Communicable Disease Investigation Reference Manual

Overview^(1,2,3)

For a more complete description of vaccinia, adverse reactions refer to the following texts:

• Centers for Disease Control and Prevention. Smallpox Vaccination and Adverse Reactions, Guidance for Clinicians, MMWR Vol 52 / RR 4 February 21, 2003. http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5204a1.htm (4/05)
• Epidemiology and Prevention of Vaccine-Preventable Diseases 2004 ("The Pink Book"), Centers for Disease Control and Prevention (CDC). http://www.cdc.gov/nip/publications/pink/def_pink_full.htm (4/05)
• Fulginiti FA, et al. Smallpox vaccination: a review, part 2 - adverse events. Clinical Infectious Diseases 2003; 37:251-71. http://www.journals.uchicago.edu/CID/journal/issues/v37n2/30999/30999.h… (4/05)

For detailed information on normal reactions (including normal variants) following smallpox vaccination, see http://www.bt.cdc.gov/training/smallpoxvaccine/reactions/normal.html(4/….

See also the Missouri Department of Health and Senior Services (DHSS) Smallpox Vaccination website (4/05), and particularly the links contained in the “Adverse Reactions & Management” section.

The smallpox vaccine currently available in the United States is a live-virus preparation of infectious vaccinia virus prepared from calf lymph. Smallpox vaccine does not contain smallpox (variola) virus or cowpox virus. Vaccinia is in the same family as cowpox and variola, but is genetically distinct from both, and its exact origin is uncertain.

Epidemiologic studies demonstrated that a high level of protection (95%) against smallpox persists from 3 to 5 years after primary vaccination and substantial but waning immunity for ten years or more. Smallpox vaccine also provides protection if administered after an exposure to variola. The lowest secondary attack rates occurred in persons vaccinated less than 7 days after exposure. (NOTE: The optimal time for use of vaccination as a control measure for contacts is within 3 days of exposure. The Centers for Disease Control and Prevention [CDC] has stated that vaccination within 3 days of exposure will prevent or significantly lessen the severity of smallpox symptoms in the vast majority of people, and vaccination 4 to 7 days after exposure likely offers some protection from disease or may modify the severity of disease.).

Smallpox vaccine contains live vaccinia virus, which replicates at the site of vaccination. In addition to a lesion at the site of vaccination, vaccination can produce swelling and tenderness of axillary and other lymph nodes, beginning 3 - 10 days after vaccination and persisting for 2 - 4 weeks after the skin lesion has healed. Fever is less common among adults, than in children after vaccination or revaccination. Vaccinia virus is present at the site of vaccination beginning at the time of development of a papule (2 to 5 days after vaccination) and until the scab separates from the skin lesion. Maximum viral shedding from the vaccination site occurs 4 - 14 days after vaccination.

Following primary smallpox vaccination, the following normal reactions are expected to occur: day 0 vaccination; day 3-5 - papule; day 6-7 vesicle with surrounding erythema, vesicle with depressed center; day 8-11 well-formed pustule; day 12+ pustule crusts over, scab; day 17-21 scab detaches, leaving a permanent scar at the site. (With revaccination, the lesion can progress faster than after primary vaccination.) Response to vaccination is evaluated on post-vaccination day 6, 7, or 8.

Along with the expected reactions summarized in the previous paragraph, certain systemic signs/symptoms are normally expected to occur. They usually appear between 8 -10 days after vaccination when the vaccine site reaction reaches the peak of the inflammatory response. These normally expected reactions (not all of which will necessarily occur in an individual vaccinee) could include:

• Soreness and/or itching at the vaccination site
• Intense erythema ringing the vaccination site
• Malaise or fatigue
• Lymphadenopathy (local)
• Myalgia, headache, chills, nausea, fatigue
• Fever

In addition, certain variations of normal reactions may occasionally be seen (note that these are not considered adverse events). These normal variants can include:

• Local satellite lesions
• Lymphangitis
• Local edema (swelling)
• Robust take (intense inflammation surrounding the primary vaccination site lesion)

Serious complications from smallpox vaccination are rare, but occur greater than 10 times more often among primary vaccinees than among revaccinees and are more frequent among infants than among older children and adults. CDC has stated that there are some more minor complications that are not as rare (e.g. about 1 out of 10 vaccinees have a fever >1000 F and about 1 out of 10-20 vaccinees feel sick enough to miss work).

• In the past, about 1,000 people for every 1 million primary vaccinees experienced reactions that, while not life-threatening, were serious.
• In the past, between 14 and 52 people out of every 1 million primary vaccinees experienced potentially life-threatening reactions to the vaccine.
• Based on past experience, CDC has estimated that 1 or 2 people in 1 million who receive the vaccine may die as a result.

In certain groups of people, complications following smallpox vaccination can be severe, see CDC web document: People Who Should Not Get the Smallpox Vaccine (Unless They Are Exposed to Smallpox), http://www.bt.cdc.gov/agent/smallpox/vaccination/contraindicationspubli… (4/05). People most likely to have adverse reactions are those who have ever been diagnosed with skin conditions (especially eczema or atopic dermatitis) and those with weakened immune systems (e.g., persons who have received a transplant, are HIV positive, are receiving treatment for cancer, or are receiving medications that suppress their immune system). These individuals should not receive smallpox vaccine unless they have been exposed to smallpox. Other persons who should not be vaccinated (in the absence of exposure to smallpox) include those who have been told by a doctor that they have a heart condition, as well as those with certain cardiac risk factors, and pregnant and breast-feeding women. In addition, smallpox vaccine is not routinely recommended for anyone under 18 years of age or for older people.

Mild Adverse Reactions

Accidental Administration: Vaccine is accidentally ingested or inadvertently injected by the intramuscular or subcutaneous route.

Inadvertent Inoculation / (or Accidental Implantation): This has been the most frequent complication of smallpox vaccination. It can occur by autoinoculation, where vaccinia vaccine or pustular material containing vaccinia is inadvertently transferred to another part of the body of the person receiving the vaccination. Accidental implantation also results from the inadvertent transfer of vaccinia vaccine or pustular material to a close contact of the vaccinee (resulting in what was previously known as Contact Vaccinia). The resulting illness can range from mild to severe. If the eye is infected, serious sequelae are possible (see Vaccinia Keratitis, below).

Bacterial Infections / (Pyogenic infections of the vaccination site): This is uncommon in adults; onset is generally 5 days post vaccination. The most common organisms are Staphylococcus aureus and Group A Beta Hemolytic Streptococci. Anaerobic organisms occasionally infect the site. Impetiginous vesiculo-pustular lesions are seen in staphylococcal infection and piled-up eschar formation is common in streptococcal infections. Mixed infections may be encountered. No topical medications should be applied.

Erythema Multiforme: Toxic and/or hypersensitivity rashes that occur 1 - 2 weeks after vaccination. The rash varies from erythematous macular lesions, to vesicles, urticaria, pustules and typical bulls-eye lesions, all under the rubric”erythema multiforme”. The benign lesions do not progress. Itching may accompany the rash. The most serious reaction, Stevens- Johnson Syndrome (SJS) is rare. Diagnosis is by typical rash seen in temporal association with primary vaccination. The vesicles and pustules do not progress into typical vaccinations and can be distinguished on this basis.

Generalized Vaccinia: Within 6 – 9 days, lesions appear on any part of the body (most often on the trunk and abdomen, less commonly on the face, limbs, palms and soles). Lesions contain vaccinia and undergo rapid evolution to scarring and are usually self-limited. Rarely, lesions may recur at 4-6 week intervals for as long as one year. Differentiate from erythema multiforme, eczema vaccinatum, progressive vaccinia, severe chickenpox, and smallpox.

Robust take: Here there is intense inflammation surrounding the vaccination lesion. The reaction is greater than 7.5cm with swelling, warmth and pain at the vaccination site, non- progressive with improvement in 24 – 72 hours. Differentiate from bacterial infections / (pyogenic infections) of the vaccination site.

Tape adhesive reactions: Sharply demarcated raised lines of erythema that correspond to adhesive tape placement.

Severe Adverse Reactions

Congenital Vaccinia / (Fetal Vaccinia): The third trimester of pregnancy appears to be a critical time for the risk to the fetus of congenital vaccinia, although there have been cases in all trimesters of pregnancy. The affected infant is often premature. The lesions in the newborn infant may be typical of generalized vaccinia or may be progressive in nature. Lesions are often confluent and extensive. Death almost always occurs before birth or shortly thereafter.

Eczema Vaccinatum: Can occur following vaccination of individuals with a history of eczema or atopic dermatitis, or following transfer of vaccinia virus to such individuals by contact with a vaccinee whose lesion is in the florid stage (i.e., by inadvertent inoculation). Because most individuals have large contiguous patches of eczematous skin in the affected areas, confluent lesions are the rule (on the face and limbs primarily). High fever with risk for secondary bacterial or fungal infections is also seen. A high mortality rate is common.

Postvaccinial Encephalitis: Onset of headache, vomiting, drowsiness, and fever 10 - 14 days after vaccination. Confusion, ataxia, paralysis, seizures, or coma may be present.

Progressive Vaccinia: Progressive vaccinia is a rare complication occurring primarily in T- cell deficient persons. These include congenital T-cell deficient children, and individuals with diseases (e.g., cancer, HIV/AIDS) or receiving treatments (e.g., immunosuppressive therapy) that result in T-cell deficiencies. The primary vaccination site fails to heal and may expand with painless progressive central necrosis at the site. Viremia may spread the vaccinia to other parts of the body; each new lesion spreads without inflammatory response. Complications include septic shock, disseminated intravascular coagulation, and superimposed microbial infections.

Vaccinia Keratitis / (Ocular Vaccinia): Inadvertent periocular or ocular inoculation with vaccinia virus following manipulation of the vaccination site. Keratitis results initially in viral replication with ulceration and ultimately in an antigen-antibody interaction leading to corneal cloudiness. Conjunctivitis and blepharitis can also occur.

Case Definition⁽³⁾

Clinical description

See Centers for Disease Control and Prevention. Smallpox Vaccination and Adverse Reactions, Smallpox Vaccination and Adverse Reactions, MMWR Vol 52 / RR 4 February 21, 2003.

Laboratory criteria:

Viral cultures are needed for suspected vaccinia, adverse reactions. Although for some adverse reactions, such as erythema multiforme, such cultures will not provide positive information because no virus will be present in the lesions, and thus cultures may not be indicated as part of the diagnostic assessment. The State Public Health Laboratory (SPHL) can perform this test. Additional virologic studies may be required to rule out other viral infections with rash, especially chickenpox, herpes simplex, adenovirus, and enterovirus as well as smallpox. The State Public Health Laboratory can perform most of these tests. At this time only CDC can perform testing for smallpox.

Information Needed for Investigation

Verify the diagnosis / Determine the source of infection to prevent other cases. Has the individual, or a close contact, recently received a smallpox vaccination? What laboratory tests were conducted and what were the results?

Establish the extent of illness. Does the case know anyone with similar symptoms? Does the case or a member of the case's household attend school, a childcare center or nursery school? Does the case or a member of the case's household work as a healthcare provider?

Vaccination History. Obtain date(s) of smallpox and varicella vaccination(s). What clinic(s) gave the vaccination(s)? What is the patient’s smallpox vaccination number (PVN)? Determine if vaccinee or contact(s) of vaccinee is pregnant. If so, notify the Department of Health and Senior Services immediately at (800-392-0272).

Notification and Control Measures:

• Contact the Senior Epidemiology Specialist for the Region if a vaccinia adverse reaction is identified or suspected. If possible (and appropriate), obtain written consent (form attached) for digital photographs to be taken of the adverse reaction. The digital photographs should be submitted with the Vaccine Adverse Event Reporting System (VAERS) form to DHSS.
• Contact the Bureau of Child Care (573-751-2450) if cases are associated with a childcare facility.
• Contact the Section for Long-term Care Regulation (573-526-0721) if cases are associated with a long-term care facility.
• Contact the Bureau of Health Facility Regulation (573-751- 6303) if cases are associated with a hospital or hospital-based long-term care facility.

Control Measures

General:

• The most important measure to prevent “Inadvertent Inoculation” from occurring is thorough handwashing with soap and water after changing the bandage or after any other contact with the vaccination site, site drainage and/or scab.
• Children who have acquired vaccinia through “Inadvertent Inoculation” should be excluded from school or daycare until the lesions are healed.
• Health care workers with adverse reaction should not care for patients until the adverse reaction has resolved. Unless, for example, the vaccinated health care worker develops a tape adhesive reaction, or a robust take, and the area(s) can still be sufficiently covered with an appropriate dressing.
• Isolation procedures are standard and contact precautions for individuals with adverse events requiring hospitalization. The smallpox vaccine does not cause smallpox.

Laboratory Procedure

Specimens: The top of the vesicle or pustule and the base of the vesicle or pustule can be tested for adenovirus, herpes simplex virus, enterovirus, varicella zoster, and vaccinia. Specimen collection and shipping containers are located in the Regional Offices, or may be obtained from the SPHL at (573) 751-0633.

In most instances, differentiation of an adverse event after vaccination from other infectious or non-infectious diseases must be accomplished. In such cases, the appropriate diagnostic tests for the alternative diseases, such as chickenpox, should be employed simultaneously with tests for vaccinia virus.

Bacterial testing of the site may be needed to differentiate between Bacterial Infections / (Pyogenic Infections of vaccination site) and Robust Take.

Reporting Requirements

Vaccinia adverse reactions are a Category I disease and shall be reported to the local health authority or to the Missouri Department of Health and Senior Services (DHSS) within 24 hours of first knowledge or suspicion by telephone, facsimile or other rapid communication. DHSS may be contacted 24 hours a day, 7 days a week at (800) 392-0272.

1. For all cases, complete a “Disease Case Report” (CD-1), VAERS form, and Smallpox Vaccine Adverse Event Follow-Up Form (Annex 4).
2. Entry of the complete CD-1 into the MOHSIS database negates the need for the paper CD-1 to be forwarded to the Regional Health Office.
3. Send the completed secondary investigation form(s) to the Regional Health Office.
4. All outbreaks or “suspected” outbreaks must be reported as soon as possible (by phone, fax or e-mail) to the Regional Communicable Disease Coordinator. This can be accomplished by completing the Missouri Outbreak Surveillance Report (CD-51).
5. Within 90 days from the conclusion of an outbreak, submit the final outbreak report to the Regional Communicable Disease Coordinator.

References

1. USAMRIID, Medical Management of Biological Casualties Handbook (5th ed.), August 2004. http://www.usamriid.army.mil/education/bluebook.htm (4/05)
2. Center for Disease Control and Prevention. Epidemiology and Prevention of Vaccine-Preventable Diseases. “Smallpox”, Atkinson W, Hamborsky J, Wolfe S, eds. 8th ed. Washington DC: Public Health Foundation, 2004: 257 – 279. www.cdc.gov/nip/publications/pink/smallpox.pdf (4/05)
3. Centers for Disease Control and Prevention. Smallpox Vaccination and Adverse Reactions, Guidance for Clinicians, MMWR Vol 52 / RR 4 February 21, 2003. http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5204a1.htm (4/05)

Web Sites

1. DHSS. Smallpox Vaccination Website (4/05)
2. CDC’s Smallpox Vaccination and Adverse Events Training Module
   http://www.bt.cdc.gov/training/smallpoxvaccine/reactions/sitemap.htm (4/05)
3. USAMRIID's Medical Management of Biological Casualties Handbook
   http://www.usamriid.army.mil/education/bluebook.htm (4/05)
4. Centers for Disease Control and Prevention Smallpox Website
   http://www.bt.cdc.gov/agent/smallpox/index.asp (4/05)
5. Center for Infectious Disease Research & Policy. Smallpox Website
   http://www1.umn.edu/cidrap/content/bt/smallpox (4/05)
6. Department of Health and Human Services Smallpox Website
   http://www.hhs.gov/smallpox (4/05)
7. Centers for Disease Control and Prevention. Smallpox Vaccination and Adverse Reactions, Guidance for Clinicians, MMWR Vol 52 / RR 4 February 21, 2003.
   http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5204a1.htm(4/05) 
8. Vaccine Adverse-Events Reporting (Annex 4)
   http://www.bt.cdc.gov/agent/smallpox/response-plan/files/annex-4.pdf (4/05)