Contraindications to Vaccination
Refer to the "Subgroups of Patients Most Likely to be Harmed"
section of this document for information on contraindications to smallpox vaccination in the preoutbreak setting. In the event of a smallpox outbreak, outbreak-specific guidance will be disseminated by Centers for Disease Control and Prevention (CDC) regarding populations to be vaccinated and specific
contraindications to vaccination.
Normal Vaccination Progression
Smallpox vaccine is administered by using the multiple-puncture technique with a bifurcated needle. The vaccinia virus replicates in the dermis of the skin; 3–5 days later, a papule forms at the vaccination site of immunocompetent vaccine-naïve persons (also referred to as first-time or primary vaccinees). The papule becomes vesicular (approximately day 5–8), then pustular, and usually enlarges to reach maximum size in 8–10 days. The pustule dries from the
center outward and forms a scab that separates 14–21 days after vaccination, usually leaving a pitted scar.
Formation by days 6–8 postvaccination of a papule, vesicle, ulcer, or
crusted lesion, surrounded by an area of induration signifies a response
to vaccination; this event is referred to as a major reaction or a take,
and usually results in a scar. During the smallpox eradication era,
persons with vaccination scars had much lower attack rates when exposed to
smallpox cases than did nonvaccinated persons. Therefore, a take has been
a surrogate correlate of immunity to smallpox. Although the level of
antibody that protects against smallpox infection is unknown, >95% of
first-time vaccinees (i.e., persons receiving their first dose of smallpox
vaccine) have increased neutralizing or hemagglutination inhibition
antibody titers.
Interpreting Vaccination Results
Vaccination-site reactions are classified into two categories: major
reactions and equivocal reactions. A major reaction indicates a successful
vaccine take and is characterized by a pustular lesion or an area of definite
induration or congestion surrounding a central lesion, which can be a scab or an
ulcer. All other responses are equivocal reactions and are nontakes. Equivocal
reactions can be caused by suboptimal vaccination technique, use of subpotent
vaccine, or residual vaccinial immunity among previously vaccinated persons.
Persons with equivocal reactions cannot be presumed to be immune to smallpox,
and revaccination is recommended.
The World Health Organization (WHO) has recommended that response to
vaccination be evaluated on postvaccination day 6, 7, or 8. These are the days
of peak viral replication, and the period during which take should be assessed
for both first-time vaccinees and revaccinees. If the response to vaccination is
evaluated too early (e.g., <6 days postvaccination), certain equivocal
responses will look reactive because of dermal hypersensitivity to vaccinial
proteins. These reactions are sometimes referred to as immediate reactions but
are not successful takes. If the response to vaccination is evaluated too late
(e.g., >8 days postvaccination), the vaccination take might be missed among
persons with prior immunity to vaccinia who might experience a more rapid
progression of the vaccination site. Responses among revaccinees that resolve in
<6 days are sometimes referred to as accelerated reactions and are not
successful takes.
Expected Range of Vaccine Reactions
A range of expected reactions occurs after vaccination.
These normal reactions do not require specific treatment and can include
fatigue, headache, myalgia, regional lymphadenopathy, lymphangitis, pruritis, and
edema at the vaccination site, as well as satellite lesions, which are benign,
secondary vaccinial lesions proximal to the central vaccination lesions.
During the smallpox eradication era, fever after vaccination occurred
frequently but was less common among adults than children. For adults, fever is
more frequently noted among first-time vaccinees than revaccinees. In one
vaccination series involving children, approximately 70% experienced >1 day
of temperatures >100ºF during the 4–14 days after primary vaccination, and
15%–20% of children experienced temperatures >102ºF. After revaccination, 35%
of children experienced temperatures >100ºF, and 5% experienced temperatures
of >102ºF.
Satellite lesions occasionally occur at the perimeter of the vaccination site
and should not be confused with the early discrete vesicles that might coalesce
into a central pox-like lesion. Satellite lesions are a benign finding, do not
require treatment, and should be cared for as vaccination sites.
Large Vaccination Reactions and Robust Takes (RTs)
Large vaccination reactions (i.e.,
>10 cm in diameter) at the site of inoculation
occur in approximately 10% of first-time vaccinees and are expected variants
of the typical evolution of the vaccination site.
However, sometimes these large vaccination reactions have been reported
as adverse events and misinterpreted as cellulitis,
requiring antibiotic treatment.
Bacterial infection of the
vaccination site is uncommon but affects children more
often than adults, because children are more likely to touch and
contaminate their vaccination sites. Specimens for bacterial cultures can be
obtained by using swabs or aspiration. Gram stains can detect normal skin flora
and are useful only when unusual pathogens are present. If empiric antibacterial
therapy is administered, therapy should be adjusted after the bacterial pathogen
and its sensitivities to various antibacterial medications are known.
Identifying RTs
Differentiating an RT from bacterial cellulitis can be difficult. RTs occur
8–10 days postvaccination, improve within 72 hours of peak of symptoms, and do
not progress clinically. Fluctuant enlarged lymph nodes are not expected and
warrant further evaluation and treatment. In contrast, secondary bacterial
infections typically occur within 5 days of vaccination or >30 days
postvaccination, and unless treated, the infection will progress. The interval
of onset to peak symptoms is the key factor in diagnosing RTs. Fever is not
helpful in distinguishing RTs from bacterial cellulitis because it is an
expected immunologic response to vaccinia vaccination.
When an RT is suspected, management includes vigilant observation, patient
education, and supportive care that includes rest of the affected limb, use of
oral nonaspirin analgesic medications, as well as oral antipruritic agents.
Salves, creams, or ointments, including topical steroids or antibacterial
medications, should not be applied to the vaccination site.
Transmission of Vaccinia Virus
Vaccinia can be transmitted from a vaccinee’s unhealed
vaccination site to other persons by close contact and can lead to the same
adverse events as in the vaccinee.
No data exist to indicate that vaccinia transmission occurs by aerosolization.
Preventing Contact Transmission
Correct hand hygiene prevents the majority of inadvertent inoculations
and contact transmissions after changing bandages or other contact with
the vaccination site. The vaccination site can
be left uncovered or covered with a porous bandage (e.g., gauze).
Preventing Contact Transmission Among Health-Care Workers
To prevent nosocomial transmission of vaccinia virus,
health-care workers when involved in direct patient care should keep their
vaccination sites covered with gauze or a similar material to absorb exudates
that contain vaccinia. This dressing should be covered with a semipermeable
dressing to provide a barrier to vaccinia virus. Using a semipermeable dressing
alone is not recommended because it might cause maceration of the vaccination
site and prolong irritation and itching, which subsequently leads to increased
touching, scratching, and contamination of hands. If maceration of the
vaccination site occurs, the lesion should be left open to air to allow the
vaccination site to dry during a period that includes no direct contact with
patients or other persons. The vaccination site should be covered during direct
patient care until the scab separates. Administrative leave should be considered
for health-care workers who are unable to adhere to the recommended
infection-control measures, which require that vaccination sites be covered
during patient care duties.
Preventing Contact Transmission in Other Settings
Transmission of vaccinia is also possible in other settings when close
personal contact with children or other persons occurs. In these situations, the
vaccination site should be covered with gauze or a similar absorbent
material, and long-sleeved clothing should be worn. Careful attention should be
paid to handwashing, which should be done with soapy warm water or hand-rub
solutions that are >60%
alcohol-based. Historically, the home was the setting where the majority of
contact transmission occurred, presumably because of intimate contact and
relaxed infection control measures.
Recognizing Vaccinia Virus Transmission
When evaluating a skin or other condition consistent with vaccinia, a history
of smallpox vaccination and exposure to a household or close contact who has
been vaccinated recently will often provide a source of the virus. A history of
exposure to vaccinia might be difficult to obtain. A person might have had an
inadvertent exposure and be unaware of being exposed to vaccinia virus, and
rarely, persons have been deliberately inoculated by others as a way to
vaccinate outside the approved vaccination programs (and possibly unwilling to
acknowledge this exposure to vaccinia). In either case, clinicians should obtain
a thorough medical history, including possible vaccinia exposure and risk
factors for smallpox vaccine-related adverse reactions. Clinicians should
counsel these patients regarding appropriate infection-control measures, care of
their lesions, and when appropriate, the infectious risks incurred through
deliberate inoculation of others. Follow-up of the patient and administration of
appropriate treatment are critical if a vaccinia-related adverse reaction develops. In addition, these patients might be at increased risk for infection from bloodborne pathogens, and they should be counseled and treated appropriately.
Adverse Reactions
Adverse reactions caused by smallpox vaccination range
from mild and self-limited to severe and life-threatening. Certain smallpox
vaccine reactions are similar to those caused by other vaccines (e.g., high
fever, anaphylaxis, and erythema multiforme [EM]). Other adverse reactions
specific to smallpox vaccination include inadvertent inoculation, ocular
vaccinia, generalized vaccinia (GV), eczema vaccinatum (EV), progressive vaccinia (PV), postvaccinial encephalopathy (PVE) and encephalomyelitis (PVEM), and fetal vaccinia. Vaccinia-specific complications can occur among vaccinees or their contacts who have been inadvertently inoculated with vaccinia.
This guidance is for evaluation and treatment of patients with
complications from smallpox vaccination administration during preoutbreak
situations. In the event of a smallpox outbreak, considering smallpox
disease will be necessary in the differential diagnosis of any recently
vaccinated person who has an acute, generalized, vesicular, pustular rash
illness. Until a determination is made regarding whether the rash is early
smallpox disease or an adverse reaction to smallpox vaccine, these
patients should be presumed to be highly infectious and placed in contact
and respiratory isolation immediately. Appropriate local, state, and
federal health and security officials should be contacted.
Common Adverse Reactions
- Local skin reactions can occur after smallpox vaccination. These include allergic reactions
to bandage and tape adhesives, robust takes (RTs), and less commonly,
bacterial infections of the vaccination site. Reactions to adhesives usually
result in sharply demarcated lines of erythema that correspond to the
placement of adhesive tape. Patients have local pruritis but no systemic
symptoms and are otherwise well. Frequent bandage changes, periodically
leaving the vaccination site open to air, or a change to paper tape might
alleviate symptoms. Care should be used to vary the positioning of tape or
bandages. This condition is self-limited and resolves when bandages are no
longer needed. Topical and oral steroid treatment for this reaction should be
avoided because the site contains live vaccinia virus. Salves, creams, or
ointments, including topical antibacterial medications, should not be applied
to the vaccination site.
- Common nonspecific rashes associated
with smallpox vaccination include fine reticular maculopapular rashes,
lymphangitic streaking, generalized urticaria, and broad, flat, roseola-like
erythematous macules and patches. These rashes are believed to be caused by
immune response to vaccination and do not contain vaccinia. Erythematous or
urticarial rashes can occur approximately 10 days (range: 4–17 days) after
first-time vaccination. The vaccinee is usually afebrile, and the rash
resolves spontaneously within 2–4 days. Nonspecific rashes are usually
self-limited. These persons appear well and benefit from simple supportive
care measures (e.g., oral anti-antihistamine agents).
Dermatologic Manifestations of Hypersensitivity Reactions
Erythema multiforme (EM), sometimes referred to as roseola vaccinia or toxic urticaria,
might appear as different types of lesions, including macules, papules,
urticaria, and typical bull’s-eye (targetoid or iris) lesions. Because the
number of clinical descriptions of vaccinia-associated EM rashes is limited,
the following details are extrapolated from common descriptions of EM
occurring after herpes simplex or mycoplasma infections. The hallmark target
lesion of EM associated with other infections usually appears with a central,
dark papule or vesicle, surrounded by a pale zone and a halo of erythema,
usually within 10 days after viral infection. The limited clinical
descriptions of EM after smallpox vaccination indicate that it follows a
similar course. The rash of EM might be extremely pruritic, lasting
<4 weeks, and patients benefit from administration of
oral antipruritics.
Less commonly, hypersensitivity reactions can appear
as a more serious condition, Stevens-Johnson syndrome (SJS). SJS can also
arise from EM and typically includes systemic symptoms with involvement of
> 2 mucosal surfaces
or 10% of body surface area. This condition requires hospitalization and
supportive care.
The role of systemic steroids for treatment of SJS is
controversial; therefore, the decision to administer systemic steroids to
patients with postvaccinial SJS should be made after consultation with
specialists in this area (e.g., dermatologists, immunologists, or infectious
disease specialists), according to the prevailing standard of care. Vaccinia immune globulin (VIG) is not
used to treat nonspecific rashes, EM, or SJS, because these lesions are
probably a manifestation of a hypersensitivity reaction and are not believed
to contain vaccinia virus.
Vaccinia-Specific Adverse Reactions
- Inadvertent inoculation is a common
but avoidable complication of smallpox vaccination. Inadvertent inoculation
occurs when vaccinia virus is transferred from a vaccination site to a second
location on the vaccinee or to a close contact. The most common sites involved
are the face, eyelid, nose, mouth, lips, genitalia, and anus. Among
immunocompetent persons, lesions follow the same course as the vaccination
site.
A primary prevention strategy to avoid inadvertent
inoculation is to instruct vaccinees and their close contacts to avoid
touching or scratching the vaccination site from the time of vaccination until
the scab separates. In addition, vigilant handwashing with soap and warm water
or hand rubs containing >60% alcohol, after touching an unhealed vaccination site or changing a vaccination dressing is critical. Lesions from an inadvertent inoculation contain live vaccinia virus, and the same contact precautions necessary for a vaccination site are necessary for these secondary lesions. Persons at highest risk for inadvertent inoculation are younger persons (e.g., children aged 1–4 years) and those with disruption of the epidermis.
Periocular and ocular implantation (hereafter referred
to as ocular vaccinial disease) accounted for the majority of reported
inadvertent inoculations and were often noted within 7–10 days of vaccination
among first-time vaccinees. Ocular vaccinial disease can occur in different
forms, including blepharitis (inflammation of the eyelid), conjunctivitis,
keratitis (inflammation of the cornea, including epithelial and stromal forms),
iritis, or combinations thereof. When evaluating a patient with the new onset of
a red eye or periocular vesicles, vaccinia infection should be considered and
history of recent vaccinia exposure (e.g., smallpox vaccination or close contact
with a vaccine recipient) should be sought. The goal of therapy of ocular
disease is to prevent complications, including corneal scarring associated with
keratitis, and the patient should be comanaged with an ophthalmologist.
Note: The 2001 Advisory Committee on Immunization Practices
(ACIP) recommendation states that VIG is contraindicated in a patient with
vaccinial keratitis. However, in November 2002, this recommendation was
reevaluated and modified by the Public Health Service. VIG should not be
withheld if a comorbid condition exists that requires administration of VIG
(e.g., eczema vaccinatum [EV] or progressive vaccinia [PV]) and should
be considered for severe ocular disease, except isolated keratitis. In these
situations, VIG should be administered if the risk of the comorbid condition is
greater than the potential risk of VIG-associated complications of keratitis.
Uncomplicated inadvertent inoculation lesions are
self-limited, resolving in approximately 3 weeks, and require no therapy. If
extensive body surface area is involved, or severe ocular vaccinia infection
(without keratitis), or severe manifestation of inoculation has occurred,
treatment with VIG can speed recovery and prevent spread of disease.
- Ocular vaccinial infections account for the majority of inadvertent inoculations.
However, data upon which to base treatment recommendations are limited. To
discuss treatment options for ocular vaccinia, CDC convened a meeting of
ophthalmology and infectious disease consultants in November 2002. On the basis
of available data and input from these consultants, the following guidance is
offered:
- Suspected ocular vaccinia infections should be
managed in consultation with an ophthalmologist to ensure a thorough and
accurate eye evaluation, including a slit-lamp examination, and the
specialized expertise needed to manage potentially vision-threatening
disease.
- Although vaccine splashes to the eye occur rarely
because of the viscosity of smallpox vaccine, these occurrences should be
managed by immediate eye-washing with water (avoid pressure irrigation,
which can cause corneal abrasion) and a baseline evaluation by an
ophthalmologist. In this situation, off-label prophylactic use of topical
ophthalmic trifluridine or vidarabine has been recommended by
ophthalmologists. Further treatment might not be necessary.
- Off-label use of topical ophthalmic trifluridine or
vidarabine has been recommended by certain ophthalmologists and can be
considered for treatment of vaccinia infection of the conjunctiva or cornea.
Prophylactic therapy with these drugs might also be considered to prevent
spread to the conjunctiva and cornea if vaccinia lesions are present on the
eyelid, including if near the lid margin, or adjacent to the eye. The
potential benefits of these drugs for prophylaxis should be balanced against
the minimal but potential risk of drug toxicity and of introducing virus
into the eye by frequent manipulation.
- Topical antivirals should be continued until all
periocular or lid lesions have healed and the scabs have fallen off, except
that topical trifluridine usually is not used for >14 days to avoid
possible toxicity. When used for >14 days, trifluridine can lead to
superficial punctate keratopathy, which resolves on discontinuation of the
medication. Topical vidarabine might be preferable for use among children
because it can be compounded into an ointment that allows less frequent
dosing and stings less initially than trifluridine.
- VIG should be considered for use in severe ocular
disease when keratitis is not present (e.g., severe blepharitis or
blepharoconjunctivitis). Severe ocular disease is defined as marked
hyperemia, edema, pustules, other focal lesions, lymphadenophy, cellulitis,
and fever. If keratitis is present with these conditions, consideration of
possible VIG use must be weighed against evidence in an animal model for
increased risk for corneal scar formation if a substantial dose is
administered during multiple days.
- VIG can be considered if the ocular disease is
severe enough to pose a substantial risk of impaired vision as a long-term
outcome (e.g., vision-threatening lid malformation). If VIG is administered
specifically to treat ocular disease in the presence of keratitis, treatment
usually should be limited to 1 dose, and the patient or guardian should be
informed of the possible risks and benefits before its use.
- Using VIG as recommended to treat other severe vaccinia disease (e.g.,
eczema vaccinatum [EV]) is indicated, even in the presence of keratitis. VIG is not recommended
for treating isolated keratitis.
- Topical ophthalmic antibacterials should be considered for prophylaxis
of bacterial infection in the presence of keratitis, including if a corneal
ulcer is present or steroids are used. In severe cases of keratitis (e.g.,
with an ulcer and stromal haze or infiltrate) and in iritis, topical
steroids should be considered after the corneal epithelium is healed to
decrease immune reaction; mydriatics are also indicated.
- Topical steroids should not be used without ophthalmologic
consultation and should not be used acutely without topical antiviral
therapy. Patients with ocular vaccinia infection, including with keratitis
or iritis, should receive careful follow-up evaluation by an ophthalmologist
to detect and treat possible late onset complications (e.g., scarring and
immune reactions).
- Generalized vaccinia (GV) is
characterized by a disseminated maculopapular or vesicular rash, frequently on
an erythematous base, that usually occurs 6–9 days after first-time
vaccination. The rash spans the spectrum of vaccinial lesions, from
maculopapules to vesicles. Maculopapules can be mistaken for erythema multiforme (EM) when they are
accompanied by a substantial component of erythema. In other instances, the
pearly vesicles of GV resemble the lesions of smallpox; however, GV does not
follow the centrifugal distribution that is characteristic of smallpox.
GV rash might be preceded by fever, but usually, patients do not appear ill.
Lesions follow the same course as the vaccination site. Lesions can be present
anywhere on the body, including the palms and soles and can be numerous or
limited. GV can appear as a regional form that is characterized by extensive
satellite vesiculation around the vaccination site, or as an eruption localized
to a body part (e.g., arm or leg), with no evidence of inadvertent inoculation.
A mild form of GV also exists, which appears with only a limited number of
scattered lesions.
The skin lesions of GV are believed to be spread by the hematogenous route and might contain vaccinia virus. Therefore, contact precautions should be
used when treating these patients. Patients should be instructed to keep
lesions covered and avoid physical contact with
others if their lesions are too
numerous to cover with bandages or clothing. The differential diagnosis of
GV includes EM, EV, inadvertent inoculation at multiple
sites, and uncommonly, early stages of PV
or other vesicular diseases (e.g., disseminated herpes or severe
chickenpox).
GV is self-limited among immunocompetent hosts. These patients appear well
and do not require VIG, but might benefit from simple supportive care measures
(e.g., nonsteroidal anti-inflammatory agents [NSAIDS] and oral antipruritics).
VIG might be beneficial in the rare case where an immunocompetent person appears
systemically ill. GV is often more severe among persons with an underlying
immunodeficiency, and these patients might benefit from early intervention with
VIG.
- Eczema vaccinatum (EV) is a
localized or generalized papular, vesicular, or pustular rash, which can occur
anywhere on the body, with a predilection for areas of previous atopic
dermatitis lesions. Persons with a history of atopic dermatitis are at highest
risk for EV. Onset of the characteristic lesions can be noted either
concurrently with or shortly after the development of the local vaccinial
lesions. EV cases resulting from secondary transmission usually appeared with
skin eruptions approximately 5–19 days after the suspected exposure. EV
lesions follow the same dermatological course as the vaccination site in a
vaccinee, and confluent lesions can occur. The rash is often accompanied by
fever and lymphadenopathy, and affected persons are systemically ill. EV tends
to be more severe among first-time vaccinees or unvaccinated contacts.
Atopic dermatitis, regardless of disease severity or
activity, is a risk factor for experiencing EV among either vaccinees or their
close contacts, but no data exist to predict the absolute risk for these
persons. The majority of primary-care providers do not distinguish between
eczema and atopic dermatitis when describing chronic exfoliative skin
conditions, including among infants and young children.
EV can be associated with systemic illness that includes fever and malaise.
Management includes hemodynamic support (e.g., as for sepsis) and meticulous
skin care (e.g., as for burn victims). Patients might require volume repletion
and vigilant monitoring of electrolytes as a result of disruption of the dermal
barrier. Patients with EV are at risk for secondary bacterial and fungal
infections of the lesions, and antibacterials and antifungals are indicated as
necessary.
One study determined that the mortality from EV
was reduced from 30%–40% to 7%
after the introduction of VIG. Therefore, establishing the diagnosis early
and not delaying treatment with
VIG is imperative to reducing mortality. Patients are usually
severely ill and can require multiple doses of
VIG. Virus can be isolated from
EV lesions, making these patients highly infectious. Infection-control
precautions should be used to prevent secondary transmission and
nosocomial infection.
- Progressive vaccinia (PV) (also
referred to as vaccinia necrosum, vaccinia gangrenosa, prolonged vaccinia, and
disseminated vaccinia), is a rare, severe, and often lethal complication that
occurs among persons with immunodeficiencies. This diagnosis should be
suspected if the initial vaccination lesion continues to progress without
apparent healing >15 days after smallpox vaccination. Anecdotal experience
suggests that, despite treatment with VIG, persons with cell-mediated immune
deficits have a poorer prognosis than those with humoral deficits.
PV is characterized by painless progressive necrosis at the vaccination site
with or without metastases to distant sites (e.g., skin, bones, and other
viscera). The vaccination lesion does not heal, presumably secondary to an
immune derangement, and progresses to an ulcerative lesion, often with central
necrosis. Initially, limited or no inflammation appears at the site, and
histopathology can reveal absence of inflammatory cells in the dermis. During
the weeks that follow, patients might experience bacterial infection and signs
of inflammation.
With
PV, vaccinia virus continues to spread locally and
can metastasize to distant sites through viremia. Live vaccinia virus
can be isolated from the skin
lesions of these patients. Infection-control precautions, which include contact isolation, are required to avoid vaccinial infection of other persons and to limit risk for secondary infections.
The differential diagnosis of PV includes severe bacterial infection, severe
chickenpox, other necrotic conditions (e.g., gangrene), and disseminated herpes
simplex infections. Persons at highest risk for PV include those with congenital
or acquired immunodeficiencies, human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS), cancer, and those on immunosuppressive
therapies for organ transplantation or autoimmune disease. The degree and type
of immunocompromise probably correlates with the risk for PV, although the
protective level of cellular count or humoral immunity is unknown.
Before the introduction of VIG and early antiviral medications, PV was
universally fatal; but after VIG was used for PV treatment, the survival rate
improved. Surgical debridement was used infrequently with variable success to
treat the primary progressive necrotic lesions of PV. Management of PV should
include aggressive therapy with VIG, intensive monitoring, and tertiary-level
supportive care. Despite advances in medical care, PV probably will continue to
be associated with a high mortality rate.
- Postvaccinial central nervous system disease after smallpox vaccination is most common among infants aged <12 months
and is a diagnosis of exclusion. Clinical symptoms reflect cerebral or cerebellar
dysfunction with headache, fever, vomiting, altered mental status, lethargy,
seizures, and coma. Central nervous system (CNS) lesions occur in the
cerebrum, medulla, and spinal cord. Lumbar puncture can reveal an increased
opening cerebral spinal fluid (CSF) pressure, and examination of CSF might
indicate monocytosis, lymphocytosis, and elevated CSF protein.
Both postvaccinial encephalopathy (PVE) and postvaccinial encephalomyelitis
(PVEM) have been described. PVE typically affects infants aged <2 years and
reflects cerebral damage as a result of vascular changes. Acute onset of
symptoms occurs 6–10 days postvaccination and can include seizures, hemiplegia,
aphasia, and transient amnesia. Associated histopathological changes include
generalized cerebral edema, mild lymphocytic menigineal infiltration, widespread
ganglion degenerative changes, and occasionally, perivascular hemorrhages.
Patients can be left with cerebral impairment and hemiplegia.
PVEM (or encephalitis) affects persons aged
>2 years and includes abrupt
onset of fever, vomiting, headache, malaise, and anorexia approximately 11–15
days after vaccination. Symptoms can progress to loss of consciousness, amnesia,
confusion, disorientation, restlessness, delirium, drowsiness, seizures, and
coma with incontinence or urinary retention, obstinate constipation, and
sometimes menigismus. CSF, although under increased pressure, reveals normal
chemistries and cell count. Histopathological features include perivenous
demyelination and microglial proliferation in demyelinated areas with
lymphocytic infiltration but limited cerebral edema. These pathological features
are similar to what is observed in other postinfectious encephalitides.
The strain of vaccinia virus used in smallpox vaccines might influence
the frequency of PVE and PVEM. Reports based on European data indicate generally
higher rates of PVE among persons vaccinated with non-NYCBOH strains. In the
United States, where the principal strain used was the NYCBOH, the occurrence of
PVE or PVEM was rare among first-time vaccinees.
No clinical criteria, radiographic findings, or laboratory tests are specific for the diagnosis of PVE. PVE/PVEM are diagnoses of exclusion, and other infectious or toxic etiologies should be considered before making
these diagnoses.
No study has indicated
that VIG can be an effective therapy for PVE or PVEM, and therefore, VIG
is not recommended for treatment of PVE or PVEM.
The incidence of PVE after smallpox vaccination with the NYCBOH strain is
low; therefore, concomitant administration of VIG at time of vaccination has
never been recommended with the NYCBOH strain.
No specific therapy exists for PVE or PVEM; however, supportive care,
anticonvulsants, and intensive care might be required. Because the clinical
symptoms of PVE or PVEM are not believed to be a result of replicating
vaccinia virus, the role of antivirals is unclear.
- Fetal vaccinia, resulting from vaccinial transmission
from mother to fetus, is a rare, but serious, complication of smallpox
vaccination during pregnancy or shortly before conception; <50 cases have
been reported in the literature. Fetal vaccinia is manifested by skin lesions
and organ involvement, and often results in fetal or neonatal death. The skin
lesions in the newborn infant are similar to those of GV or PV and can be
confluent and extensive. The number of affected pregnancies maintained until
term is limited. Affected pregnancies have been reported among women
vaccinated in all three trimesters, among first-time vaccinees as well as in
those being revaccinated, and among nonvaccinated contacts of vaccinees.
Because fetal vaccinia is so rare, the frequency of, and risks for, fetal
vaccinia cannot be reliably determined. Whether virus infects the fetus
through blood or by direct contact with infected amniotic fluid is unknown. No
known reliable intrauterine diagnostic test is available to confirm fetal
infection.
Apart from the characteristic pattern of fetal vaccinia, smallpox vaccination
of pregnant women has not been clearly associated with prematurity, low birth
weight, and fetal loss. In addition, smallpox vaccine has not been demonstrated
to cause congenital malformations.
VIG might be considered for a viable infant born with lesions, although no
data exist for determining the appropriate dosage or estimating efficacy. If a
pregnant woman is inadvertently vaccinated or if she becomes pregnant within 4
weeks after vaccinia vaccination, she should be counseled regarding the basis of
concern for the fetus. However, given the rarity of congenital vaccinia among
live-born infants, vaccination during pregnancy should not ordinarily be a
reason to consider termination of pregnancy. No indication exists for routine,
prophylactic use of VIG for an unintentionally vaccinated pregnant woman;
however, VIG should not be withheld if a pregnant woman experiences a condition
where VIG is needed (e.g., EV).
Other Vaccine-Specific Adverse Events
Less frequently reported adverse events temporally associated with after
smallpox vaccination include myocarditis, pericarditis, precipitation of
erythema nodosum leprosum or neuritis among leprosy patients, and
osteomyelitis (sometimes confirmed by recovery of vaccinia virus). Reported
skin changes at the vaccination scar have included malignant tumors (e.g.,
melanoma, discoid lupus, and localized myxedema as a symptom of Graves
disease). Reported neurologic complications after smallpox vaccination include
transverse myelitis, seizures, paralysis, polyneuritis, and brachial
neuritis.
Whether these conditions are caused by smallpox vaccination or represent
coincidental occurrences after vaccination is unclear. Temporal association
alone does not prove causation.
Revaccination of Persons with History of Adverse Events
Persons with a history of an adverse reaction to smallpox vaccination that
leads to deferral should not knowingly be placed in a situation where they might
be exposed to smallpox. No absolute contraindications exist regarding
vaccination of persons with high-risk exposures to smallpox; persons at greatest
risk for experiencing serious vaccination complications are also at greatest
risk for death from smallpox. In this situation, the benefits of smallpox
vaccination probably outweigh the risks for an adverse reaction from smallpox
vaccine.
Prophylaxis for Persons at High Risk Inadvertently Exposed to
Vaccinia Virus Either Through Vaccination or Contact Transmission
Historically, VIG was administered prophylactically to
persons at increased risk for vaccine-related adverse events
who required vaccination or who were inadvertently vaccinated. However, VIG
administration is not without risk, and the efficacy of VIG as a
prophylactic against vaccinial infection has not been studied in a controlled
setting.
Until VIG is evaluated for such use, it is not recommended for prophylaxis when persons with contraindications to smallpox
vaccination are inadvertently exposed to vaccinia and are otherwise
well. Such persons should have careful clinical follow-up to ensure prompt diagnosis
and treatment of an adverse event, if one occurs. Furthermore, in the
absence of circulating smallpox virus, VIG is not recommended for concomitant use with
smallpox vaccination among persons with contraindications. As recommended by the Advisory
Committee on Immunization Practices (ACIP), careful screening criteria should be
used to exclude persons with contraindications from preoutbreak smallpox
vaccination programs.
Laboratory Diagnostics
Clinical evaluation and a careful patient history of recent smallpox
vaccination or contact with a recent vaccinee are the mainstays of diagnosis of
smallpox vaccine-related adverse events. In situations where clinical diagnosis
is not straightforward, laboratory diagnostics for vaccinia might be helpful and
might prevent inappropriate use of potentially toxic therapies. However,
diagnostics for conditions easily confused with vaccinia infection (i.e.,
varicella, herpes zoster, herpes simplex, and enteroviruses), should be
considered first, in particular for a nonvaccinee or someone believed to be a
noncontact of a vaccinee.
Serologic testing for vaccinia is probably uninformative
because it cannot be used to distinguish vaccinia immunity from vaccinia
infection unless baseline antibody titers are available. Diagnostic tests for
vaccinia are available only for research
purposes, but are undergoing multicenter validation studies that might enable
the Federal Drug Administration (FDA) to approve the test reagents for diagnostic use.
Laboratory Specimen Collection
A suspected case of
an adverse event after smallpox vaccination should
be promptly reported to the appropriate local,
state, or territorial health department. When appropriate,
public health officials might recommend that clinical specimens be
collected for further evaluation of a possible case. Specimen collection
guidelines are available at www.bt.cdc.gov/agent/smallpox/vaccination/vaccinia-specimen-collection.asp.
Treatments
Vaccinia Immune Globulin (VIG)
VIG is a sterile solution of the immunoglobulin fraction
of plasma, containing antibodies to vaccinia virus from persons who were
vaccinated with smallpox vaccine. The available preparation of VIG is a
previously licensed intramuscular (IM) product (VIGIM) (produced by Baxter
Healthcare Corporation in 1994) containing 0.01% thimerosal (a mercury
derivative) as a preservative. Two new intravenous (IV) preparations (VIGIV) are
in production and do not contain thimerosal. All preparations
of VIG will be available as Investigational New Drug (IND) products through CDC
and Department of Defense (DoD).
VIG has demonstrated efficacy in the treatment of smallpox vaccine adverse
reactions that are secondary to continued vaccinia virus replication after
vaccination. Such adverse reactions include EV, PV, or vaccinia necrosum, and
severe cases of GV. VIG has no proven effectiveness for postvaccinia central
nervous system disease.
VIG is recommended for treating EV and PV. Because the majority of cases of
GV are self-limited, VIG is recommended for treating GV only if the patient is
seriously ill or has serious underlying disease that is a risk factor for a
complication of vaccination (e.g., such immunocompromised conditions as
HIV/AIDS). VIG can also be useful in treating ocular vaccinia that results from
inadvertent implantation. When ocular vaccinia with keratitis is present,
consideration of VIG should include the possible increased risk for corneal
scarring.
VIG Side Effects
- VIG administration has been associated with mild, moderate,
and severe adverse reactions. Mild adverse reactions include local pain
and tenderness, swelling, and erythema at the injection site after intramuscular (IM)
administration of immunoglobulins and can persist from hours to 1–2 days after
administration.
- Moderate adverse reactions include joint pain,
diarrhea, dizziness, hyperkinesis, drowsiness, pruritis, rash, perspiration,
and vasodilation. Back and abdominal pain, nausea, and vomiting can occur
within the first 10 minutes of injection. Chills, fever, headache, myalgia,
and fatigue can begin at the end of infusion and continue for hours. More
severe reactions of this type might require pretreatment with corticosteroids
or acetaminophen, if another dose of VIG is required.
- Serious adverse events associated with administration of
intravenous (IV) VIG are expected to be similar to those observed with other intravenous
immune globulin (IVIG) products, and can include hypotension, anaphylaxis and
anaphylactoid systemic reactions, renal dysfunction, and aseptic meningitis
syndrome (AMS). When AMS occurs, it usually begins from within hours to 2 days
after treatment and can occur more frequently in association with high dosage
(2 g/kg body weight) therapy. It is characterized by severe headache, nuchal
rigidity, drowsiness, fever, photophobia, painful eye movements, nausea, and
vomiting. Discontinuation of IVIG treatment has resulted in remission of AMS
within days without sequelae.
- Anaphylaxis and anaphylactoid systemic reactions have
been reported after IM or IV injection of human immunoglobulin preparations.
The symptoms of classic anaphylactic reactions include flushing, facial
swelling, dyspnea, cyanosis, anxiety, nausea, vomiting, malaise, hypotension,
loss of consciousness, and in certain cases, death. Symptoms appear from
within seconds to hours after infusion. The treatment of such reactions is
immediate discontinuation of immune globulin and administration of
epinephrine, oxygen, antihistamines, IV steroids, and cardiorespiratory
support.
- When proteins prepared from human blood or plasma are administered, the
potential for transmission of infectious agents cannot be totally excluded.
This also applies to infectious agents that might not have been discovered or
characterized when the current preparations of VIG were formulated. To reduce
the risk of transmitting infectious agents, stringent controls are applied in
the selection of blood and plasma donors, and prescribed standards are used at
plasma-collection centers, testing laboratories, and fractionation facilities.
VIG Risks and Contraindications
- Contraindications to VIG administration include an
acute allergic reaction to thimerosal (for VIGIM) or a history of a severe
reaction after administration of human immunoglobulin preparations. Persons
with selective immunoglobulin A (IgA) deficiency might have antibodies to IgA
and could have anaphylactic reactions to subsequent administration of blood
products that contain IgA.
- Whether VIG can cause fetal harm when administered to
a pregnant woman or if it affects reproductive capacity is unknown. Although
clinical experience with other preparations containing immunoglobulins
indicates that no fetal adverse events result from immunoglobulins, no studies
have evaluated the adverse effects of VIG on the fetus. VIG should be
administered to a pregnant woman only if clearly needed. Similarly, whether
VIG is excreted in breast milk is unknown; therefore, caution should be
exercised when VIG is administered to a nursing woman.
- VIG is made from human plasma; therefore, a possible risk of transmission
of viruses and a theoretical risk of transmission-adventitious agents that can
cause Creutzfeldt-Jacob disease exist. The risk that these products contain
infectious agents has been reduced by questioning plasma donors about risk
factors for infection and by testing for the presence of certain viruses in
the plasma. Furthermore, manufacturing processes have been validated for their
ability to inactivate and remove viruses.
VIG Administration
Detailed instructions regarding the administration of IM
and IV VIG are included in the Investigator’s Brochure portion of the investigational new drug (IND)
materials that accompany the products. Refer to the original guideline document
for further details.
Cidofovir
Cidofovir, a nucleotide analogue of cytosine, has demonstrated
antiviral activity against certain orthopoxviruses in cell-based in vitro and
animal model studies. Its effectiveness in the treatment of vaccinia-related
complications among humans is unknown. Cidofovir has been demonstrated to be
nephrotoxic among humans and carcinogenic among animals, even at low doses. It
is administered with probenecid and hydration.
Cidofovir is approved by the United States Food and Drug Administration (FDA) for treating cytomegalovirus (CMV) retinitis among patients with acquired immune deficiency syndrome (AIDS). Its use for treating smallpox vaccination complications is recommended only under IND protocol sponsored by CDC. (Refer to the original guideline document for more information on the IND protocol.)
Cidofovir will be released for civilian use by CDC and
for military use by DoD, if 1) a patient fails to respond to VIG treatment; 2) a patient is near death; or 3) all inventories of VIG have been exhausted. This proposed use of cidofovir is investigational and has not been studied among humans; therefore, the benefit of cidofovir therapy for vaccinia-related complications is uncertain. Insufficient information exists to determine the
appropriate dosing and accompanying hydration and dosing of probenecid if
antiviral therapy is needed to treat smallpox vaccine-related adverse events
among the pediatric age group. Dosages for these patients should be determined
in consultation with specialists at CDC and the Department of Defense (DoD).
Additional information regarding dosing and administration of cidofovir is
included in the Investigator’s Brochure that accompanies the release of this
product to the clinician when cidofovir is used under the IND protocol.
Cidofovir Side Effects
- The major complication of cidofovir therapy is renal
toxicity, which is sometimes irreversible, results in renal failure, and
requires dialysis to prevent death. To reduce the renal toxicity of cidofovir,
it must be administered with careful IV hydration and with probenecid, a renal
tubular blocking agent. Cidofovir has also been associated with neutropenia,
proteinuria, decreased intraocular pressure/ocular hypotony, anterior
uveitis/iritis, and metabolic acidosis. Cidofovir-related carcinogenicity,
teratogenicity, and hypospermia have been reported in animal studies.
- Probenecid has been associated with headache, anorexia, nausea, vomiting,
urinary frequency, hypersensitivity reactions, anemia, hemolytic anemia,
nephritic syndrome, hepatic necrosis, gout, uric acid stones, and renal colic.
Probenecid should be used with caution among children, pregnant women and
persons with sulfa drug allergy (see manufacturer’s package insert).
Cidofovir Administration
Details for administration of cidofovir are included with
the medication
and IND materials that are shipped by CDC. Refer to the
original guideline document for further details.
Requests for Clinical Consultation and IND Therapies and for
Registries Enrollment
In October 2002, ACIP recommended that enhanced terrorism preparedness should
include vaccination of smallpox public health response and health-care teams.
Implementation of this vaccination program was determined to be the
responsibility of the states and territories in conjunction with local
predesignated hospitals. Before participation in the vaccination program, states
and territories should establish a comprehensive program to manage vaccinees and
their contacts who experience an adverse event after smallpox vaccination.
Hospitals that participate should assign physicians with expertise in infectious
diseases, neurology, dermatology, allergy/immunology, and ophthalmology to
assess and manage adverse events among vaccinees and their contacts. Vaccinees
and their affected contacts should have access to evaluation and medical care
for a suspected adverse event 24 hours/day and 7 days/week. CDC will provide
consultation to state and territorial public health officials, their surrogate
providers, and other requesting physicians regarding recognition, evaluation,
diagnosis, and treatment of adverse events after smallpox vaccination through an
information line for clinicians that will be staffed 24 hours/day, 7 days/week.
In addition, CDC will provide consultation for evaluation and care of persons
with contraindications to smallpox vaccination that have an inadvertent exposure
to vaccinia virus (e.g., vaccination of a pregnant woman or a person with atopic
dermatitis). These persons also will be enrolled in a vaccination registry for
prospective follow-up.
Referring providers should complete a thorough
vaccination history and physical examination on all patients with
a suspected adverse event before accessing CDC’s Clinician Information Line. In
addition, high-resolution digital photographs of dermatological manifestations of adverse
events can aid in the recognition of specific dermatological manifestations of
adverse events and should be obtained with the patient’s
permission and forwarded whenever possible. Providers seeking assistance should first
contact their state health department before accessing the CDC consultation
service or requesting VIG or cidofovir (Refer to Box 3 in the
original guideline document).
To aid providers in discerning the presence or severity
of vaccine-related complications, CDC has developed draft clinical evaluation
tools to assist with expected adverse events (refer to the original guideline
document).
Smallpox Vaccine Adverse Event Reporting
Providers are strongly encouraged to report serious adverse events to Vaccine Adverse Event Reporting System (VAERS) after the administration of
the smallpox vaccine (Refer to Box 4 in original guideline document). VAERS is
a passive reporting system for safety monitoring of all vaccines licensed in
the United States, and is jointly managed by CDC and FDA. CDC and FDA will
monitor smallpox vaccine-related adverse event reports daily, and will
provide enhanced surveillance of adverse events after administration of the
smallpox vaccine. However, adverse events that are judged to be serious or unexpected
and which require CDC consultation or IND therapies (VIG or cidofovir) should
not be solely reported to VAERS. These cases should instead be immediately
reported by phone to the appropriate state health department officials and CDC,
who will assist the reporting provider with completion of a VAERS form.
All other smallpox vaccine adverse events that are serious, but do not
require CDC consultation or administration of IND therapies, should be reported
directly to VAERS within 48 hours of recognition. All other adverse events
should be directly reported to VAERS within 1 week.
Additional Information
CDC, in collaboration with the U.S. Department of Health and Human Services,
has developed a website, which is available at
www.bt.cdc.gov/training/smallpoxvaccine/reactions. Information and
photographs related to smallpox vaccination, normal vaccination reactions,
adverse events after vaccination, and treatments for adverse reactions can be
located at this website.
