Surveillance Guidelines for Smallpox Vaccine (vaccinia)
Adverse Reactions

Prepared by
Christine Casey, MD¹
Claudia Vellozzi, MD²
Gina T. Mootrey, DO²
Louisa E. Chapman, MD²
Mary McCauley²
Martha H. Roper, MD²
Inger Damon, MD³
David L. Swerdlow, MD^3
1Immunization Safety Office, Office of the Chief Science Officer, Office of the Director
²National Immunization Program
³National Center for Infectious Diseases

The material in this report originated in the National Immunization Program, Anne Schuchat, MD, Director.

Corresponding preparer: Christine Casey, Immunization Safety Office, Office of the Chief of Science, 1600 Clifton Road, NE, MS E-61, Atlanta, GA 30329. Telephone: 404-639-2973; Fax: 404-639-8834; Email: [email protected].

Summary

CDC and the U.S. Food and Drug Administration rely on state and local health departments, health-care providers, and the public to report the occurrence of adverse events after vaccination to the Vaccine Adverse Event Reporting System. With such data, trends can be accurately monitored, unusual occurrences of adverse events can be detected, and the safety of vaccination intervention activities can be evaluated.

On January 24, 2003, the U.S. Department of Health and Human Services (DHHS) implemented a preparedness program in which smallpox (vaccinia) vaccine was administered to federal, state, and local volunteers who might be first responders during a biologic terrorism event. As part of the DHHS Smallpox Preparedness and Response Program, CDC in consultation with experts, established surveillance case definitions for adverse events after smallpox vaccination. Adverse reactions after smallpox vaccination identified during the 1960s surveillance activities were classified on the basis of clinical description and included eczema vaccinatum; fetal vaccinia; generalized vaccinia; accidental autoinoculation, nonocular; ocular vaccinia; progressive vaccinia; erythema multiforme major; postvaccinial encephalitis or encephalomyelitis; and pyogenic infection of the vaccination site.

This report provides uniform criteria used for the surveillance case definition and classification for these previously recognized adverse reactions used during the DHHS Smallpox Preparedness and Response Program. Inadvertent inoculation was changed to more precisely describe this event as inadvertent autoinoculation and contact transmission, nonocular and ocular vaccinia. Pyogenic infection also was renamed superinfection of the vaccination site or regional lymph nodes. Finally, case definitions were developed for a new cardiac adverse reaction (myo/pericarditis) and for a cardiac adverse event (dilated cardiomyopathy) and are included in this report. 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.

Introduction

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 (1). Comparable surveillance guidelines for the classification and reporting of adverse reactions after vaccination are nominal and have not commonly include standardized case definitions (2,3). 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 CDC and the Office of the Assistant Secretary of Defense for Health Affairs during the mandatory Department of Defense (DoD) and voluntary U.S. DHHS smallpox vaccination programs that were designed to increase national preparedness in the event of a biologic terrorism attack (4--6).

Adverse reactions caused by smallpox vaccination range from mild and self-limited to severe and life-threatening. During the recent smallpox vaccination programs, CDC, DoD, and the joint Advisory Committee on Immunization Practices (ACIP)-Armed Forces Epidemiological Board (AFEB) Smallpox Vaccine Safety Working Group (SVS WG) relied on surveillance data from the smallpox pre-eradication era to estimate frequencies of adverse reactions expected during these vaccination programs. These estimates might be limited because the targeted population during the 1960s was mostly children who had never been previously vaccinated; the recent program targeted healthy adults, some of whom had received smallpox vaccines (6). Furthermore, adverse reactions during the 1960s were classified and reported by providers on the basis of subjective clinical diagnosis, and standard collection or analytical tools were not applied to the clinical data (7--11). Without explicit criteria for identifying cases for public health surveillance, state health departments and individual practitioners often apply different criteria for reporting similar cases (1). Surveillance data for adverse reactions after smallpox vaccination must be aggressively pursued and standardized to assess accurately the frequency of adverse events after smallpox vaccination.

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 (12).

Reporting Guidelines

These 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 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 (Table 1). 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) (13) should be reported within 48 hours; all other events should be reported within 1 week (14). Reports can be submitted to VAERS at 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).

Case Definition and Classification

ACIP-AFEB SVS WG was responsible for safety oversight of the DHHS and 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 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 (15).

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 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

Vaccination progression and normal local reactions are difficult to distinguish from a superinfection of the vaccination site or regional lymph nodes. Secondary infections (i.e., superinfections) of the vaccination site are uncommon (rate: 0.55 per 10,000 vacinees) (16) and are typically mild to moderate in clinical severity (Box 1). Persons at greatest risk are children and those who frequently manipulate and contaminate the vaccination site. Occlusive dressings might lead to maceration and increased risk for infection. Secondary streptococcal bacterial infection has been reported (9), but anaerobic organisms and mixed infections also might be expected.

Distinguishing superinfection of the vaccination site or regional lymph nodes can be particularly challenging because both a bacterial cellulitis and a variant of the normal major reaction or RT have similar signs and symptoms.

Robust Take

An RT is a vaccinial cellulitis and is defined as >3 inches (7.5 cm) of redness with swelling, pain, and warmth at the vaccination site. These symptoms peak on days 6--12 postvaccination and regress within the following 24--72 hours. RTs can occur in up to 16% of smallpox vaccinees (16,17). Suspected bacterial cellulitis after smallpox vaccination is often treated empirically with antibiotics without a period of observation, and bacterial or other cultures are rarely obtained. As clinicians have gained experience with smallpox vaccination, some have ceased treating empirically with antibiotics in favor of close observation. Clinical observations suggest that the majority of vaccinees' local symptoms resolved without intervention, leading providers to conclude that these cases were RTs (CDC, unpublished data, 2002). In contrast to an RT, superinfections refer to cellulitis caused by agents other than vaccinia.

Unintentional Transfer of Vaccinia Virus

Inadvertent Autoinoculation

Unintentional transfer of vaccinia virus includes transfer from the vaccination site (or probable site of inoculation in a person infected with vaccinia through contract transmission) to elsewhere on the vaccinee's (or contact's) body, which is called inadvertent autoinoculation (Box 2). Smallpox vaccinees or contacts can transfer vaccinia virus to their hands or fomites, which becomes a source for infection elsewhere on the body. The most common nonocular sites are the face, nose, mouth, lips, genitalia, and anus. Lesions at autoinoculation sites progress through the same stages (e.g., papular, vesicular, pustular, crusting, and scab) as the vaccination site. When autoinoculation occurs >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 and burns (17).

Contact Transmission

When the virus is transferred from the vaccinee to a close contact, this transmission is termed contact transmission. Persons in close contact with a recent vaccinee or associated vectors (e.g., distant lesions on a vaccinee resulting from inadvertent autoinoculation, clothing, bedding, or bandages contaminated by vaccinia) might acquire vaccinia infection. Vaccinia virus is shed from the vaccination site or from distant lesions caused by autoinoculation, GV, EV, or PV (Box 3). Viral shedding might occur until the scab detaches from the vaccination site or distant lesions; virus can survive for several days on clothing, bedding, or other fomites (18). Although virus exists in the scab, it is bound in the fibrinous matrix, and the scab is not thought to be highly infectious (17). Infection acquired through contact transmission can result in the same adverse events observed after smallpox vaccination.

Ocular Vaccinia

In the case of either contact transmission or inadvertent autoinoculation, if the virus is transferred to the eye and surrounding orbit, this transmission is referred to as ocular vaccinia. Ocular vaccinial infections result from the transfer of vaccinia from the vaccine site or other lesion containing vaccinia to or near the eye. These infections account for the majority of inadvertent inoculations (11) (Box 4). Infections can be clinically mild to severe and can lead to vision loss. When suspected, ocular vaccinia infections should be evaluated with a thorough eye examination, including use of a slit lamp. These cases should be managed in consultation with an ophthalmologist.

Diffuse Dermatologic Complications

Diffuse dermatologic complications include two groups. The first includes erythema multiforme minor and Stevens-Johnson syndrome, which are clinically defined elsewhere in the dermatologic literature (19,20), and other nonspecific postvaccination rashes with lesions that are thought to be free of vaccinia virus. For surveillance purposes, clinical diagnosis is adequate for case classification. The second group includes adverse reactions thought to be caused by replicating vaccinia virus recovered from skin lesions, which can be associated with risk for autoinoculation or contact transmission (21).

Generalized Vaccinia

GV is a disseminated vesicular or pustular rash and is usually benign and self-limited among immunocompetent hosts (Box 5). GV might be accompanied by fever and can produce skin lesions anywhere on the body. 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 (e.g., arm or leg). The skin lesions of GV are thought to contain virus spread by the hematogenous route. First-time vaccinees are at higher risk for GV than revaccinees (22). GV is often more severe among persons with underlying immunodeficiency who might have been inadvertently vaccinated; these patients might benefit from early intervention with VIG. GV should not be confused with multiple inadvertent inoculations that might occur in the presence of acute or chronic exfoliative, erosive, or blistering skin disease, including Darier's disease.* GV also should be differentiated from EV, which typically occurs in persons with a history of atopic dermatitis and is often associated with systemic illness.

Eczema Vaccinatum

Persons with a history of atopic dermatitis (i.e., eczema) are at highest risk for EV (Box 6). Onset of the characteristic lesions can occur concurrently or shortly after the occurrence of the reaction at the vaccination site. 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 (Jennerian 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, unvaccinated close contacts of vaccinees, and young children.

Early diagnosis of EV and administration of VIG is helpful to reduce associated morbidity and mortality. Two thirds of potential smallpox vaccinees failed to recall an exclusionary dermatologic condition such as atopic dermatitis (eczema) in themselves or their close contacts (23). Poor recall and inconsistent diagnosis of atopic dermatitis contributes to a challenging screening program to exclude persons at risk for EV (24). Therefore, when evaluating vaccinees or close contacts of recent vaccinees with a clinical presentation consistent with EV, despite a negative self-reported history of atopic dermatitis or Darier's disease, clinicians should consider EV and assess for treatment with VIG.

Progressive Vaccinia

PV is rare, severe, and often fatal and results when a vaccination site fails to heal and vaccinia virus replication persists. The skin surrounding the vaccination site becomes vaccinia infected, and secondary metastatic vaccinia lesions can occur (Box 7). Lesions can appear necrotic, fungated, piled-up, or well demarcated. Concomitant bacterial superinfection also can occur. PV typically occurs in persons with an underlying humoral or cellular immune deficit. Management of PV should include aggressive therapy with VIG or second line agent cidofovir, intensive monitoring, and tertiary-level supportive care (17).

Rare Reactions

Fetal Vaccinia

Rarely, smallpox vaccination of a pregnant woman can result in fetal vaccinia (Box 8). Transmission to the fetus can occur any time during pregnancy. The route of transmission is unknown but is presumed to be through viremia. Abortion, stillbirth, or live birth (usually premature followed by death) or birth of a surviving but pox-scarred infant can occur after the mother's exposure to vaccinia. Fetal or newborn skin lesions have been described as macular, papular, vesicular, pustular, or as scars or areas of epidermolysis (15).

Postvaccinial Central Nervous System Disease

Another rare adverse reaction is postvaccinial central nervous system (CNS) disease such as postvaccinial encephalitis (PVE) or encephalomyelitis (PVEM). CNS disease after smallpox vaccination is most common among infants aged <12 months (10) (Box 9). Clinical symptoms reflect cerebral or cerebellar dysfunction with headache, fever, vomiting, altered mental status, lethargy, seizures, and coma. CNS lesions have been reported in the cerebrum, medulla, and spinal cord. Both PVE and PVEM have been described (11,25). No clinical criteria, radiologic findings, or laboratory tests exist that are diagnostic for PVE or PVEM. Other infectious or toxic etiologies should be considered and ruled out; the diagnosis of PVE or PVEM after smallpox vaccination is a diagnosis of exclusion.

Cardiac

Myo/pericarditis

An adverse reaction previously reported but not well described is myo/pericarditis. During 1950--1970, both myocarditis and pericarditis were reported after smallpox vaccination in Europe and Australia, where the vaccinia strains used are considered more reactogenic than the New York City Board of Health (NYCBOH) vaccine used in the United States (26--28). In the United States, six cases were reported before the resumption of smallpox vaccination in late 2002 (29--34). Findings from the DHHS and DoD smallpox programs support a causal relation between smallpox vaccination with the NYCBOH strain and myo/pericarditis (35--38). Myo/pericarditis refers to inflammatory disease of the myocardium, pericardium, or both. The clinical presentation of inflammatory heart disease can include pain, dyspnea, and palpitations that range from subtle to severe. Results of specific cardiac diagnostic testing are variable. The case definition (Box 10) was designed to include the spectrum of abnormalities found in inflammatory heart disease (39).

Dilated Cardiomyopathy

An adverse event noted in temporal association to smallpox vaccination but not demonstrated to be linked etiologically to smallpox vaccination is dilated cardiomyopathy (DCM). DCM is a known sequelae of viral myocarditis and can present weeks to months after acute infection (40). Although DCM has not been reported in association with vaccinia vaccination, three DCM cases with symptom onset after smallpox vaccination were identified among DHHS vaccinees (12,41,42). The causal relation between smallpox vaccination and these cases of DCM is unclear. However, because vaccinia might induce myo/pericarditis and DCM is a rare but recognized outcome of viral myocarditis, an etiologic association between the occurrence of DCM after smallpox vaccination is biologically plausible. The case definition for DCM should be used for surveillance in the context of smallpox preparedness programs (Box 11).

Case Classification

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

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 (25). 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) (43), 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 (17). 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 (17). 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 (17).

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. Accurate classification of vaccinia adverse reactions is necessary for appropriate use of VIG and cidofovir for the treatment of select vaccinia reactions.

Conclusions

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 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-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.

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Date last reviewed: 1/19/2006