protozoa. Prions, the smallest transmissible agents, are nothing but protein, and are the cause of, for example, mad cow disease.
Amebae
(dysentary)
Plasmodium
(malaria)
Mad Cow Disease
Variant CJD

3. Little Nasty Things Protozoa Bacteria Viruses Prions E. coli
B. anthracis
(Anthrax)
Y. pestis
(Plague)
Influenza
Varicella
(Chickenpox)
Variola
(Smallpox)
The other two major classes of microorganisms are bacteria and viruses. Bacteria, such as (POINT) Bacillus anthracis, the agent of anthrax, and (POINT) Yersinia p . . ., are larger than viruses and more complex. Viruses are smaller, and cannot be treated with standard antibiotics. Although there are some antiviral agents, we lack antivirals effective against smallpox, and many other viruses.
Amebae
(dysentary)
Plasmodium
(malaria)
Mad Cow Disease
Variant CJD

4. Little Nasty Things Protozoa Bacteria Viruses Prions DNA Viruses
RNA Viruses
Viruses consist of nucleic acid (such as [POINT] DNA or RNA), a protein coat, and little else. Smallpox is an orthopoxvirus, one of the largest and most complex viruses.

5. Little Nasty Things Protozoa Bacteria Viruses Prions DNA Viruses
RNA Viruses
(ortho)Pox Viruses
Other Pox Viruses
Many
Other
Viruses
Variola is another name for smallpox. Besides variola, Other members of the Poxvirus family include Vaccinia and Cowpox viruses, Monkeypox, and others.
Variola (smallpox)
Major & Minor
Vaccinia/Cowpox
Monkeypox
Molluscum
ORF (parapox)
Milker’s nodules
Tanapox, others

6. An Orthopox Virus Variola (smallpox) Vaccinia major minor
Orthopoxvirus are among the largest and most complex viruses. Besides variola major, the more common and more severe form, there was a pandemic of variola minor around the turn of last century (NEXT PAGE),
Variola (smallpox)
major
minor
Vaccinia

7. Variola minor, early 1900’s
Which was first found in south Africa (NEXT)

8. Variola minor, early 1900’s
And florida, (NEXT). . .

9. Variola minor, early 1900’s
before spreading to europe, up through north america and down into latin america In variola minor, less than 1% of cases die Variola major strains, our major concern, about 30% of cases die. In both types, the demographics of its victims are similar (NEXT)

10. Epidemiology Winter & Early spring Age Distribution
Like measles and chickenpox
Virus killed by heat and humidity
Age Distribution
Historically affected younger children and unvaccinated persons
Outbreak now would match age distribution of population since there is little immunity
To make surveillance more difficult, Smallpox is a disease of winter and early spring, exactly like other rash illnesses such as . . .
Because of immunity in smallpox-endemic areas, Smallpox historically affected.
Now, we think that the outbreak would match Except that mortality might be a bit less among middle-aged adults due to the residual effects of the vaccine

11. Transmission Person  Person
Primarily droplet, or aerosol
No animal reservoir or vector
Very contagious, but less than measles or chickenpox
Less transmissible (lower 2° attack rates)
Persons are very sick before contagious
Smallpox spreads person to person, mostly by droplets, which means that most of the transmission occurs among people who have been is the same room as a case, or within 6 feet. However, there is some transmission by aerosol, so that, particularly in persons who are coughing, persons in larger areas have been infected.
Historically, outbreaks spread slowly; Secondary (household) attack rates are 60%, not 90% as in chickenpox or measles, and person who are sick are usually in bed and not walking around spreading the virus.
However, smallpox in droplet nuclei can live between a few hours and a few days in the environment, so that bed linens or clothing could become a vehicle for transmission, (NEXT)

12. 18th Century: Native American Blankets
A fact exploited by British settlers in the 18th century to decimate Native American populations whose livelihoods interfered with their use of land (NEXT)

13. Time Course of Infection
Entry through Oropharynx or Lungs
Virus Multiplies in Lymph Nodes
Spreads through Bloodstream (1° viremia)
Multiplies again in Lymph nodes, Spleen, Bone Marrow
Spreads through Bloodstream (2° viremia)
Prodrome: Fever, Headache, Backache, SICK!
Multiplies in mouth and Dermis (deep layer of skin)  Rash
NOT
Infectious
(12-14 d )
Infected persons are not contagious during the 2 week incubation period, during which time there are 3 cycles of replication: Virus enters through mucous membranes in the mouth or respiratory tract, and multiply for the 1st time
After spreading through the bloodstream (which cases no symptoms) the virus undergoes a second round of multiplication (NEXT)
Then the virus spreads again, in preparation for its final round of multiplication near the blood vessels in the skin, and the mouth gums, and palate (which is, of course, its “exit strategy”)
Persons are also NOT contagious during the prodrome even though they can feel pretty terrible. That may be the saving grace of any smallpox epidemic: by the time persons are contagious, they have a rash, which you can see, and they usually been in bed for a few days.
NOT
Infectious
(2-4 d)
VERY
Infectious

14. Fever Curve of Typical Smallpox Case
In this temperature chart, which is not to scale, you can see that there is a little over 2 days of fever (POINT) before the rash(POINT to plus signs). That means that taking the temperatures of persons exposed to smallpox is a way to identify possible smallpox before new cases become contagious (SHOWN BY the RED part of the arrow) (POINT).
We can use this information to help us respond to a smallpox outbreak. But first, I am going to show you how to identify a smallpox rash. Those of you who are eating in the auditorium may wish to finish up your lunches, uh, sooner rather than later (NEXT)

15. Here is a picture of a little boy 3 days after his smallpox rash started. . .(NEXT)

16. 5 days after it started . . .(NEXT)

17. And 7 days after it started
And 7 days after it started. Note that the lesions are all pretty far along, that they are pustules, which means that rather than being filled with clear liquid, they are filled with pus (which is why they are all white) and that they are all pretty deeply embedded in the skin. That is why smallpox causes scarring, and why the vesicles, or pustules, look kind of thick, instead of thin like a soap bubble.

18. This is what smallpox pustules look like 2 weeks after the rash begins, when the scabs start to separate and fall off.
[[Incidentally, there is live smallpox in those scabs, but there are no report of transmission through smallpox scabs, so we consider them non-infectious.]]

19. Last case of smallpox in Bengledesh (now healthy)
There is a lot of scarring and loss of pigment in the oil-producing glands of the face, such as in on (POINT) this little boy’s forehead.

20. Early Chickenpox
Although early chickenpox can involve the face (NEXT)

21. Chickenpox: Varicella-Zoster Virus (VZV)
Early on, it usually involves the trunk or the legs (NEXT)

22. Chickenpox: Superficial Vesicles
2 points to remember are that (1) smallpox causes vesicle more often than pustules. Vesicles are clear liquid filled balloons in the skin, while pustules are white, because they are filled with pus, which is mostly dead white blood cells. Smallpox lesions are vesicles for only a day or two and then quickly become pustules.
(2) Smallpox lesions are firm and deeply embedded into the skin, while chickenpox lesions are near the outermost layer of skin, resulting in a very thin balloon that looks like it would pop with light scratch (NEXT)

23. Chickenpox
Also, notice that chickenpox lesions are in different stages of development: In the green circle you can see some early bumps, or papules, of chickenpox while in the dotted black circle you can see a popped vesicle that is probably a few days older (NEXT)

24. Smallpox: ~1 week into rash
In this smallpox picture, all the lesions are more or less in the same stage of development, almost all white pustules, all the same size, very dense around the face forearms, and hands, and they really look firmly attached

25. Chickenpox
NOT Smallpox: Again, early papular lesions (POINT) right next to later vesicular lesions (POINT) (NEXT)

26. Chickenpox Different sizes & stages
Chickenpox lesions of various shapes and sizes.

27. Smallpox
Note the umbilication of these lesions, which is a common feature in poxvirus infections

28. Coxsackie A16Virus
Coxsackie virus, which causes hand-foot-and-mouth disease, has the palm and sole involvement of smallpox, but is intensely painful in a tingly way, and it hurts to touch anything.

29. Smallpox Boy with smallpox, note the Umbilication,
deep set into the skin,
all lesions pretty much the same stage

30. Molluscum Contagiosum
Molluscum contagiosum, another poxvirus specific for humans, looks a lot like smallpox, with fairly deep vesicles that become pustular and that umbilicate as they do in smallpox, shown (POINT) here, and (NEXT)
Molluscum Contagiosum

31. Molluscum Contagiosum
here. But I don’t worry too much about confusing smallpox with mollluscum, because, and this is the most important point, (NEXT)

32. Man Severely Ill with Smallpox
Persons with the rash are SICK!!!! And not likely to be walkiing around . . .next

33. Start on Face, (fore)Arms, Mouth Palms and Soles
Smallpox Lesions:
Start on Face, (fore)Arms, Mouth
Palms and Soles
Deeply Embedded into Skin
Similar Stage of Development
Occur in Very Sick Persons
So to summarize, ( . . .and particularly the mouth)

34. Smallpox Complications
Hemorrhagic-type Smallpox: 1 in 20 cases
More common in pregnant women
Flat-type Smallpox: 1 in 20 cases
Encephalitis
Variola major: 1 in 500 cases
Variola minor: 1 in 2000 cases
Ocular Infection
Blindness in 1% of cases
Infection transmitted to child in late pregnancy
Two atypical forms of smallpox include hemorrhagic-type smallpox, in which there is Bleeding into lesions, is more common in pregnancy, and is almost always fatal; and flat-type smallpox, characterized by grey, Flat velvety lesions. This type is also almost always fatal as the skin turns into crepe paper and literally slips off.
A feared complication of both smallpox and of vaccination is enceph . . .
. .. Blindness, which occurs in about 1% of cases

35. Case Presentation 20 y/o woman with Fever, Misery X 2 days
Today, rash appeared on face & arms
Temp 103oF Blood Pressure106/78
Pulse 116/minute Breathing Rate 18/minute
Mentally sound, Lungs clear
Scattered macules (“spots”) and vesicles noted
Diagnosis – Chicken pox (Varicella Zoster virus)
Treatment – oral Acyclovir, recheck in 2 days
(NEXT) if tight skip next three slides Let’s look at what diagnosing a case of chickenpox might be like: a 20 year-old college student, living in a crowded dormitory, present to student health with

36. What if this wasn’t Chickenpox?
Patient had history of chickenpox as a child
Unusually severe for atypical or second infection
Need to Diagnose Smallpox ASAP
“Needle in a haystack”
But what if this wasn’t chickenpox at all? For example, suppose that the patient had forgotten to tell the doctor that she had chickenpox as a child. A second bout of severe chickenpox is pretty rare. What should the doctor do? The point is, the vast majority of smallpox-like illness will be a non-smallpox illness, so finding smallpox is like looking for a needle in a haystack (NEXT)

37. What if this wasn’t Chickenpox?
Patient had history of chickenpox as a child
Unusually severe for atypical or second infection
Need to Diagnose Smallpox ASAP
“Match in a haystack”
What would we do if we couldn’t rule out smallpox? Would we want to wait a week to make sure? I don’t think so – I think the needle in the haystack analogy is wrong, because smallpox would be more akin to a lit match in a haystack.

38. Infection Control Nightmare (Yugoslavia 1972)
1 case  Vaccination of 20,000,000
To miss the diagnosis by a few weeks would be, even in the best case scenario, a public health nightmare, as ron pointed out earlier. (NEXT)

39. Hospital Infection Control
Respiratory Isolation Critical
NOTIFY IMMEDIATELY
Hospital Infection Control
Local Health Department
If a hospitalized patient is suspected to have smallpox, immediate Resp isolation in a negative pressure room is critical, and the hospital infection control department and the local health department should be notified immediately. (NEXT)
Fortunately, CDC has provided some guidance as to when to sound the smallpox alarm. I will finish today

40. CDC’s Interim Smallpox Response Plan
I will finish by discussing just a portion of what is available in the CDC’s I.S.R.P I should reiterate that the following are my personal views gleaned from perusing the second draft of the document, which is freely available on the worldwide web
Self-declared “Work in Progress”

41. Smallpox Response Plan
Surveillance
Outbreak Investigation
Outbreak Containment
Vaccination
Quarantine/Isolation
Public/Media Communication
The ISRP includes guidelines for . . (CLICK 5 TIMES TO GO THRU OUTLINE)
The plans for outbreak containment are controversial on at least two fronts

42. Smallpox Response Plan
Surveillance
Outbreak Investigation
Outbreak Containment
Vaccination
Quarantine/Isolation
Public/Media Communication
The ISRP includes guidelines for . . (CLICK 5 TIMES TO GO THRU OUTLINE)

43. Smallpox Response Plan
Surveillance
Outbreak Investigation
Outbreak Containment
Vaccination
Quarantine/Isolation
Public/Media Communication
. . (CLICK 5 TIMES TO GO THRU OUTLINE)

44. Smallpox Response Plan
Surveillance
Outbreak Investigation
Outbreak Containment
Vaccination
Isolation/Quarantine
Public/Media Communication
Isolation being defined as confining individuals to a location, in general limited to persons who are sick and contagious, or who may become sick; while quarantine is defined as population-level measures to restrict free movement of persons, and designed to prevent the spread of disease.

45. Smallpox Response Plan
Surveillance
Outbreak Investigation
Outbreak Containment
Vaccination
Quarantine/Isolation
Public/Media Communication

46. Surveillance Pre-event (baseline) Rash Surveillance
Notification for suspected smallpox case, outbreak, contamination or distribution:
Local Health Department
State Health Department  CDC
Emergency Preparedness and Response Branch
Bioterrorism Preparedness and Response Program
Poxvirus Section, Division of Viral and Rickettsial Diseases
Case Definitions and Clinical Appearance
CDC proposes that local health department begin surveillance for rash illnesses now, for training as much as anything else, and has set up a chain of notification for suspect smallpox that instructs callers to contact BOTH their local and state health departments, who then contact CDC.
Let’s review the criteria for a judging a possible smallpox case (NEXT)

47. Surveillance: Case Definition
Major Criteria
Fever > 102°F before rash onset
Classical smallpox lesions
Lesions at same stage of development
Minor Criteria
Patient is “toxic” or moribund
Rash began on forarms, face, or mouth
Rash includes palms and soles
Centrifugal distribution (extremities > trunk)
Slow evolution of rash

48. Surveillance: Smallpox Case Categories
Low Probability
No Fever
Fever and no other major and <4 minor criteria
Moderate Probability: Fever +
1 other major, or
> 4minor criteria
High Probability: all 3 major criteria

49. Outbreak Investigation
Active Surveillance for Smallpox
Local, state, national, international
Surveillance for Adverse Vaccine Reactions
Epi Investigation of Cases
Contact Tracing
Specimen Collection & Transportation
Laboratory Confirmation (at CDC )
Detecting Smallpox Directly in Tissues
Viral Culture
Molecular Fingerprinting using PCR
Note that Every one of these activities will require a massive mobilization of public health workers (and probably the recruitment of other, minimally trained persons)

50. Outbreak Containment: Vaccination Activities
CDC vaccine deployment strategy
Set up vaccination clinics
Educate a pool of vaccinators
Recognize vaccine “take”
Recognize and treat adverse events
Safe handling of vaccine
MASS VS. TARGETED VACCINATION?
Which begs the question of who are you going to vaccinate: everyone (“mass vaccination”) or just persons in range of the outbreak (targeted, or “ring” vaccination)

51. Outbreak Containment: Ring Vaccination
Strategy used for smallpox elimination
Avoids recurring cost of mass vaccination
Avoids unacceptably high, recurring risk of mass vaccination
Strengthen public health surveillance infrastructure for ALL infectious diseases
Smallpox vaccine prevents only smallpox
Setting the scientifc stage for what is likely to be a largely political battle over the next few years, CDC has come down clearly on the side of

52. Isolation of Smallpox Victim in Australia
The other controverisal part of outbreak containment, from a public health standpoint, will be Isolation & Quarentine. Isolation is confining individuals to a location, in general limited to persons who are sick and contagious, or who may become sick; while quarantine is defined as population-level measures to restrict free movement of persons, and designed to prevent the spread of disease.

53. Outbreak Containment: Isolation Categories
Isolation Units (smallpox hospitals): contagious persons
Observation Units (for persons with fever but no rash after smallpox contact): possibly contagious persons awaiting triage
Home Fever Surveillance with travel restriction: for exposed or vaccinated persons
Isolation units which will basically be our smallpox hospitals for confirmed cases, should have full medical capabiilties, including intensive care units, and will be staffed only by vaccinated persons.
. . .similar to isolation units, observation units will only be staffed by vaccinated persons

54. Outbreak Containment: Levels of Quarantine
Education/Notification
Suspension of Gatherings
Restriction on Travel
Blockade (“cordon sanitaire”) and community-wide interventions
Most quarantine plans are graded, and absolute quarantine seems highly unlikely. The levels of quarantine increase from simple notification of where outbreak activity is occurring, in an effort to minimize travel into those areas, to And community-wide interventions such as citywide vaccination It is assumed that voluntary cooperation will be sufficient to meet the objectives of any quarantine. However, the plan argues strongly that police powers are inherent to state health jurisdictions in the event of a smallpox emergency and that these powers be formalized and reviewed by each state. Furthmore the document suggests that sections 70.2, 311,and 360 of the Public Health Service Act empower the director of the CDC to assist state agencies, or to usurp control if the state response is deemed inadequate

55. Communication Training for Local/State Health Departments
Webcasts
Workshops
Direct public education
During an Event:
Contact Information
Education of General Public
Media Relations
CDC has already begun to train local and state health department in smallpox recognition in aspects of the plan, and is will be providing additional resources for training, public education, and media management in crisis situations (NEXT)

56. Other Critical Issues Infrastructure Development
Inter-Agency Coordination
(SKIP if after 12:53) It should be obvious that funding will be needed to get much of the baseline activity underway. Though not explored in the document, it is clear that there is room for synergy between bioterrorist preparedness and the overall strength of our public health instititions, especially in the areas of surveillance, expanded lab capacity, and surge capacity in the case of crises. The trick is going to be how to fulfill the mission of bioterrorism preparedness without taking out too much from other portions of the public health pie—hopefully this can be acomplished by maximizing the general application of anti-bioterrorist technology and expertise to all diseases of public health importance.

57. Final Thoughts
Smallpox can be recognized early in the course of an outbreak, incumbent on:
Provider and public awareness
Public health surveillance capacity
Outbreaks probably not avoidable, but could (theoretically) be contained
Prodromal symptoms
Rash identifiable
Contagious persons unlikely to travel extensively
In summary, . . .

58. Final Thoughts II
Public health agencies will play a critical role in incident command (i.e., what do we do now?)
Important but political
Uncomfortable decisions
Unprecedented (not yet available) public health “surge capacity” is crucial to early outbreak containment
Dual-use infrastructure may become important method of efficiently using smallpox resources
One of the mistakes we learned from the anthrax outbreak is that public health agencies will have to play a more proactive, take-charge role in the aftermath of a bioterrorist event, which will lead to some uncomfortable decision-making. And finally, a unprecedented amount of surge capacity, or the ability to hugely and suddenly ramp-up the number of persons and resources engaged in infectious disease public health, must be built into our public health infrastructure in a way that is SUSTAINABLE and ADAPTABLE. It is a daunting challenge ahead, but we have no choice but to move forward. If public health does not step up to the plate, who will?

59. Questions & Answers Smallpox plan available at: http://www. bt. cdc
Questions & Answers Smallpox plan available at: /Smallpox/RPG/index.asp

60. Summary III Cancer AIDS
BT funding should be used in a way that does not threaten public health funding for established diseases, that kill a known number of people yearly.
Cancer
AIDS

61. Summary IV
BT funding should be used in a way that does not threaten public health funding for established diseases, that kill a known number of people yearly.
Cancer
AIDS

62. Summary V Bioterrorism
BT funding should be used in a way that does not threaten public health funding for established diseases, that kill a known number of people yearly.
Bioterrorism

63. Summary VI Cancer BT AIDS
BT funding should be used in a way that does not threaten public health funding for established diseases, that kill a known number of people yearly.
Cancer BT
AIDS

64. Summary VII Cancer AIDS BT
BT funding should be used in a way that does not threaten public health funding for established diseases, that kill a known number of people yearly.
AIDS BT

65. Smallpox Vaccination Complications (a live virus vaccine)
Disseminated vaccinia
Eczema vaccinatum
Pre-AIDS!
Points:
For each 1 million vaccinated, there were ~ 250 complications
Vaccine immune globulin (VIG) Rx is needed - short supply