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## Complete Summary

#### GUIDELINE TITLE

Surveillance guidelines for smallpox vaccine (vaccinia) adverse
reactions.

#### BIBLIOGRAPHIC SOURCE(S)

Casey C, Vellozzi C, Mootrey GT, Chapman LE, McCauley M, Roper MH, Damon
I, Swerdlow DL. Surveillance guidelines for smallpox vaccine (vaccinia)
adverse reactions. MMWR Recomm Rep 2006 Feb 3;55(RR-1):1-16. \[43
references\]
[PubMed](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16456528)

#### GUIDELINE STATUS

This is the current release of the guideline.

### \*\* REGULATORY ALERT \*\*

#### FDA WARNING/REGULATORY ALERT

**Note from the National Guideline Clearinghouse**: This guideline
references a drug(s)/intervention(s) for which important revised
regulatory and/or warning information has been released.

-   [June 8, 2007, Troponin-I
    Immunoassay](http://www.fda.gov/medwatch/safety/2007/safety07.htm#Architect):
    Class I Recall of all lots of the Architect Stat Troponin-I
    Immunoassay. The assay may report falsely elevated or falsely
    decreased results at and near a low level, which may impact patient
    treatment.

-   [May 23, 2007, Gadolinium-based Contrast
    Agents](http://www.fda.gov/medwatch/safety/2007/safety07.htm#Gadolinium):
    The addition of a boxed warning and new warnings about the risk of
    nephrogenic systemic fibrosis (NSF) to the full prescribing
    information for all gadolinium-based contrast agents (GBCAs).

### COMPLETE SUMMARY CONTENT

 \*\* REGULATORY ALERT \*\*\
 SCOPE\
 METHODOLOGY - including Rating Scheme and Cost Analysis\
 RECOMMENDATIONS\
 EVIDENCE SUPPORTING THE RECOMMENDATIONS\
 BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS\
 QUALIFYING STATEMENTS\
 IMPLEMENTATION OF THE GUIDELINE\
 INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT
CATEGORIES\
 IDENTIFYING INFORMATION AND AVAILABILITY\
 DISCLAIMER

### SCOPE

#### DISEASE/CONDITION(S)

Adverse events after smallpox vaccination, including

-   Superinfection of the vaccination site or regional lymph nodes

-   Inadvertent autoinoculation (nonocular)

-   Contact transmission (nonocular)

-   Ocular vaccinia

-   Eczema vaccinatum

-   Progressive vaccinia

-   Erythema multiforme major or Stevens-Johnson Syndrome

-   Fetal vaccinia

-   Postvaccinial central nervous system disease

-   Myo/pericarditis

-   Dilated cardiomyopathy

#### GUIDELINE CATEGORY

Diagnosis\
Evaluation\
Management

#### CLINICAL SPECIALTY

Allergy and Immunology\
Dermatology\
Family Practice\
Infectious Diseases\
Internal Medicine\
Obstetrics and Gynecology\
Ophthalmology\
Pathology\
Pediatrics\
Pharmacology\
Preventive Medicine

#### INTENDED USERS

Advanced Practice Nurses\
Health Care Providers\
Nurses\
Patients\
Physician Assistants\
Physicians\
Public Health Departments

#### GUIDELINE OBJECTIVE(S)

To provide uniform criteria used for the surveillance case definition
and classification for adverse events and reactions associated with
smallpox vaccination

#### TARGET POPULATION

Persons presenting with adverse reactions or adverse events after
smallpox vaccination

#### INTERVENTIONS AND PRACTICES CONSIDERED

1.  Use of surveillance case definitions and classification system
    utilizing, as appropriate

    -   History and physical examination

    -   Laboratory results

    -   Radiographic findings

2.  Reporting of adverse events associated with smallpox vaccination to
    the Vaccine Adverse Events Reporting System (VAERS)

#### MAJOR OUTCOMES CONSIDERED

Not stated

### METHODOLOGY

#### METHODS USED TO COLLECT/SELECT EVIDENCE

Searches of Electronic Databases\
Searches of Unpublished Data

#### DESCRIPTION OF METHODS USED TO COLLECT/SELECT THE EVIDENCE

Not stated

#### NUMBER OF SOURCE DOCUMENTS

Not stated

#### METHODS USED TO ASSESS THE QUALITY AND STRENGTH OF THE EVIDENCE

Not stated

#### RATING SCHEME FOR THE STRENGTH OF THE EVIDENCE

Not applicable

#### METHODS USED TO ANALYZE THE EVIDENCE

Review

#### DESCRIPTION OF THE METHODS USED TO ANALYZE THE EVIDENCE

Not stated

#### METHODS USED TO FORMULATE THE RECOMMENDATIONS

Expert Consensus

#### DESCRIPTION OF METHODS USED TO FORMULATE THE RECOMMENDATIONS

The joint Advisory Committee on Immunization Practices (ACIP)-Armed
Forces Epidemiological Board (AFEB) Smallpox Vaccine Safety Working
Group (SVS WG) was responsible for safety oversight of the Department of
Health and Human Services (DHHS) and Department of Defense (DoD)
smallpox preparedness programs. The majority of the case definitions for
vaccinia adverse reactions were drafted by the Vaccinia Case Definition
Development working group in collaboration with ACIP-AFEB SVS WG. The
Vaccinia Case Definition Development working group membership included
Centers for Disease Control and Prevention (CDC) and DoD medical
epidemiologists, smallpox eradication experts, ophthalmologists,
dermatologists, cardiologists, and infectious-disease specialists. These
work groups contributed to the development of case definitions by
completing literature searches, translating publications, coordinating
or participating in meetings, collecting or analyzing data,
investigating cases, providing subject-matter expertise, and drafting
and revising case definitions. The case definition for fetal vaccinia
was developed by CDC and DoD for use in the development of the National
Smallpox Vaccine in Pregnancy Registry.

#### RATING SCHEME FOR THE STRENGTH OF THE RECOMMENDATIONS

Not applicable

#### COST ANALYSIS

A formal cost analysis was not performed and published cost analyses
were not reviewed.

#### METHOD OF GUIDELINE VALIDATION

Not stated

#### DESCRIPTION OF METHOD OF GUIDELINE VALIDATION

Not applicable

### RECOMMENDATIONS

#### MAJOR RECOMMENDATIONS

**[Introduction]{.underline}**

Surveillance guidelines that include standardized case definitions for
reporting of notifiable infectious diseases are important public health
tools that contribute to the assessment of disease trends, measurement
of intervention effectiveness, and detection of disease outbreaks.
Comparable surveillance guidelines for the classification and reporting
of adverse reactions after vaccination are nominal and have not commonly
included standardized case definitions. The term vaccine-related
\"complication\" is often used interchangeably with the terms \"side
effects\" or \"adverse reaction\" and should be distinguished from the
term \"adverse event.\" An adverse reaction is an untoward effect that
occurs after a vaccination and is extraneous to the vaccine\'s primary
purpose of producing immunity (e.g., eczema vaccinatum). Adverse
reactions have been demonstrated to be caused by the vaccination. In
contrast, adverse events are untoward effects observed or reported after
vaccinations, but a causal relation between the two have yet to be
established. This report focuses on adverse reactions known to be caused
by smallpox vaccine (with the exception of dilated cardiomyopathy that
has not been shown to have a causal relation) on the basis of scientific
evidence. Uniform criteria for classification of adverse reaction
reports after smallpox (vaccinia) vaccination have been established.
Criteria for dilated cardiomyopathy, an adverse event (not shown to have
a causal relation with smallpox vaccination), also have been
established. These case definitions and reporting guidelines were used
by the Centers for Disease Control and Prevention (CDC) and the Office
of the Assistant Secretary of Defense for Health Affairs during the
mandatory Department of Defense (DoD) and voluntary U.S. Department of
Health and Human Services (DHHS) smallpox vaccination programs that were
designed to increase national preparedness in the event of a biologic
terrorism attack.

This report describes the case definitions used to classify reported
adverse events during the DHHS smallpox vaccination program. The overall
safety surveillance system and related findings are reported elsewhere.

**[Reporting Guidelines]{.underline}**

The following surveillance case definitions establish reporting criteria
for prospective or retrospective classification of cases. Clinical,
laboratory, and epidemiologic information are necessary for accurate
case classification, which could not be obtained without cooperation and
information exchange between treating health-care providers, state
health officials, laboratorians, and the CDC. Any adverse event after
smallpox vaccination should be reported to state health departments and
the Vaccine Adverse Events Reporting System (VAERS), particularly those
events known to be adverse reactions (see Table below). Any adverse
reaction that requires treatment with vaccine immune globulin (VIG) or
cidofovir should be reported immediately, and adverse events that meet
the regulatory criteria for \"serious\" (i.e., those resulting in
hospitalization, permanent disability, life-threatening illness, or
death) should be reported within 48 hours; all other events should be
reported within 1 week. Reports can be submitted to VAERS at
[http://www.vaers.hhs.gov](http://www.vaers.hhs.gov/), 877-721-0366, or
P.O. Box 1100, Rockville, MD 20849-1100. Report forms and assistance
with reporting are available from VAERS (800-822-7967).

**Table. Adverse Events After Smallpox Vaccination That Are Recommended
to be Reported to the Vaccine Adverse Event Reporting System and to
State Health Departments^1^**

+-----------------------------------------------------------------------+
| -   Superinfection of the vaccination site or regional lymph nodes^2^ |
|                                                                       |
| -   Inadvertent autoinoculation (nonocular)                           |
|                                                                       |
| -   Contact transmission (nonocular)                                  |
|                                                                       |
| -   Ocular vaccinia                                                   |
|                                                                       |
| -   Generalized vaccinia                                              |
|                                                                       |
| -   Eczema vaccinatum                                                 |
|                                                                       |
| -   Progressive vaccinia                                              |
|                                                                       |
| -   Erythema multiforme major or Stevens-Johnson Syndrome^3^          |
|                                                                       |
| -   Fetal vaccinia                                                    |
|                                                                       |
| -   Postvaccinial central nervous system disease                      |
|                                                                       |
| -   Myo/pericarditis                                                  |
|                                                                       |
| -   Dilated cardiomyopathy^4^                                         |
+-----------------------------------------------------------------------+

^1^ Any adverse event that is of concern to the clinician or patient
should be reported.\
^2^ Previously referred to as pyogenic infection of vaccination site\
^3^ Clinically defined\
^4^ Causal association with smallpox vaccination has not been shown.

**[Case Definition and Classification]{.underline}**

For all cases, exposure to vaccinia is required; vaccination, close
contact with a recent vaccinee, or intrauterine exposure can fulfill
this criterion. Vaccinia virus can be transmitted from the vaccination
site to close contacts of persons who received smallpox vaccine, and
these contacts can experience the same adverse reactions as vaccinees.

Smallpox vaccine adverse events can be divided into several categories.
Localized reactions include a superinfection of the vaccination site or
regional lymph nodes and robust take (RT). Unintentional transfer of
vaccinia virus includes transfer from the vaccination site to elsewhere
on the vaccinee\'s body and is called inadvertent autoinoculation. When
the virus is transferred from the vaccinee to a close contact, it is
called contact transmission. In either case, if the virus is transferred
to the eye and surrounding orbit, it is referred to as ocular vaccinia.
Diffuse dermatologic complications include two groups. The first group
(hypersensitivity rashes) includes nonspecific, postvaccination rash,
erythema multiforme minor, and Stevens-Johnson syndrome. These lesions
are not thought to contain vaccinia virus, and because these terms are
defined elsewhere in the dermatologic literature, they are not included
in this report. The second group of diffuse dermatologic complications
is thought to be caused by replicating vaccinia virus that can be
recovered from the rash of generalized vaccinia (GV) (usually a benign,
self-limiting condition), eczema vaccinatum (EV) (often associated with
substantial morbidity), and progressive vaccinia (PV) (which is
generally fatal). Rare adverse reactions include fetal vaccinia and
postvaccinial central nervous system diseases such as post-vaccinial
encephalitis or encephalomyelitis. Other reactions previously reported
but not well described include the newly characterized cardiac adverse
reaction, myo/pericarditis (M/P) or the newly described cardiac adverse
event dilated cardiomyopathy (DCM), which has not been yet been
demonstrated to be etiologically linked.

**Localized Reactions**

[Superinfection of the Vaccination Site or Regional Lymph
Nodes]{.underline}

Surveillance Case Definition for Superinfection of the Vaccination Site
or Regional Lymph Nodes After Smallpox Vaccination for Use in Smallpox
Vaccine Adverse Event Monitoring And Response

+-----------------------------------------------------------------------+
| Superinfection of the vaccination site or regional lymph nodes is     |
| defined as a nonvaccinial superinfection (e.g., superinfection caused |
| by bacterial, fungal, atypical, or viral organisms) that produces a   |
| local inflammatory response at the site of vaccination and can        |
| present with the same signs and symptoms as vaccinia virus            |
| replication at the vaccination site.\                                 |
| \                                                                     |
| **Case definition for superinfection of the vaccination site or       |
| regional lymph nodes**\                                               |
| \                                                                     |
| A **suspected case** of superinfection of the vaccination site or     |
| regional lymph nodes is defined by the following criteria:            |
|                                                                       |
| -   Vaccination site or regional lymph nodes with three or more of    |
|     the following findings:                                           |
|                                                                       |
|     -   Dolor (pain and/or tenderness)                                |
|                                                                       |
|     -   Calor (warmth)                                                |
|                                                                       |
|     -   Rubor (redness)                                               |
|                                                                       |
|     -   Other (regional lymphadenopathy; lymphangitic streaking;      |
|         edema, induration, and/or swelling; fluctuance; and blister   |
|         with pus or honey-crusted plaque)                             |
|                                                                       |
| > and                                                                 |
|                                                                       |
| -   Temporal criterion:                                               |
|                                                                       |
|     -   Onset or peak symptoms occur from day of vaccination to day 5 |
|         after vaccination and/or day 13-60 after vaccination          |
|         (excludes days 6-12 after vaccination)                        |
|                                                                       |
| > and                                                                 |
|                                                                       |
| -   Clinical course:                                                  |
|                                                                       |
|     -   Clinical criteria persist or worsen for hours to days after   |
|         vaccination; patient report is adequate.                      |
|                                                                       |
| A **confirmed case** of superinfection of the vaccination site or     |
| regional lymph nodes is defined by the following criteria:            |
|                                                                       |
| -   Vaccination site or regional lymph nodes with three or more of    |
|     the following findings:                                           |
|                                                                       |
|     -   Dolor (pain and/or tenderness)                                |
|                                                                       |
|     -   Calor (warmth)                                                |
|                                                                       |
|     -   Rubor (redness)                                               |
|                                                                       |
|     -   Other (regional lymphadenopathy; lymphangitic streaking;      |
|         edema, induration, and/or swelling; fluctuance; and blister   |
|         with pus or honey-crusted plaque)                             |
|                                                                       |
| > and                                                                 |
|                                                                       |
| -   Temporal criterion:                                               |
|                                                                       |
|     -   Symptoms occur from day of vaccination to 60 days after       |
|         vaccination (inclusive)                                       |
|                                                                       |
| > and                                                                 |
|                                                                       |
| -   Laboratory criteria having one or more of the following findings: |
|                                                                       |
|     -   Positive results of pathogenic culture (e.g., bacterial,      |
|         fungal, atypical, or nonvaccinial viral culture)              |
|                                                                       |
|     -   Positive microscopy results (e.g., Gram stain, silver stain,  |
|         acid-fast bacillus stain, or darkfield)                       |
|                                                                       |
|     -   Positive result of bioburden testing^1^ of the vaccinia       |
|         vaccine vial                                                  |
|                                                                       |
| > or                                                                  |
|                                                                       |
| -   Radiographic findings:                                            |
|                                                                       |
|     -   Findings consistent with superinfection (e.g.,                |
|         lymphadenopathy or abscess) by magnetic resonance imaging,    |
|         computed tomography scan, or ultrasound.                      |
+-----------------------------------------------------------------------+

^1^ Bioburden is referred to as the number of microorganisms on a
contaminated object; it is also called bioload. For testing of vaccinia
vaccine vial, a positive bioburden test indicates that the accepted
limits of bioload have been exceeded and the vaccine is not suitable for
use.

**Unintentional Transfer of Vaccinia Virus**

[Inadvertent Autoinoculation]{.underline}

Surveillance Case Definition for Inadvertent Autoinoculation (Nonocular)
for Use in Smallpox Vaccine Adverse Event Monitoring and Response

+-----------------------------------------------------------------------+
| Inadvertent autoinoculation occurs when a person who has received     |
| smallpox vaccine or experienced inoculation from contact might        |
| physically transfer vaccinia virus from vaccination or contact site   |
| to another part of the body through scratching or through inanimate   |
| objects such as clothing, dressings, or bedding. The most common      |
| sites of inadvertent autoinoculation, nonocular are the face, nose,   |
| mouth, lips, genitalia, and anus. Lesions at autoinoculation sites    |
| progress through the same papular, vesicular, and pustular stages as  |
| the vaccination site. When autoinoculation occurs more than 5 days    |
| postvaccination, the developing immune response might attenuate the   |
| lesions and their progression. Persons at highest risk for            |
| inadvertent autoinoculation are children aged 1-4 years and those     |
| with disruption of the epidermis, including, but not limited to,      |
| abrasions or burns.\                                                  |
| \                                                                     |
| **Case definition for inadvertent autoinoculation (nonocular)**\      |
| \                                                                     |
| A **suspected case** of inadvertent autoinoculation is defined by the |
| following criteria:                                                   |
|                                                                       |
| -   Affected person has been recently vaccinated and had one or more  |
|     lesions at one or more sites beyond the boundaries of the         |
|     dressing that was used. Lesions progress morphologically through  |
|     papule, vesicle, pustule, and scab,\* and                         |
|                                                                       |
| -   Lesions appear up to 10 days after the period beginning with      |
|     initial vaccination or contact through final resolution and       |
|     scarring of lesions at vaccination or contact inoculation site.   |
|                                                                       |
| A **probable case** of inadvertent autoinoculation meets the criteria |
| for a suspected case and                                              |
|                                                                       |
| -   Does not meet the case definition for generalized vaccinia\*,     |
|     eczema vaccinatum, or progressive vaccinia, and                   |
|                                                                       |
| -   Other likely etiologies (e.g., bacterial or viral infection) have |
|     been excluded.                                                    |
|                                                                       |
| A **confirmed case** of inadvertent autoinoculation meets the         |
| criteria for a suspected or probable case of inadvertent              |
| autoinoculation and has the following laboratory evidence of vaccinia |
| infection (on the basis of testing skin lesions distant from the      |
| vaccination site in a vaccinee):                                      |
|                                                                       |
| -   Positive test results for vaccinia polymerase chain reaction      |
|     (PCR) assay or antigen detection techniques (e.g., direct         |
|     fluorescent assay or direct fluorescent antibody)                 |
|                                                                       |
| > or                                                                  |
|                                                                       |
| -   Demonstration of vaccinia virus by culture                        |
|                                                                       |
| **Note:** Histopathologic examination showing typical orthopox        |
| cytopathic changes or electron microscopy of biopsy specimens         |
| revealing orthopox virus are strongly suggestive of infection with    |
| vaccinia and should be confirmed by subsequent PCR or culture.        |
+-----------------------------------------------------------------------+

\*Generalized vaccinia should be considered if [\>]{.underline}20
lesions are present.

[Contact Transmission]{.underline}

Surveillance Case Definition for Contact Transmission (Nonocular) for
Use in Smallpox Vaccine Adverse Event Monitoring and Response

+-----------------------------------------------------------------------+
| Contact transmission of vaccinia virus occurs when virus shed from    |
| smallpox vaccination sites or from distant lesions in persons with    |
| inadvertent autoinoculation, generalized vaccinia (GV), eczema        |
| vaccinatum (EV), or progressive vaccinia (PV) is transferred to       |
| another person. Virus might be shed until the scab heals. The virus   |
| can survive for several days on clothing, bedding, or other inanimate |
| surfaces. An unvaccinated or nonrecently vaccinated person in close   |
| contact (i.e., touching a person\'s lesions or vaccination site,      |
| clothing, bedding, or bandages) with a vaccinee or their inanimate    |
| objects might acquire vaccinia infection. Infection acquired through  |
| contact transmission can result in inadvertent autoinoculation from   |
| the exposure site to additional sites (including ocular vaccinia) or  |
| can result in other adverse reactions.\                               |
| \                                                                     |
| **Case definition for contact transmission (nonocular)**\             |
| \                                                                     |
| A **suspected case** of contract transmission is defined as           |
|                                                                       |
| -   The development of one or more lesions that progress through      |
|     papule, vesicle, or pustule stages                                |
|                                                                       |
| -   History of close contact with                                     |
|                                                                       |
|     -   Someone who has received the vaccine \<3 weeks before the     |
|         exposure, or                                                  |
|                                                                       |
|     -   Someone who has had autoinoculation GV, EV, and PV diagnosed; |
|         and                                                           |
|                                                                       |
|     -   Lesions appear 3-9 days after vaccinia exposure.              |
|                                                                       |
| A **probable case** of contact transmission meets the case definition |
| for suspected case, and other likely etiologies (e.g., bacterial or   |
| viral infection) have been excluded.\                                 |
| \                                                                     |
| For a **confirmed case** of contact transmission, laboratory evidence |
| of vaccinia infection exists on the basis of testing skin lesions in  |
| a close contact of a known vaccinee. Laboratory evidence of vaccinia  |
| infection includes                                                    |
|                                                                       |
| -   Positive test results for vaccinia polymerase chain reaction      |
|     (PCR) assay or antigen detection techniques (e.g., direct         |
|     fluorescent antibody)                                             |
|                                                                       |
| > or                                                                  |
|                                                                       |
| -   Demonstration of vaccinia virus by culture                        |
|                                                                       |
| **Note**: Histopathologic examination showing typical orthopox        |
| cytopathic changes or electron microscopy of biopsy specimens         |
| revealing orthopox virus is strongly suggestive of infection with     |
| vaccinia and should be confirmed by subsequent PCR or culture.        |
+-----------------------------------------------------------------------+

[Ocular Vaccinia]{.underline}

Surveillance Case Definition for Ocular Vaccinia for Use in Smallpox
Vaccine Adverse Event Monitoring and Response

+-----------------------------------------------------------------------+
| Ocular vaccinia is the appearance of lesions suspicious for vaccinia  |
| in or near the eye in a vaccinee (or close contact of a vaccinee) up  |
| to 10 days after the period beginning with initial vaccinia exposure  |
| through final resolution and scarring of lesions at vaccination site  |
| or exposure site, to include periocular^1^ involvement, lid           |
| involvement (blepharitis^2^), conjunctival involvement                |
| (conjunctivitis^3^), and/or corneal involvement (keratitis^4^).\      |
| \                                                                     |
| **Case definition for ocular vaccinia**\                              |
| \                                                                     |
| A **suspected case** of ocular vaccinia is defined as the new onset   |
| of erythema or edema of the conjunctiva (conjunctivitis), eyelid      |
| (blepharitis), or periocular area or inflammation of the cornea       |
| (keratitis) in a recent vaccinee (or close contact of vaccinee) that  |
| cannot be ascribed to another ocular diagnosis\                       |
| \                                                                     |
| and                                                                   |
|                                                                       |
| -   Temporal criteria of                                              |
|                                                                       |
|     -   Onset after vaccinia exposure but not more than 10 days after |
|         the period beginning with initial vaccinia exposure through   |
|         final resolution and scarring of lesions at vaccination site  |
|         or exposure site                                              |
|                                                                       |
| > or                                                                  |
|                                                                       |
| -   Onset during the presence of visible vaccinia lesions before scab |
|     separation                                                        |
|                                                                       |
| A **probable case** of ocular vaccinia is the presentation in or near |
| the eye of lesions consistent with vaccinia infection to include      |
| formation of vesicles that progress to pustules that umbilicate and   |
| indurate in a manner similar to a normal vaccinia reaction (**Note:** |
| see exceptions/differences to conjunctival and cornea clinical        |
| presentation footnotes 3 and 4)\                                      |
| \                                                                     |
| and                                                                   |
|                                                                       |
| -   Temporal criteria of                                              |
|                                                                       |
|     -   Onset after vaccinia exposure but not more than 10 days after |
|         the period beginning with initial vaccinia exposure through   |
|         final resolution and scarring of lesions at vaccination site  |
|         or exposure site                                              |
|                                                                       |
| > or                                                                  |
|                                                                       |
| -   Onset during the presence of visible vaccinia lesions before scab |
|     separation                                                        |
|                                                                       |
| A **confirmed case** of ocular vaccinia meets the criteria as a       |
| probable or suspected case of ocular vaccinia with laboratory         |
| evidence of vaccinia infection (testing lesions on or near the eye).  |
| Laboratory evidence includes                                          |
|                                                                       |
| -   Positive test results for vaccinia polymerase chain reaction      |
|     assay or antigen detection techniques (e.g., direct fluorescent   |
|     antibody)                                                         |
|                                                                       |
| > or                                                                  |
|                                                                       |
| -   Demonstration of vaccinia virus by culture                        |
+-----------------------------------------------------------------------+

^1^ Periocular involvement (generally above the brow or below the
inferior orbital rim) Papules, vesicles, or pustules not involving the
ocular adnexa, lids, lid margins, or canthi.\
^2^ Blepharitis: (lid involvement): Mild\--few pustules, mild edema, and
no fever; Severe\--pustules, edema, hyperemia, lymphadenopathy
(preauricular or submandibular), cellulitis, and fever.\
^3^ Conjunctivitis (involvement of membrane that lines inner surface of
the eyelid and exposed surface of the eyeball, excluding the cornea):
Conjunctiva might be inflamed (red) with serous or mucopurulent
discharge if lesions involve the conjunctiva or cornea. Symptoms of
ocular irritation (foreign body sensation) might be present with onset
of erythema. Conjunctival lesions typically form vesicles that rapidly
ulcerate and form raised \"moist appearing\" white lesions (rather than
pustules that scab) before final resolution: Mild\--mild hyperemia or
edema, no membranes or focal lesions; Severe\--marked hyperemia, edema,
membranes, focal lesions, lymphadenopathy (preauricular and/or
submandibular), and fever.\
^4^ Keratitis (corneal involvement): Corneal lesions might present as a
grey-appearing superficial punctuate keratitis that might later coalesce
to form a geographic epithelial defect resembling herpes simplex
keratitis. Stromal corneal lesions might present as small subepithelial
opacities resembling those observed in epidemic keratoconjunctivitis,
might be associated with epithelial defect, and might progress to
corneal haze/clouding: Mild\--grey epitheliitis, no epithelial defect,
and no stromal haze or infiltrate (cloudy cornea); Moderate\--epithelial
defect; Severe\--ulcer, stromal haze, or infiltrate.

[Generalized Vaccinia]{.underline}

Surveillance Case Definition for Generalized Vaccinia After Smallpox
Vaccination for Use in Smallpox Vaccine Adverse Event Monitoring and
Response

+-----------------------------------------------------------------------+
| Generalized vaccinia (GV) is a disseminated vesicular or pustular     |
| rash appearing anywhere on the body [\>]{.underline}4 days after      |
| smallpox vaccination and might be accompanied by fever. GV also can   |
| appear as a regional form that is characterized by extensive          |
| vesiculation around the vaccination site or as an eruption localized  |
| to a single body region. The skin lesions of GV are thought to        |
| contain virus spread by the hematogenous route. Primary vaccinees are |
| at higher risk for GV than revaccinees. GV is usually self-limited    |
| among immunocompetent hosts. Vaccinia immune globulin (VIG) might be  |
| beneficial in the rare case where an immunocompetent person appears   |
| systemically ill. GV is often more severe among persons with          |
| underlying immunodeficiency, and these patients might benefit from    |
| early intervention with VIG.\                                         |
| \                                                                     |
| **Notes:**                                                            |
|                                                                       |
| 1.  Systemic symptoms might be present.                               |
|                                                                       |
| 2.  At early onset of some cases, skin lesions might be macules or    |
|     slightly elevated papules; in late cases, lesions might have      |
|     developed scabs.                                                  |
|                                                                       |
| 3.  History or clinical signs of eczema/atopic dermatitis or          |
|     Darier\'s disease or severe illness should prompt evaluation for  |
|     eczema vaccinatum.                                                |
|                                                                       |
| 4.  Presence of acute or chronic exfoliative, erosive, or blistering  |
|     skin disease (e.g., acute burn and epidermolytic hyperkeratosis)  |
|     should prompt consideration of multiple inadvertent inoculations. |
|                                                                       |
| 5.  A vaccinial skin eruption characterized by grouped vesicles or    |
|     pustules close to or surrounding the vaccination site but do not  |
|     appear to be satellite lesions (e.g., on the basis of the         |
|     presence of a large number of lesions and evidence that the       |
|     lesions are caused by hematogenous spread of vaccinia) might      |
|     constitute a regional form of generalized vaccinia.               |
|                                                                       |
| **Case definition for generalized vaccinia**\                         |
| \                                                                     |
| A **probable case** of generalized vaccinia occurs in persons         |
| recently vaccinated or in a close contact of a recent vaccinee and    |
| meets the following criteria:                                         |
|                                                                       |
| -   A vesicular or pustular eruption at one or more body areas        |
|     distant from the vaccination site or inadvertent inoculation site |
|                                                                       |
| -   Skin eruption occurring approximately 4-19 days after smallpox    |
|     vaccination or contact with someone vaccinated against smallpox   |
|                                                                       |
| -   Lesions follow approximately the same morphologic progression as  |
|     a primary vaccination site (i.e., papule, vesicle, pustule, scab, |
|     and scar)                                                         |
|                                                                       |
| -   Unlikely that autoinoculation accounts for skin eruption          |
|                                                                       |
| -   Other likely etiologies have been excluded.                       |
|                                                                       |
| A **confirmed case** of generalized vaccinia can occur in a recent    |
| vaccinee, a known close contact of a recent vaccinee, or someone with |
| no known contact but who otherwise meets the criteria for a probable  |
| case and no laboratory evidence of vaccinia infection (on the basis   |
| of testing skin lesions distal from vaccination site in a vaccinee or |
| distal to likely inoculation site \[if identifiable\]) exists in a    |
| close contact of a known vaccinee or in a patient who is not known to |
| be a close contact.                                                   |
|                                                                       |
| -   Laboratory evidence of vaccinia infection includes                |
|                                                                       |
|     -   Demonstration of vaccinia virus by culture                    |
|                                                                       |
| > or                                                                  |
|                                                                       |
| -   Histopathologic examination shows typical orthopox cytopathic     |
|     changes, and either polymerase chain reaction assay or antigen    |
|     detection techniques (e.g., direct fluorescent antibody)          |
|     revealing vaccinia or electron microscopy of biopsy specimens     |
|     revealing orthopox virus are strongly suggestive of infection     |
|     with vaccinia and should be confirmed by subsequent culture.      |
+-----------------------------------------------------------------------+

[Eczema Vaccinatum]{.underline}

Surveillance Case Definition for Eczema Vaccinatum After Smallpox
Vaccination for Use in Smallpox Vaccine Adverse Event Monitoring and
Response

+-----------------------------------------------------------------------+
| Eczema vaccinatum (EV) is a localized or generalized papular,         |
| vesicular, pustular, or erosive rash syndrome that can occur anywhere |
| on the body, with a predilection for areas currently or previously    |
| affected by 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 lesion in        |
| vaccinees. EV cases resulting from secondary transmission usually     |
| appear with skin eruptions approximately 5-19 days after the          |
| suspected exposure. EV lesions follow the same dermatologic course    |
| (progression) as the vaccination site in a vaccinee, and confluent or |
| erosive lesions can occur. The rash is often accompanied by fever and |
| lymphadenopathy, and affected persons are frequently systemically     |
| ill. EV tends to be most severe among first-time vaccinees, young     |
| children, and unvaccinated close contacts of vaccinees. Before the    |
| availability of vaccinia immune globulin (VIG), this condition had a  |
| high mortality. Establishing the diagnosis early and treating with    |
| VIG is crucial in reducing mortality.\                                |
| \                                                                     |
| **Notes:**                                                            |
|                                                                       |
| 1.  Although a history consistent with eczema/atopic dermatitis or    |
|     Darier\'s disease (i.e., keratosis follicularis) is included in   |
|     the surveillance definition for EV, clinicians evaluating         |
|     vaccinees or close contacts of recent vaccinees with a            |
|     presentation consistent with EV who do not report having one of   |
|     these dermatologic conditions should still consider EV as a       |
|     clinical diagnosis and assess for treatment with VIG.             |
|                                                                       |
| 2.  Lesions of EV are in approximately the same stage of morphologic  |
|     development as each other and progress.                           |
|                                                                       |
| **Case definition for eczema vaccinatum**\                            |
| \                                                                     |
| A **probable case** of EV occurs in persons recently vaccinated or in |
| a known close contact of a recent vaccinee and meets the following    |
| criteria:                                                             |
|                                                                       |
| -   A history of or current exfoliative skin condition consistent     |
|     with a diagnosis of eczema/atopic dermatitis or Darier\'s disease |
|                                                                       |
| > and                                                                 |
|                                                                       |
| -   Multiple skin lesions that developed                              |
|                                                                       |
|     -   In a vaccinated person concurrently or soon after lesion at   |
|         vaccination site or in a close contact of a recent vaccinee   |
|         up to 3 weeks after exposure, if time of relevant exposure is |
|         known                                                         |
|                                                                       |
|     -   Are distant from the vaccination or likely inoculation site   |
|         (i.e., are unlikely to be satellite lesions)                  |
|                                                                       |
| > and                                                                 |
|                                                                       |
| -   Are or have become vesicular/pustular sometime during their       |
|     evolution (i.e., do not remain macular or papular). Erosive or    |
|     ulcerative lesions might be observed.                             |
|                                                                       |
| > and                                                                 |
|                                                                       |
| -   Other likely etiologies have been excluded such as eczema         |
|     herpeticum (which can be particularly difficult to distinguish),  |
|     smallpox, chickenpox, disseminated herpes zoster, or pustular     |
|     (bacterial) impetigo.                                             |
|                                                                       |
| A **confirmed case** of EV can occur in a recent vaccinee, a known    |
| close contact of a recent vaccinee, or someone with no known contact  |
| but who otherwise meets the criteria for a probable case and          |
| laboratory evidence of vaccinia infection exists (on the basis of     |
| testing skin lesions distal from vaccination site in a vaccinee or    |
| distal to likely inoculation site, if identifiable) in a close        |
| contact of a known vaccinee or in a patient who is not known to be a  |
| close contact.                                                        |
|                                                                       |
| -   Laboratory evidence of vaccinia infection includes                |
|                                                                       |
|     -   Demonstration of vaccinia virus by culture                    |
|                                                                       |
| > or                                                                  |
|                                                                       |
| -   Polymerase chain reaction assay or antigen detection techniques   |
|     (e.g., direct fluorescent antibody) revealing vaccinia,           |
|     histopathologic examination showing typical orthopox cytopathic   |
|     changes, and electron microscopy of biopsy specimens revealing    |
|     orthopox virus are strongly suggestive of infection with vaccinia |
|     and should be confirmed by subsequent culture.                    |
+-----------------------------------------------------------------------+

[Progressive Vaccinia]{.underline}

Surveillance Case Definition for Progressive Vaccinia for Use in
Smallpox Vaccine Adverse Event Monitoring and Response

+-----------------------------------------------------------------------+
| Progressive vaccinia (PV) refers to continued vaccinia virus          |
| replication with progressive infection of skin surrounding the        |
| vaccination site or inadvertent inoculation site and sometimes the    |
| occurrence of secondary metastatic lesions in a person with           |
| underlying immune deficit (humoral or cellular). The condition is     |
| rare, severe, and often lethal. The description of the vaccination    |
| site lesion is usually that of a necrotic lesion; however, this is    |
| not the only presentation described with PV. Lesions can appear       |
| \"clean,\" fungated, piled-up, well-demarcated, or have bacterial     |
| superinfection.\                                                      |
| \                                                                     |
| **Case definition for progressive vaccinia**\                         |
| \                                                                     |
| A **suspected case** of PV occurs in persons recently vaccinated or   |
| in a known close contact of a recent vaccinee and meets the following |
| criteria:                                                             |
|                                                                       |
| -   Have a known or suspected depressed or defective immune system    |
|     (suspicion might arise as result of clinical suspicion of PV)     |
|                                                                       |
| > and                                                                 |
|                                                                       |
| -   Have a vaccination site lesion or inadvertent inoculation site    |
|     with one of the following criteria:                               |
|                                                                       |
|     -   No or minimal inflammatory response around lesion associated  |
|         with a nonhealing or enlarging vaccination lesion             |
|                                                                       |
|     -   Progressive expansion at or after 15 days of vaccination, or  |
|                                                                       |
|     -   Failure to heal or failure of lesion to regress at or after   |
|         15 days of vaccination                                        |
|                                                                       |
| > and                                                                 |
|                                                                       |
| -   Other likely etiologies (e.g., bacterial superinfection) have     |
|     been excluded.                                                    |
|                                                                       |
| A **probable case** of PV occurs in persons recently vaccinated or in |
| a known close contact of a recent vaccinee and meets the following    |
| criteria:                                                             |
|                                                                       |
| -   A known or suspected depressed or defective immune system         |
|                                                                       |
| > and                                                                 |
|                                                                       |
| -   A vaccination site lesion or inadvertent inoculation site with    |
|     one of the following criteria:                                    |
|                                                                       |
|     -   No or minimal inflammatory response around lesion associated  |
|         with a nonhealing or enlarging vaccination lesion             |
|                                                                       |
|     -   Progressive expansion at or after 21 days of vaccination, or  |
|                                                                       |
|     -   Failure to heal or failure of lesion to regress at or after   |
|         21 days of vaccination                                        |
|                                                                       |
| > and                                                                 |
|                                                                       |
| -   Other likely etiologies (e.g., bacterial superinfection) have     |
|     been excluded.                                                    |
|                                                                       |
| A **confirmed case** of PV can occur in a recent vaccinee, a known    |
| close contact of a recent vaccinee, or someone with no known contact  |
| but who otherwise meets the criteria for a suspected case and         |
| laboratory evidence of vaccinia infection (on the basis of testing    |
| skin lesions at least 15 days after vaccination or likely time of     |
| inoculation in a close contact of a recent vaccinee or in persons     |
| with no known contact with a vaccinee) exist\                         |
| \                                                                     |
| Laboratory evidence of vaccinia infection include                     |
|                                                                       |
| -   Demonstration of vaccinia virus by culture                        |
|                                                                       |
| > or                                                                  |
|                                                                       |
| -   Histopathologic examination showing typical orthopox cytopathic   |
|     changes, and either polymerase chain reaction assay or antigen    |
|     detection techniques (e.g., direct fluorescent antibody)          |
|     revealing vaccinia or electron microscopy of biopsy specimens     |
|     revealing orthopox virus are strongly suggestive of infection     |
|     with vaccinia and should be confirmed by subsequent culture.      |
+-----------------------------------------------------------------------+

**Rare Reactions**

[Fetal Vaccinia]{.underline}

Surveillance Case Definition for Fetal Vaccinia for Use in Smallpox
Vaccine Adverse Event Monitoring and Response

+-----------------------------------------------------------------------+
| Fetal vaccinia is a rare but serious complication resulting from      |
| vaccinia infection in utero that can occur in any trimester of        |
| pregnancy. It has been characterized by the presence of multiple skin |
| lesions, including macules, papules, vesicles, pustules, scars,       |
| ulcers, areas of maceration, and epidermolysis (blisters or bullae).  |
| When fetal vaccinia occurs, the outcome is usually fetal death,       |
| stillbirth, or premature birth of a neonate that dies shortly after   |
| birth. Survival of babies with apparent in utero infection such as    |
| scarring has also been described. Vaccinia infection in products of   |
| conception occurs rarely.\                                            |
| \                                                                     |
| **Case definition for fetal vaccinia**\                               |
| \                                                                     |
| A **suspected case** of fetal vaccinia is the presence of any skin    |
| lesion in a fetus or newborn exposed to vaccinia virus in utero and   |
| no other attributable cause.\                                         |
| \                                                                     |
| A **probable case** of fetal vaccinia is the presence of multiple     |
| skin lesions that might include macules, papules, vesicles, pustules, |
| scars, ulcers, areas of maceration, or epidermolysis                  |
| (blisters/bullae) in a fetus or newborn exposed to vaccinia in utero  |
| and no other attributable cause.\                                     |
| \                                                                     |
| A **confirmed case** of fetal vaccinia meets the criteria for a       |
| probable case and has laboratory evidence for vaccinial infection:\   |
| \                                                                     |
| Laboratory criteria for diagnosis includes                            |
|                                                                       |
| -   Positive test results for vaccinia virus by polymerase chain      |
|     reaction assay or antigen detection techniques (e.g., direct      |
|     fluorescent antibody), or                                         |
|                                                                       |
| -   Demonstration of vaccinia virus by culture                        |
|                                                                       |
| **Vaccinia infection**: Fetus, newborn, or product of conception with |
| laboratory evidence of infection and without any clinical symptoms or |
| signs.                                                                |
+-----------------------------------------------------------------------+

[Postvaccinial Central Nervous System Disease]{.underline}

Surveillance Case Definition for Postvaccinial Central Nervous System
Disease After Smallpox Vaccination for Use in Smallpox Vaccine Adverse
Event Monitoring and Response

+-----------------------------------------------------------------------+
| Postvaccinial central nervous system disease is an inflammation of    |
| the parenchyma of the central nervous system after smallpox           |
| vaccination. When the inflammation occurs in the brain it is called   |
| \"encephalitis,\" and when it occurs in the spinal cord it is called  |
| \"myelitis.\" Confirmation of diagnosis is made only on the basis of  |
| the demonstration of central nervous system (CNS) inflammation by     |
| histopathology or neuroimaging, but might be suggested by clinical    |
| features.^1^\                                                         |
| \                                                                     |
| **Case definition for encephalitis**\                                 |
| \                                                                     |
| A **suspected case** of encephalitis is defined as the presence of    |
| the acute onset of                                                    |
|                                                                       |
| -   Encephalopathy (e.g., depressed or altered level of               |
|     consciousness, lethargy, or personality change lasting \>24       |
|     hours)                                                            |
|                                                                       |
| -   Clinical evidence suggestive of cerebral inflammation to include  |
|     one of the following:                                             |
|                                                                       |
|     -   Fever (temperature \>100°F \[\>38°C\]) or hypothermia         |
|         (temperature \<95°F \[\<35°C\])                               |
|                                                                       |
|     -   Meningismus (i.e., nuchal rigidity and photo/phonophobia)     |
|                                                                       |
|     -   Cerebrospinal fluid (CSF) pleocytosis (\>5 white blood        |
|         cells/mm^3^)                                                  |
|                                                                       |
|     -   Presence of focal neurologic deficit                          |
|                                                                       |
|     -   Electroencephalography findings consistent with encephalitis  |
|                                                                       |
|     -   Neuroimaging findings on magnetic resonance imaging           |
|         consistent with acute inflammation (with or without meninges) |
|         or demyelination of the nervous system                        |
|                                                                       |
|     -   Seizures (either new onset or exacerbation of previously      |
|         controlled seizures)                                          |
|                                                                       |
| > and                                                                 |
|                                                                       |
| -   No alternative (investigated) etiologies are found for presenting |
|     sign and symptoms.                                                |
|                                                                       |
| A **probable case** of encephalitis is defined by the acute onset of  |
|                                                                       |
| -   Encephalopathy as outlined for a suspected case                   |
|                                                                       |
| > and                                                                 |
|                                                                       |
| -   Two or more of the criterion listed for suspected encephalitis as |
|     clinical evidence suggestive of cerebral inflammation             |
|                                                                       |
| > and                                                                 |
|                                                                       |
| -   No alternative (investigated) etiologies are found for presenting |
|     sign and symptoms                                                 |
|                                                                       |
| A **confirmed case** of encephalitis is defined as                    |
|                                                                       |
| -   Demonstration of acute cerebral inflammation (with or without     |
|     meninges) or demyelination by histopathology                      |
|                                                                       |
| > and                                                                 |
|                                                                       |
| -   No alternative (investigated) etiologies are found for presenting |
|     sign and symptoms                                                 |
|                                                                       |
| **Case definition for acute myelitis**\                               |
| \                                                                     |
| A **suspected case** of myelitis is defined as presence of the acute  |
| onset of                                                              |
|                                                                       |
| -   Myelopathy (development of sensory, motor, or autonomic           |
|     dysfunction attributable to the spinal cord, including upper- and |
|     lower-motor neuron weakness, sensory level, and bowel or bladder  |
|     dysfunction)                                                      |
|                                                                       |
| > and                                                                 |
|                                                                       |
| -   Additional evidence suggestive of spinal cord inflammation, to    |
|     include one of the following:                                     |
|                                                                       |
|     -   Fever (temperature \>100ºF \[\>38ºC\]) or hypothermia         |
|         (temperature \<95°F \[\<35°C\])                               |
|                                                                       |
|     -   CSF pleocytosis (\>5 white blood cells/mm^3^)                 |
|                                                                       |
|     -   Presence of focal neurologic deficit                          |
|                                                                       |
|     -   Electromyographic (EMG) studies suggestive of central (spinal |
|         cord) dysfunction                                             |
|                                                                       |
|     -   Neuroimaging findings on MRI demonstrating acute inflammation |
|         (with or without meninges) or demyelination of the spinal     |
|         cord                                                          |
|                                                                       |
| > and                                                                 |
|                                                                       |
| -   No alternative (investigated) etiologies are found for presenting |
|     sign and symptoms.                                                |
|                                                                       |
| A **probable case** of myelitis is defined by the acute onset of      |
|                                                                       |
| -   Myelopathy as outlined for a suspected case                       |
|                                                                       |
| > and                                                                 |
|                                                                       |
| -   Two or more of the criterion listed for suspected myelitis as     |
|     evidence suggestive of spinal cord inflammation                   |
|                                                                       |
| > and                                                                 |
|                                                                       |
| -   No alternative (investigated) etiologies are found for presenting |
|     sign and symptoms.                                                |
|                                                                       |
| A **confirmed case** of myelitis is defined by                        |
|                                                                       |
| -   Demonstration of acute spinal cord inflammation (with or without  |
|     meninges) or demyelination by histopathology                      |
|                                                                       |
| > and                                                                 |
|                                                                       |
| -   No alternative (investigated) etiologies are found for presenting |
|     sign and symptoms.                                                |
|                                                                       |
| **Note**: Cases fulfilling the criteria for both encephalitis and     |
| myelitis in any category would be classified as encephalomyelitis.    |
+-----------------------------------------------------------------------+

^1^ Some cases of postvaccinial encephalomyelitis might be caused by
direct infection of the CNS by vaccinia virus, resulting in acute
cytotoxic neuronal damage and inflammation. However, laboratory evidence
of virus replication is lacking in the majority of cases and might be
attributable to immunopathological mechanisms instead. In the majority
of cases, histopathologic findings similar to other \"postinfectious\"
encephalitides are found, suggestive of an inflammatory demyelinating
condition (acute disseminated encephalitis/encephalomyelitis \[ADEM\]).
The distinction between these two pathologic mechanisms might be
difficult to make clinically in the early stages of illness. A diagnosis
of ADEM might be favored by a longer interval of onset after
vaccination; magnetic resonance imaging findings of multifocal areas of
increased signal on T2, fluid attenuation inversion recovery, and
diffusion weighted imaging sequences, suggestive of acute demyelination;
and an absence of CSF pleocytosis.

**Cardiac**

[Myo/pericarditis]{.underline}

Surveillance Case Definition for Myo/pericarditis for Use in Smallpox
Vaccine Adverse Event Monitoring and Response

+-----------------------------------------------------------------------+
| **Myo/pericarditis**\                                                 |
| \                                                                     |
| Myo/pericarditis is defined as a spectrum of disease caused by        |
| inflammation of the myocardium and/or pericardium. Patients might     |
| have symptoms and signs consistent with myocarditis, pericarditis, or |
| both. For the purpose of surveillance reporting, patients with        |
| myocarditis or pericarditis will be reported as having                |
| myo/pericarditis. These categories are intended for surveillance      |
| purposes and not for use in individual diagnosis or treatment         |
| decisions.\                                                           |
| \                                                                     |
| **Case definition for acute myocarditis**\                            |
| \                                                                     |
| A **suspected case** of acute myocarditis is defined by the following |
| criteria and the absence of evidence of any other likely cause of     |
| symptoms or findings below:                                           |
|                                                                       |
| -   Presence of dyspnea, palpitations, or chest pain of probable      |
|     cardiac origin in a patient with either one of the following:     |
|                                                                       |
|     -   Electrocardiogram (ECG) abnormalities beyond normal variants, |
|         not documented previously, including                          |
|                                                                       |
|         -   ST-segment or T-wave abnormalities                        |
|                                                                       |
|         -   Paroxysmal or sustained atrial or ventricular arrhythmias |
|                                                                       |
|         -   Atrioventricular (AV) nodal conduction delays or          |
|             intraventricular conduction defects                       |
|                                                                       |
|         -   Continuous ambulatory electrocardiographic monitoring     |
|             that detects frequent atrial or ventricular ectopy        |
|                                                                       |
| > or                                                                  |
|                                                                       |
| -   Evidence of focal or diffuse depressed left-ventricular (LV)      |
|     function of indeterminate age identified by an imaging study      |
|     (e.g., echocardiography or radionuclide ventriculography).        |
|                                                                       |
| A **probable case** of acute myocarditis, in addition to the above    |
| symptoms and in the absence of evidence of any other likely cause of  |
| symptoms, has one of the following:                                   |
|                                                                       |
| -   Elevated cardiac enzymes, specifically, abnormal levels of        |
|     cardiac troponin I, troponin T, or creatine kinase myocardial     |
|     band (a troponin test is preferred)                               |
|                                                                       |
| -   Evidence of focal or diffuse depressed LV function identified by  |
|     an imaging study (e.g., echocardiography or radionuclide          |
|     ventriculography) that is documented to be of new onset or of     |
|     increased degree of severity (in the absence of a previous study, |
|     findings of depressed LV function are considered of new onset if, |
|     on followup studies, these findings resolve, improve, or worsen)  |
|                                                                       |
| > or                                                                  |
|                                                                       |
| -   Abnormal result of cardiac radionuclide imaging (e.g., cardiac    |
|     magnetic resonance imaging \[MRI\] with gadolinium or gallium-67  |
|     imaging) indicating myocardial inflammation                       |
|                                                                       |
| A case of acute myocarditis is confirmed if histopathologic evidence  |
| of myocardial inflammation is found at endomyocardial biopsy or       |
| autopsy.\                                                             |
| \                                                                     |
| **Case definition for acute pericarditis**\                           |
| \                                                                     |
| A **suspected case** of acute pericarditis is defined by the presence |
| of                                                                    |
|                                                                       |
| -   Typical chest pain (i.e., pain made worse by lying down and       |
|     relieved by sitting up and/or leaning forward) and                |
|                                                                       |
| -   No evidence of any other likely cause of such chest pain          |
|                                                                       |
| A **probable case** of acute pericarditis is a suspected case of      |
| pericarditis, or a case in a person with pleuritic or other chest     |
| pain not characteristic of any other disease, that, in addition, has  |
| one or more of the following:                                         |
|                                                                       |
| -   Pericardial rub, an auscultatory sign with one to three           |
|     components per beat                                               |
|                                                                       |
| -   ECG with diffuse ST-segment elevations or PR depressions without  |
|     reciprocal ST depressions that are not previously documented      |
|                                                                       |
| -   Echocardiogram indicating the presence of an abnormal collection  |
|     of pericardial fluid (e.g., anterior and posterior pericardial    |
|     effusion or a large posterior pericardial effusion alone)         |
|                                                                       |
| **Note**: A case of acute pericarditis is confirmed if                |
| histopathologic evidence of pericardial inflammation is evident from  |
| pericardial tissue obtained at surgery or autopsy.                    |
+-----------------------------------------------------------------------+

[Dilated Cardiomyopathy]{.underline}

Surveillance Case Definition for Dilated Cardiomyopathy for Use in
Smallpox Vaccine Adverse Event Monitoring and Response

+-----------------------------------------------------------------------+
| Dilated cardiomyopathy (DCM) is defined by the World Health           |
| Organization as a disease of the heart muscle characterized by        |
| dilatation and impaired contraction of the left ventricle or both     |
| ventricles. It might be idiopathic, familial/genetic, viral, and/or   |
| immune, alcoholic/toxic, or associated with recognized cardiovascular |
| disease in which the degree of myocardial dysfunction is not          |
| explained by the abnormal loading conditions or the extent of         |
| ischemic damage. Histology is nonspecific. Presentation is usually    |
| with heart failure, which is often progressive. Arrhythmias,          |
| thromboembolism, and sudden death are common and can occur at any     |
| stage. Despite full cardiac workup, the etiology of DCM often cannot  |
| be determined. Because other viruses are known to cause DCM, the      |
| occurrence of DCM after smallpox vaccination is plausible, although   |
| not previously described. Because histologic findings of DCM are      |
| often nonspecific, endomyocardial biopsy is not likely to confirm an  |
| etiologic role for vaccinia but might rule out other known etiologies |
| of DCM (e.g., sarcoidosis and amyloidosis). The following case        |
| definition describes the structural and functional cardiac criteria   |
| and clinical conditions required to define a case of DCM for use in   |
| the smallpox adverse events monitoring and response activity.\        |
| \                                                                     |
| **Case definition for dilated cardiomyopathy after smallpox           |
| vaccination**\                                                        |
| \                                                                     |
| Smallpox vaccinees are defined as having DCM if they meet all of the  |
| following criteria:                                                   |
|                                                                       |
| -   Cardiac muscle dysfunction exists, characterized by ventricular   |
|     dilatation (e.g., left ventricular end-diastolic dimension        |
|     \>55 mm) and impaired contraction of one or both ventricles       |
|     (e.g., left ventricular ejection fraction [\<]{.underline}0.45)   |
|                                                                       |
| -   No evidence of DCM or congestive heart failure before             |
|     vaccination, either by history (e.g., dyspnea on exertion and     |
|     fatigue) or by cardiac evaluation, including chest radiography or |
|     echocardiography if available                                     |
|                                                                       |
| -   No other cardiac or noncardiac disease can account for the        |
|     symptoms or abnormalities present. If another cardiac disease     |
|     coexists, it is not sufficient to cause the degree of myocardial  |
|     dysfunction present (e.g., ischemic or valvular heart disease or  |
|     longstanding hypertension). No other etiology of DCM can be       |
|     determined, such as alcohol or cocaine use, hypertension, morbid  |
|     obesity, or other causes.                                         |
+-----------------------------------------------------------------------+

**[Case Classification]{.underline}**

Case definitions are designed to identify the entities under
surveillance, not to define the certainty of an etiologic relation
between the entities under surveillance and vaccinia exposure. Thus,
cases are classified as suspected if they have compatible clinical
features but either further investigation is required or investigation
of the case did not provide enough supporting evidence for the
diagnosis. Cases are classified as probable if they have compatible
clinical features and information is supportive of, but not definitive
for, the diagnosis. Cases are classified as confirmed if pathognomonic
findings or other evidence definitely supporting the diagnosis is
documented. In certain instances, confirmation is made on the basis of
verification of the presence of vaccinia or of orthopox virus DNA by
culture or polymerase chain reaction (PCR) detection. Confirmation also
might be determined on the basis of other evidence in instances in which
vaccinia presence is not a pathognomonic feature of the entity under
surveillance (e.g., myocarditis or pericarditis, both of which are
believed to be an immune-mediated response to vaccination rather than
mediated through vaccinia viral infection).

Classification of certain smallpox adverse vaccine reactions can be
confounded by lack of information or the absence of pathognomonic
findings. This is illustrated by the limited understanding of the
vaccinia virus\' pathogenesis and the relevance of vaccinia testing in
conditions such as postvaccinial CNS diseases and fetal vaccinia. No
large-scale study examining the cerebral spinal fluid (CSF) of smallpox
vaccinees exists; therefore, the significance of the presence or absence
of vaccinia neutralizing antibodies or vaccinia virus recovered from the
CSF of a vaccinee with CNS findings is not fully understood. Testing for
the presence or absence of vaccinia virus cannot confirm or refute a
smallpox vaccine-associated etiology for these conditions. Conversely,
the inability to recover vaccinia virus from burnt-out lesions from an
infant exposed to vaccinia in utero and born with skin lesions
compatible with fetal vaccinia does not mean that intrauterine infection
did not occur. To address these limitations, the suspected category for
these adverse reactions allows a clinically compatible case with
indeterminate or no testing to remain under consideration.

**[Vaccinia Laboratory Diagnostics]{.underline}**

The smallpox vaccine is made from live vaccinia virus, a species of the
Orthopoxvirus genus, and protects against smallpox disease. It does not
contain the related Orthopoxvirus variola, which is the causative agent
of smallpox disease. When evaluating a reported adverse event after
smallpox vaccination, standard laboratory testing should be conducted to
rule out other infections, including viral infections (e.g., herpes
zoster, varicella, enteroviruses, and herpes simplex). During an
outbreak of other orthopoxviruses (e.g., monkeypox and smallpox),
specific testing also should be completed for these viruses.

Laboratory testing for vaccinia is still largely a research tool
assisting the evaluation, diagnosis, and treatment of adverse reactions
after smallpox vaccination. Testing is available through the Laboratory
Response Network (LRN), which can be accessed through state and local
health departments with confirmatory testing at CDC. Diagnostic
techniques that can aid in the detection of vaccinia include electron
microscopy (EM), viral culture, and PCR. Although these tests can
identify orthopoxviruses, only certain PCR tests or biologic
characterization of viral growth on chick chorioallantoic membrane
specifically identifies the presence of vaccinia virus. Positive results
for EM, PCR, and viral culture should be interpreted with caution. EM or
culture results compatible with orthopox virus and presumed to be
vaccinia might be another zoonotic orthopox virus or, in the worst case
scenario, variola itself. Experience with vaccinia diagnostics is
limited. Molecular contamination resulting in false-positive PCR results
can occur. Therefore, use of appropriate controls is essential. PCR
techniques, which test for orthopoxvirus nucleic acid presence, at LRN
have undergone multicenter validation studies, and these data along with
clinical experience with these assays is being compiled to enable the
U.S. Food and Drug Administration to review the test reagents and assay
for wider diagnostic use. Serologic testing of single serum samples for
vaccinia is of limited value because it cannot discern existing immunity
from recent infection. Testing of paired acute and convalescent sera
antibody titers is rarely available during initial assessment of a
suspected vaccinia adverse event.

#### CLINICAL ALGORITHM(S)

None provided

### EVIDENCE SUPPORTING THE RECOMMENDATIONS

#### TYPE OF EVIDENCE SUPPORTING THE RECOMMENDATIONS

The type of evidence supporting the recommendations is not specifically
stated.

### BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS

#### POTENTIAL BENEFITS

-   The smallpox vaccine surveillance case definitions presented in the
    report can be used in future vaccination programs to ensure uniform
    reporting guidelines and case classification.

-   Accurate classification of vaccinia adverse reactions is necessary
    for appropriate use of vaccinia immune globulin (VIG) and cidofovir
    for the treatment of select vaccinia reactions.

#### POTENTIAL HARMS

Positive results for electron microscopy (EM), polymerase chain reaction
(PCR), and viral culture should be interpreted with caution. EM or
culture results compatible with orthopox virus and presumed to be
vaccinia might be another zoonotic orthopox virus or, in the worst case
scenario, variola itself. Experience with vaccinia diagnostics is
limited. Molecular contamination resulting in false-positive PCR results
can occur.

### QUALIFYING STATEMENTS

#### QUALIFYING STATEMENTS

Surveillance case definitions rely on a constellation of clinical,
laboratory, and epidemiologic criteria for classification. They are not
intended to replace clinical judgment and should not be used to direct
individual patient care, assess causality, or determine disability
compensation or reimbursement for medical care. The definitions have
been developed specifically for the surveillance of adverse events
during the voluntary Department of Health and Human Services (DHHS)
civilian smallpox preparedness and response program and might not apply
to vaccinees in other settings (e.g., clinical trials). These
surveillance case definitions might not apply to the international
community, which administers non-New York City Board of Health (NYCBOH)
vaccinia strains and faces different considerations in health-care use
and surveillance systems. These case definitions are a component of a
dynamic surveillance process. As knowledge and experience increase, they
might be modified or improved. Ongoing input from health-care providers
and health departments are important for the successful implementation
and use of these case definitions.

### IMPLEMENTATION OF THE GUIDELINE

#### DESCRIPTION OF IMPLEMENTATION STRATEGY

These case definitions and reporting guidelines were used by the Centers
for Disease Control and Prevention (CDC) and the Office of the Assistant
Secretary of Defense for Health Affairs during the mandatory Department
of Defense (DoD) and voluntary U.S. Department of Health and Human
Services (DHHS) smallpox vaccination programs that were designed to
increase national preparedness in the event of a biologic terrorism
attack.

**Surveillance Results and Outcome**

The voluntary DHHS civilian smallpox preparedness and response program
established adverse event case monitoring capacity and response within
CDC and state and local health departments. Data collected were derived
from the standardized case definitions and enabled rapid classification,
reporting, and the ability to compare adverse reaction surveillance data
from various sources.

#### IMPLEMENTATION TOOLS

Foreign Language Translations\
Patient Resources\
Pocket Guide/Reference Cards\
Staff Training/Competency Material

For information about
[availability](#identifying-information-and-availability), see the
\"Availability of Companion Documents\" and \"Patient Resources\" fields
below.

### INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT CATEGORIES

#### IOM CARE NEED

Getting Better

#### IOM DOMAIN

Effectiveness\
Patient-centeredness

### IDENTIFYING INFORMATION AND AVAILABILITY

#### BIBLIOGRAPHIC SOURCE(S)

Casey C, Vellozzi C, Mootrey GT, Chapman LE, McCauley M, Roper MH, Damon
I, Swerdlow DL. Surveillance guidelines for smallpox vaccine (vaccinia)
adverse reactions. MMWR Recomm Rep 2006 Feb 3;55(RR-1):1-16. \[43
references\]
[PubMed](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16456528)

#### ADAPTATION

Not applicable: The guideline was not adapted from another source.

#### DATE RELEASED

2006 Feb 3

#### GUIDELINE DEVELOPER(S)

Centers for Disease Control and Prevention - Federal Government Agency
\[U.S.\]

#### SOURCE(S) OF FUNDING

United States Government

#### GUIDELINE COMMITTEE

The Vaccinia Case Definition Development Working Group

#### COMPOSITION OF GROUP THAT AUTHORED THE GUIDELINE

**The Vaccinia Case Definition Development Working Group**

Francisco Averhoff, MD, Karen Broder, MD, Christine Casey, MD, Inger
Damon, MD, Michael Deming, MD, Daniel B. Fishbein, MD, Susan Goldstein,
MD, La Mar Hasbrouck, MD, James D Heffelfinger, MD, Barbara Herwaldt,
MD, Kristen Kenyan, Katrin Kohl, MD, Andrew Kroger, MD, Herschel W.
Lawson, MD, Sheryl Lyss, MD, Anne C. Moore, MD, Gina T. Mootrey, DO,
Juliette Morgan, MD, Joe Mulinare, MD, Linda Neff, PhD, Monica E. Parise
MD, Russell Regnery PhD, Martha H. Roper, MD, Scott Santibanez, MD,
Richard A. Schieber, MD, James Sejvar, MD, Jane F. Seward, MBBS, David
L. Swerdlow, MD, Bruce C. Tierney, MD, Thomas J. Török, MD, Claudia
Vellozzi, MD, Charles R. Vitek, MD, CDC; J Edwin Atwood, MD, R. Dana
Bradshaw, MD, Limone C. Collins, MD, Laurie L. Duran, Robert E. Eckart,
MD, Renata J. Engler, MD, Jeffrey S. Halsell, MD, Mylene T. Huynh, MD,
Robert J. Labutta, MD, Felisa S. Lewis, MD, Scott A. Norton, MD,
Margaret Ryan, MD, US Department of Defense; Vincent A. Fulginiti, MD,
Health Science Center, University of Arizona; J. Michael Lane, MD
(retired), Smallpox Eradication Program, Communicable Disease Center;
Laurence S. Sperling, MD, Section of Preventive Cardiology, Emory
University School of Medicine, Atlanta, Georgia

**Advisory Committee on Immunization Practices-Armed Forces
Epidemiological Board Smallpox Vaccine Safety Working Group**

*Chairs*: John F. Modlin, MD, Dartmouth Medical School; John Neff, MD,
University of Washington, Seattle; Guthrie Birkhead, MD, New York State
Department of Health\
*Members*: Fernando A. Guerra, MD, San Antonio Metropolitan Health
District, Texas; Pierce Gardner, MD, New York State University-Stony
Brook; Gregory Poland, MD, Mayo Clinic; W. Dana Flanders, MD, Emory
University, Rollins School of Public Health, Atlanta, Georgia; Gregory
C. Gray, MD, University of Iowa College of Public Health, Iowa City;
Robert Shope, MD, University of Texas at Galveston (deceased); Rose
Marie Robertson, MD, American Heart Association; Clyde Yancy, MD,
University of Texas Southwestern, Dallas; Toby Maurer, MD, Tim Berger,
MD, University of California-San Francisco; Kent A. Sepkowitz, MD,
Memorial Sloan Kettering; Jane Siegel, MD, University of Texas
Southwestern, Dallas\
*Ex-Officio Representatives: DoD*: James R. Riddle, DVM, Roger L.
Gibson, PhD, U.S. Air Force, Office of Health Affairs; John D.
Grabenstein, PhD, U.S. Army, Military Vaccine Agency, Office of the Army
Surgeon General, U.S. Department of Defense. Karen Goldenthal, MD, Ann
McMahon, MD, Center for Biologics Evaluation and Research, U.S. Food and
Drug Administration; Vito M. Caserta, MD, Carol Konchan, MD, Health
Resources and Services Administration; Linda Quick, MD, Louisa Chapman,
MD, National Immunization Program, CDC\
*Consultants*: Michael D. Blum, MD, Leslie A. Killion, MD, Wyeth
Research

#### FINANCIAL DISCLOSURES/CONFLICTS OF INTEREST

The Centers for Disease Control and Prevention (CDC), their planners,
and their content experts wish to disclose they have no financial
interests or other relationships with the manufacturers of commercial
products, suppliers of commercial services, or commercial supporters.

#### GUIDELINE STATUS

This is the current release of the guideline.

#### GUIDELINE AVAILABILITY

Electronic copies: Available from the Centers for Disease Control and
Prevention (CDC) Web site:

-   [HTML Format](http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5501a1.htm)

-   [Portable Document Format
    (PDF)](http://www.cdc.gov/mmwr/PDF/rr/rr5501.pdf)

Print copies: Available from the Centers for Disease Control and
Prevention, MMWR, Atlanta, GA 30333. Additional copies can be purchased
from the Superintendent of Documents, U.S. Government Printing Office,
Washington, DC 20402-9325; (202) 783-3238.

#### AVAILABILITY OF COMPANION DOCUMENTS

The following are available:

-   Pocket reference guide for the smallpox vaccine adverse events.
    Atlanta (GA): Centers for Disease Control and Prevention
    (CDC); 2002. 3 p. Electronic copies: Available in Portable Document
    Format (PDF) from the [CDC Web
    site](http://www.bt.cdc.gov/training/smallpoxvaccine/reactions/SmallpoxVaccinationGuide.pdf).

Print copies: Available from the Centers for Disease Control and
Prevention, MMWR, Atlanta, GA 30333. To order copies of the pocket guide
please see the [Immunization Educational and Training
Materials](https://www2.cdc.gov/nchstp_od/PIWeb/NIPorderform.asp)
(99-7392) Brochure - Smallpox Vaccination, Method and Reactions, 2002.

Additional information regarding smallpox preparation and response
activities is available from the [CDC Web
site](http://www.bt.cdc.gov/agent/smallpox/prep/cdc-prep.asp).

Additionally, a Continuing Education activity is available from the
[Centers for Disease Control and Prevention (CDC) Web
site](http://www2a.cdc.gov/ce/availableactivities.asp).

**Related Guideline**

Cono J, Casey CG, Bell DM. Smallpox vaccination and adverse reactions.
Guidance for clinicians. MMWR Recomm Rep 2003 Feb 21;52(RR-4):1-28. See
the [National Guideline Clearinghouse (NGC)
summary](http://www.guideline.gov/summary/summary.aspx?doc_id=3597&nbr=002823).

#### PATIENT RESOURCES

The following are available:

-   Fact sheets: smallpox basics for the general public. Atlanta (GA):
    Centers for Disease Control and Prevention (CDC); 2003 Jan.

-   Smallpox pre-vaccination information packet. Atlanta (GA): Centers
    for Disease Control and Prevention (CDC); 2003 Jan. 34 p.

-   Vaccine information statement. What you need to know. Atlanta (GA):
    Centers for Disease Control and Prevention (CDC); 2003 Jan. 3 p.
    (Available in English and Spanish).

Electronic copies of these and other related materials are available
from the [CDC Web
site](http://www.bt.cdc.gov/agent/smallpox/vaccination/index.asp#patient).

Please note: This patient information is intended to provide health
professionals with information to share with their patients to help them
better understand their health and their diagnosed disorders. By
providing access to this patient information, it is not the intention of
NGC to provide specific medical advice for particular patients. Rather
we urge patients and their representatives to review this material and
then to consult with a licensed health professional for evaluation of
treatment options suitable for them as well as for diagnosis and answers
to their personal medical questions. This patient information has been
derived and prepared from a guideline for health care professionals
included on NGC by the authors or publishers of that original guideline.
The patient information is not reviewed by NGC to establish whether or
not it accurately reflects the original guideline\'s content.

#### NGC STATUS

This NGC summary was completed by ECRI on February 9, 2006. This summary
was updated by ECRI Institute on May 17, 2007 following the U.S. Food
and Drug Administration (FDA) advisory on Gadolinium-based contrast
agents. This summary was updated by ECRI Institute on June 20, 2007
following the U.S. Food and Drug Administration (FDA) advisory on
gadolinium-based contrast agents. This summary was updated by ECRI
Institute on July 12, 2007 following the U.S. Food and Drug
Administration (FDA) advisory on Troponin-1 Immunoassay.

#### COPYRIGHT STATEMENT

No copyright restrictions apply.

### DISCLAIMER

#### NGC DISCLAIMER

The National Guideline Clearinghouse™ (NGC) does not develop, produce,
approve, or endorse the guidelines represented on this site.

All guidelines summarized by NGC and hosted on our site are produced
under the auspices of medical specialty societies, relevant professional
associations, public or private organizations, other government
agencies, health care organizations or plans, and similar entities.

Guidelines represented on the NGC Web site are submitted by guideline
developers, and are screened solely to determine that they meet the NGC
Inclusion Criteria which may be found at
<http://www.guideline.gov/about/inclusion.aspx> .

NGC, AHRQ, and its contractor ECRI Institute make no warranties
concerning the content or clinical efficacy or effectiveness of the
clinical practice guidelines and related materials represented on this
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Readers with questions regarding guideline content are directed to
contact the guideline developer.

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Date Modified: 11/3/2008