WEBCAST TRANSCRIPT

Transcript of "Evaluation, Management, and Treatment of Adverse Events
of Smallpox Vaccine"\
Presented by Dr. Lisa Rotz, 6 December 2002, on the satellite broadcast
of "CDC Bioterrorism Update: Smallpox Preparedness"

(Associated graphics can be found at\
[www.bt.cdc.gov/agent/smallpox/training/webcast/dec2002/files/eval-ae.ppt](http://www.bt.cdc.gov/agent/smallpox/training/webcast/dec2002/files/eval-ae.ppt)
and
[www.bt.cdc.gov/agent/smallpox/training/webcast/dec2002/files/eval-ae.pdf](http://www.bt.cdc.gov/agent/smallpox/training/webcast/dec2002/files/eval-ae.pdf).)

Lisa Rotz, MD, Chief, Epidemiology, Surveillance and Response Branch,
Bioterrorism Preparedness and Response Program, National Center for
Infectious Diseases, CDC

(Slides 1 and 2 are title and objectives, respectively)

# ROTZ:

Today I will discuss the complications that can occur following smallpox
vaccination, and more specifically, how to recognize, evaluate, and
treat them.

## Slide 3

The vaccine currently used in the United States, Dryvax, is a
lyophilized product that requires reconstitution before administration.

## Slide 4

It was originally prepared from lymph harvested from the skin of calves
that were infected with live vaccinia virus. Dryvax also contains the
antibiotics polymyxin B, streptomycin, tetracycline, and neomycin and is
reconstituted with a diluent that made up of 50% glycerin with a small
amount of phenol as a preservative.

## Slide 5

The newer vaccines being produced use more modern cell culture
production techniques and won't contain antibiotics. However, they'll
probably be distributed as a freeze dried powder and require
reconstitution with a diluent before administration... similar to
Dryvax.

## Slide 6

The usual response to primary vaccination, or re-vaccination after a
long period of time is called a "major", or primary response. This
involves the development of a papule at the vaccination site, 2-5 days
following vaccination, that evolves into a pustule by days 7-10. The
maximum site response occurs around days 8 to 10, and is when the
greatest amount of erythema or swelling is seen. Axillary lymph nodes
may also be more swollen at this time. The site lesion then starts to
dry up to form a scab at about day 14, with separation of the scab
beginning around 21 days after vaccination.

## Slide 7

This picture demonstrates the usual progression of a vaccination site,
with the papule progressing to a vesicle by day 4 and then forming a
pustule by day 7. By 2 weeks, the site is starting to scab over and is
fully scabbed by 3 weeks. Scab separation then begins and is usually
complete by week 4.

## Slide 8

Data from the recent dilutional studies of smallpox vaccine showed that
the pustule size was the same regardless of the dilution and was usually
around 12 millimeters, or about a half an inch. The diameter of erythema
was a little bigger in people getting undiluted vaccine.

## Slide 9

Most primary vaccinees or distant re-vaccinees can expect some amount of
tenderness, swelling, and redness at the vaccination site. They can also
expect to have swollen axillary lymph nodes that can sometimes persist
for several weeks.

## Slide 10

Fever most often occurs in people being vaccinated for the first time,
and can be greater than 100 degrees Fahrenheit in more than 18% of
vaccine recipients. Peak temperature elevation generally occurs about
the time the vaccine site inflammatory reaction is at its greatest, on
about days 8-10. General malaise and muscle aches may also occur and may
be severe enough in some people to alter their normal activities for a
couple of days.

## Slide 11

There is a range of expected reactions that can occur at the vaccine
site. Some people may experience swelling, and some may develop
lymphangitis or satellite lesions.

## Slide 12

This image demonstrates the red streaking of lymphangitis. This is
usually due to a normal robust reaction at the site but can be seen in
secondary bacterial cellulitis. It can also be confused with allergic
reactions to the dressing tape.

## Slide 13

Here is an example of a satellite lesion near the vaccination site.
These usually heal at the same rate as the primary vaccination site.

## Slide 14

There are several other local reactions that can occur at the
vaccination site, in addition to the expected reactions; an allergic
reaction to the tape used to hold on the site bandage, a larger, more
robust site reaction, or a secondary bacterial infection.

## Slide 15

This picture demonstrates a local reaction due to a tape allergy. This
can usually be distinguished from lymphangitis by observing that the
reaction only occurs in the distribution of the tape.

## Slide 16

Usually, individuals with reactions to tape have no other systemic
symptoms and can be treated by changing the type of tape or increasing
the frequency of dressing changes. Antihistamines or non steroidal
anti-inflammatory medications can be used if the local reaction is
severe enough to cause discomfort. Steroid treatment is generally not
needed or recommended.

## Slide 17

Some individuals can have a robust primary reaction that presents with a
large amount of erythema, swelling, pain, and warmth at the vaccine
site. The redness and swelling can sometimes be greater than 3 inches or
even involve the entire upper arm. This peak reaction is seen on days
8-10, corresponding to the same time when the peak vaccine inflammatory
reaction usually occurs. Unlike bacterial cellulitis, the clinical
course usually isn't progressive, and the symptoms improve over a couple
of days without specific therapy. In recent studies, this robust take
occurred in 5%-15% of vaccine recipients. Both people getting vaccinated
for the first time and people getting revaccinated after a long period
since their last vaccination can have these robust takes.

## Slide 18

Here we see an example of a robust take. Note the large area of erythema
and swelling, and the lymphangitic streaking. Swollen axillary lymph
nodes are also often present and can be painful.

## Slide 19

Persons with robust takes should be followed carefully. Some can have
fever but most don't usually experience high fevers or other severe
systemic symptoms. This robust reaction generally improves in 1 to 2
days with only symptomatic treatment.

## Slide 20

This is an example of a secondary bacterial infection of the vaccination
site. Note the increased size and raised borders of the lesion.

## Slide 21

Individuals suspected of having bacterial cellulitis at the site should
be evaluated with gram stain and culture of the lesion, and blood
cultures if systemic symptoms like high fever and malaise are present.
An elevated peripheral white blood cell count may also be more
consistent with a bacterial infection. The most common organisms causing
secondary infections are Staphylococcus aureus and Group A streptococci.
Some anaerobic or mixed infections can be seen, and may occur if
occlusive dressings are used for prolonged periods that prevent aeration
of the site and promote an anaerobic environment. Antibiotic therapy
should be guided by culture and sensitivities.

## Slide 22

Two studies were done in the U.S. during the late 1960's that looked at
adverse events associated with smallpox vaccination. These studies are
most often quoted when discussing the rates of smallpox vaccine adverse
events. One was a National surveillance study while the other was a
survey of physicians in 10 states. The results of these studies prompted
public health officials to re-evaluate the ongoing routine smallpox
vaccination program in the United States, and ultimately led to the
discontinuation of that program in 1972.

## Slide 23

The most common adverse event associated with vaccination in these
studies included: inadvertent inoculation; eczema vaccinatum;
generalized vaccinia; progressive vaccinia, also called vaccinia
necrosum; post-vaccinial encephalitis; and other dermatologic conditions
or rashes. We'll discuss each of these adverse events in more detail.

## Slide 24

This table shows the range of adverse event rates reported from both of
these studies. The differences seen in the rates between the two studies
is due to different data collection methods. The 10 state survey
probably more accurately reflects the rates for the less serious
complications that were frequently unreported, while the national study
captured the rates of the more serious adverse events through national
reporting and VIG distribution mechanisms.

## Slide 25

One of the biggest concerns regarding smallpox vaccination in today's
society is that adverse events may be higher because of the greater
number of immunosuppressed people. We may also have more people affected
by eczema or atopic dermatitis. Both of these conditions have a higher
risk for serious complications associated with vaccination. In addition,
adverse event rates are higher among primary vaccinees, and currently
there is a higher percentage of individuals who were not vaccinated as
children because routine vaccinations were stopped in 1972.

## Slide 26

Some of the dermatologic manifestations that can follow vaccination
include non-specific rashes. Most are mild, require no specific
treatment, and last only a few days. These rashes generally occur about
10 days after vaccination, and can be only a few lesions or a
generalized rash that is erythematous, macular or urticarial. These
rashes usually don't become vesicular. They don't appear to be a result
of systemic dissemination of the virus and may be due to a non-specific
immune reaction. Antihistamines can be used if the individual is
experiencing itching from the rash.

## Slide 27

Occasionally, more severe non-specific immune reactions such as erythema
multiforme or Stevens-Johnson syndrome can be seen following
vaccination. This picture shows erythema multiforme following
vaccination.

## Slide 28

Erythema multiforme can present as macules, papules, urticarial lesions
or the typical bulls eye lesions. The lesions usually do not progress to
vesicles and don't contain live vaccinia virus because they are not a
result of disseminated vaccinia virus. Vaccinia Immune Globulin, or VIG
is not effective or indicated for the treatment of this complication.

## Slide 29

Inadvertent inoculation is the accidental transfer of vaccinia virus
from the vaccine site to another area of the body or to another person.
This is the most common adverse event seen following vaccination.
Transfer to another body site results in a second, similar skin lesion
that progresses through the same stages of resolution as the vaccination
site. The most common body sites affected are the face, eyelid, nose,
mouth, and other mucosal surfaces. Transfer of vaccinia virus to another
person can result in a lesion similar to a typical vaccine site lesion,
or can lead to other more severe adverse reactions, especially in people
with certain underlying medical conditions like eczema, atopic
dermatitis, or immune suppression.

## Slide 30

Inadvertent inoculation of the eyelid can lead to significant swelling
and redness of the eyelid and periorbital area.

## Slide 31

Usually, lesions resulting from inadvertent inoculation are
uncomplicated and don't require specific therapy other than good site
care. If there are multiple, clinically significant lesions, or lesions
that cause the individual a great deal of discomfort, VIG may help speed
the recovery if given early in the course before neutralizing antibodies
appear on their own.

## Slide 32

Inoculation of the virus in the eye can result in several clinical
manifestations including blepharitis or infection of the eyelid,
conjunctivitis, keratitis or iritis, or a combination of these
conditions. Ocular vaccinia should be managed in consultation with an
ophthalmologist as the treatment and monitoring of these eye
complications can be complex and may involve the use of current
ophthalmologic antiviral agents and possibly vaccinia immune globulin.

## Slide 33

Generalized vaccinia usually presents as a rash that develops into
vesicular or pustular lesions distal from the vaccination site. This
vesicular rash may involve only a few, scattered lesions but can also be
more extensive and generalized in nature. Fever and other systemic
symptoms may be present but are usually not severe.

## Slide 34

Here we see several pustular lesions of generalized vaccinia located on
the lower legs.

## Slide 35

The differential diagnosis for this vaccine complication includes other
non-specific immune rashes that can also occur following vaccination,
eczema vaccinatum, metastatic lesions of early progressive vaccinia, or
non--vaccinia related conditions such as disseminated herpes or severe
varicella.

## Slide 36

In a person with a normal immune system, generalized vaccinia is usually
self-limited, and doesn't require specific therapy. VIG may be utilized
in cases where the individual is more seriously ill or has an underlying
immune problem. This complication is felt to result from hematogenous
spread of the virus and the rash lesions do contain live vaccinia virus
unlike the other non-specific rashes that can occur following
vaccination.

## Slide 37

Eczema vaccinatum is one of the more serious adverse events that can
result from smallpox vaccination. This complication can occur in
individuals with active eczema or atopic dermatitis, or in those with a
history of these conditions even when the condition is not active. A
less severe form of eczema vaccinatum can also occur in people with
other skin disorders, like psoriasis or burns, that are currently active
and effecting the integrity of the skin. Some of the most severe cases
of eczema vaccinatum have occurred in people with eczema or atopic
dermatitis who were contacts to recently vaccinated individuals. Good
medical history screening of potential vaccine recipients and their
close contacts for the presence or a history of these conditions is the
most important way to reduce the occurrence of this adverse event.

## Slide 38

The rash of eczema vaccinatum can occur anywhere on the body but has a
predilection for areas effected by atopic dermatitis or eczema. The rash
can be quite extensive and even become confluent with papular,
vesicular, or pustular lesions. Patients with significant skin
involvement can become severely ill.

## Slide 39

This picture demonstrates the extensive skin involvement of eczema
vaccinatum in a close contact to a recently vaccinated person. Extensive
skin involvement may result from inoculation of vaccinia virus in skin
sites with compromised dermal integrity due to eczema or other skin
conditions or may be the result of hematogenous spread following initial
infection with the virus. Lesions of eczema vaccinatum can result in
skin discoloration or scarring following resolution.

## Slide 40

Eczema vaccinatum can be quite severe and even result in death.
Management of this complication involves treatment with VIG and
supportive care, including good fluid management and skin care as is
done with other conditions like burns that effect large areas of the
skin. It is also important to remember that the lesions contain vaccinia
virus that can be shed into the patient's room environment. Strict
contact precautions should be followed by care givers to prevent
nosocomial transmission of virus from the lesions to themselves or to
other patients. If extensive skin lesions are present there is a
possibility for greater amounts of virus to be shed into the room
environment from the lesion drainage. Additional precautions may be
needed to prevent potential contamination of other areas outside of the
room from air current transportation of virus. Healthcare personnel who
are pregnant or who have eczema, atopic dermatitis, or immune system
problems themselves, should not be utilized to care for EV patients.

## Slide 41

Progressive vaccinia or vaccinia necrosum is a rare but serious adverse
event that can occur in people with cellular immunodeficiencies or in
individuals with humoral or immune globulin deficiencies.

## Slide 42

Persons with progressive vaccinia usually present with a non-healing,
expanding vaccination site. The site often ulcerates and central
necrosis, or necrosis of the surrounding skin can occur. There is
generally little or no inflammation at the site initially, because of
the poor local immune response to the infection that is induced by
vaccination. This lack of adequate local immune response presumably
allows the virus to spread locally and systemically. Medical conditions
or medications that suppress the immune system would put a person at
risk for this complication. Therefore, careful medical history screening
of potential vaccinees and their close contacts for conditions such as
leukemia or HIV, or the use of medications like steroids or other immune
suppressive drugs, is important in preventing this adverse event. It is
currently unknown exactly what level of cellular or humoral immune
depression would put a person at risk for this complication.

## Slide 43

This woman had chronic lymphocytic leukemia. Notice how the infection
from the vaccine site has spread to involve the surrounding skin and the
necrotic appearance of the area. This woman also has metastatic lesions
on her neck and other areas of her body presumably from hematogenous
spread of the virus.

## Slide 44

Progressive vaccinia was historically treated with aggressive VIG
therapy, and sometimes with surgical debridement to remove necrotic
tissue and reduce the overall viral burden on the immune system.
Antiviral therapy was utilized at that time with varying degrees of
success and it is unclear how effective newer antivirals today would be
in the treatment of this complication. Progressive vaccinia lesions also
contain vaccinia virus and appropriate precautions should be taken to
prevent the contact transmission of virus.

## Slide 45

Post-vaccinial encephalitis is also a very rare but serious vaccine
complication. It was more frequently seen in vaccinated infants less
than 1 year old or in older adolescents or adults receiving their first
vaccination. It can present with a variety of CNS manifestations from
confusion to seizures or coma. Death results in about 15%-25% of the
cases, while 25% had some degree of residual neurologic sequelae.

## Slide 46

Symptoms of post-vaccinial encephalitis usually occurred between 9 and
14 days following vaccination and it's diagnosis involves excluding
other potential causes for encephalitis. The pathophysiology of this
complication is not well understood but it is thought to be a result of
a post vaccination immune response, similar to other post-infectious
encephalitidies. It has not been causally linked to the presence of
vaccinia virus in the CNS.

## Slide 47

VIG was not effective in treating this complication and is therefore not
indicated. Treatment is supportive and may require intensive care
monitoring and anticonvulsive therapy.

## Slide 48 (added into training module -- not in broadcast)

This is a picture of an infant infected with vaccinia virus in utero.
Intrauterine infection of a fetus is referred to as fetal vaccinia.

## Slide 49

Fetal vaccinia is a very rare complication that can occur following
primary vaccination of a pregnant woman in the second or third
trimester, from hematogenous spread of virus to the amniotic fluid or
directly to the fetus. Only about 50 cases of this complication have
been reported in the literature. Studies are contradictory as to whether
spontaneous abortions were increased in pregnant women vaccinated during
the first trimester.

## Slide 50

When fetal vaccinia did occur, death of the infant usually happened
in-utero, or in the prenatal period. For infants born alive with
vaccinia lesions, VIG may be considered, though no data exists regarding
the dosage or efficacy of this treatment for fetal vaccinia. There is no
known reliable intrauterine diagnostic test to confirm fetal infection.

## Slide 51

The diagnosis of smallpox vaccine adverse events is most often done with
a thorough history and clinical evaluation. Viral isolation or PCR
detection of vaccinia virus for adverse events that are associated with
viral replication or dissemination is also helpful in confirming these
vaccine complications. For individuals who are being evaluated for a
possible complication that may have resulted from contact transmission
of vaccinia, diagnostic testing to rule out other more common causes of
vesicular rashes should also be done. On a separate note, serologic and
cell mediated immunity testing following vaccination are currently
research tools to assess the immune response to vaccination, and not
tools to determine whether vaccination was successful. The level of
these immune responses that correlates with protection against smallpox
is unknown. That's why we look to the skin site reaction to determine if
a vaccination was successful, because "major" or primary reactions
following vaccination correlated well with immunity to smallpox during
the eradication period.

## Slide 52

The primary treatment for adverse events involving uncontrolled
replication or dissemination of vaccinia virus following vaccination is
VIG. VIG is a human immune globulin product derived from the plasma of
persons vaccinated with vaccinia vaccine. It is effective in the
treatment of eczema vaccinatum, serious generalized vaccinia, and
serious manifestations of inadvertent inoculation such as ocular
vaccinia. VIG is also indicated for progressive vaccinia and has
variable effectiveness in treating this complication. Since post
vaccinial encephalitis is not due to virus multiplication, VIG is not
effective in treating this adverse event.

## Slide 53

Currently, CDC is the only source of VIG for use in treating vaccine
adverse events in the civilian population. It is not licensed at this
time and must be utilized under an Investigational New Drug or IND
Protocol. A new intravenous formulation of VIG is being produced and
will be available for treatment of adverse events. But, stores of this
and the previously produced intramuscular product are still limited and
VIG should be reserved for use in the treatment of more serious vaccine
complications.

## Slide 54

Side effects from VIG are rare and are similar to those seen with other
human derived immune globulin products as listed here.

## Slide 55

People with selective IgA deficiency or those who have had a severe
allergic reaction to other immune globulin products can also experience
a severe anaphylactic response to VIG. The intramuscular formulation of
VIG contains thimerosal and people with a severe allergy to this
component could also experience an allergic reaction to IM VIG. VIG use
in the presence of vaccinial keratitis may increase the possibility of
corneal scarring but might be considered if an ophthalmology specialist
feels that more serious consequences of keratitis can be prevented with
this treatment.

## Slide 56

The initial treatment dose for VIG is 0.6 milliliters per kilogram,
which is about 100 milligrams per kilogram. Because the total dose can
be large, the IM VIG dose is often divided and given in multiple sites
or with several injections over a 24 hour period. Administration of the
IV product can usually be done during a single intravenous
administration over an hour or so depending on the total dose.

## Slide 57

Cidofovir is an antiviral medication that is currently licensed for the
treatment of CMV retinitis. In vitro and animal studies with this drug
have shown some activity against vaccinia virus, but it is unclear how
well it would work in treating vaccinia infections in humans. Because it
is not licensed for this indication, use of cidofovir for treating
vaccinia infections should be done under an investigational new drug
protocol with careful monitoring.

## Slide 58

Cidofovir is a second line treatment for complications of smallpox
vaccination as VIG is still considered the standard treatment. CDC is
developing the investigative protocol for use of this medication.
Probenicid and hydration should be used with cidofovir to help reduce
the risk of renal toxicity.

## Slide 59

Cidofovir has been associated with these side effects. The occurrence of
renal toxicity can be decreased with careful pre- and post infusion
hydration along with the use of probenicid.

## Slide 60

Cidofovir has a long half live and therefore only requires once weekly
administration. The dose of cidofovir for vaccinia infections not
responsive to VIG is the same as the dose used for treatment of CMV
retinitis. Renal function should be carefully monitored. If the patient
is still experiencing serious symptoms of the vaccinia infection 1 week
following the first dose of cidofovir, a second dose may be considered.
Because cidofovir itself can have severe side effects, and we don't know
how effective it will be in treating vaccinia adverse events, good
clinical evaluation and follow-up is essential. There is little to no
experience with the use or dosing of cidofovir in children and
probenicid is not otherwise recommended for use in children under 2
years of age.

## Slide 61 (slide not used in broadcast)

In summary: it is very important for public health and medical personnel
to again become familiar with smallpox vaccine, the expected vaccine
reactions, and the evaluation and management of vaccine adverse events.
The CDC website has several educational resources that can help. CDC
personnel are available to consult with public health officials and
clinicians on the evaluation and management of smallpox vaccine adverse
events and CDC will provide VIG and Cidofovir under an IND protocol,
when indicated, to treat these complications. Thank you for your
attention.

END

For more information, visit
[www.cdc.gov/smallpox](http://www.cdc.gov/smallpox), or call the CDC
public response hotline\
at (888) 246-2675 (English), (888) 246-2857 (Español), or (866) 874-2646
(TTY)