# Presentation: 740680

## Large Vaccination Reactions and Robust TakesBacterial Superinfection of Site

**Notes:**
Bacterial infection of the vaccination site is uncommon and affects children more often than adults, as children are more likely to touch and contaminate their vaccination sites.  In a 1963 US National survey, 433 complications were reported among 14 million smallpox vaccinees; of these 2 were secondary bacterial infections of the vaccination site.   One case resolved without sequelae, while the other resulted in a nonfatal case of acute streptococcal glomerulonephritis.  Other reports describe the occurrence of bacterial superinfection at the vaccination site, but do not provide details regarding the causative organism(s).

Aerobic, anaerobic, and mixed infections can occur.  Impetiginous vesicles and pustules may be seen in staphylococcal infections, and eschar formation may occur with streptococcal infections.  Specimens for bacterial cultures can be obtained using swabs or aspiration.  Gram stains may represent normal skin flora, but could be useful when unusual pathogens are present.  If empiric antibacterial therapy is given, therapy may be adjusted once the bacterial pathogen and its sensitivities are known.
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References
[i] Neff JM, ,Lane JM, Pert JH, Moore R, Millar JD, Henderson DA. Complications of Smallpox Vaccination I. National Survey in the United States, 1963. NEJM 1967 276:125-132.												
Annotation:  In contrast, note the impetignous changes associated with the uncommon bacterial superinfection of the vaccination site.
Source:  J. Michael Lane, Teaching Slide set

## Robust TakesDefinition

- Area of redness greater than 3 inches
- Swelling
- Warmth
- Pain at Vaccination Site

**Notes:**
It can be difficult to differentiate a large vaccination site reaction, also called robust take (RT), from bacterial cellulitis.  In winter 2001, CDC vaccinated 191 federal public health smallpox response team members.  Nine vaccinees (5%) met the case definition for a robust take, with an area of redness greater than 3 inches in diameter, and swelling, warmth, and pain at the vaccination site ([i]).  Six affected vaccinees were treated for a suspected bacterial cellulitis.  Three affected vaccinees did not seek medical care and therefore did not receive antibiotic therapy.  All affected vaccinees reported peak of symptoms 8-10 days following vaccination and improvement of symptoms within 24-72 hours whether or not they were treated with antibiotics.  Cases did not cluster by age, gender, vaccination status, or vaccine lot number.
==========================Reference:
[i] CDC EIS abstract; unpub manuscript.

## Robust TakesDifferentiation

- Robust Take
- Onset 8-10 days post-vaccination
- Clinical improvement within 72 hours
- Lack of clinical progression
- Secondary Bacterial Infection
- Onset within 5 days post-vaccination, OR
- Greater than 30 days post-vaccination

**Notes:**
Robust takes are distinguished from the inflammation associated with bacterial infections by an interval of onset of 8-10 days post vaccination, clinical improvement within 72 hours of peak of symptoms, and lack of clinical progression. Therefore, interval onset from time of vaccination until peak of symptoms is the most important distinguishing feature of RT.  Secondary bacterial infections, such as pyogenic abcesses have been reported following the administration of other vaccines.  Secondary bacterial infection typically occurs within 5 days of vaccination or greater than 30 days post-vaccination ([i], [ii], [iii]).   Fever is a less helpful clinical indicator since it is an expected immunological response to vaccinia vaccination.  
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References:
[i] Greaves WL, Hinman AR, Facklam RR, Allman KC, et al. Streptococcal abscesses following diphtheria-tetanus toxoid-pertussis vaccination. Pediatr Infect Dis.
 1982;1:388-390.
[ii] Simon PA, Chen RT, Elliott JA, Schwartz B. Outbreak of pyogenic abscesses after diphtheria and tetanus toxoids and pertussis vaccination. Pediatr Infect Dis J. 1993;12: 368-371.
[iii] Stetler HC, Garbe PL, Dwyer DM, Facklam RR, et al. Outbreaks of Group A Streptococcal abscessed following Diphtheria-Tetanus Toxoid-Pertussis vaccination. Pediatrics. 1985;75:299-303.

## Robust TakesClinical Management

- Vigilant observation
- Patient Education
- Supportive care
- Rest of affected limb
- Oral, non-steroidal anti-inflammatory medications
- Oral anti-pruritic agents
- Do NOT apply salves, creams or ointments to vaccination site

**Notes:**
When a robust take is suspected, management includes vigilant observation, patient education, and supportive care that includes rest of the affected limb, use of oral non-steroidal anti-inflammatory medications, as well as oral anti-pruritic agents.  Salves, creams or ointments, especially topical steroids or antibiotics, should not be applied to the vaccination site.   
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References:[i] Greaves WL, Hinman AR, Facklam RR, Allman KC, et al. Streptococcal abscesses following diphtheria-tetanus toxoid-pertussis vaccination. Pediatr Infect Dis. 1982;1:388-390.
[ii] Simon PA, Chen RT, Elliott JA, Schwartz B. Outbreak of pyogenic abscesses after diphtheria and tetanus toxoids and pertussis vaccination. Pediatr Infect Dis J. 1993;12: 368-371.
[iii] Stetler HC, Garbe PL, Dwyer DM, Facklam RR, et al. Outbreaks of Group A Streptococcal abscessed following Diphtheria-Tetanus Toxoid-Pertussis vaccination. Pediatrics. 1985;75:299-303.

## Vaccinia Specific Adverse Events

**Notes:**
Vaccinia can be transmitted from a vaccinee’s unhealed vaccination site to other persons by close contact and can lead to the same adverse events as vaccination.  

## Vaccinia Adverse Events

- Contact Transmission Cases
- Eczema vaccinatum
- Inadvertent inoculation
- 5-19 days after suspected exposure
- Rate of 2 to 6 per 100,000 first-time vaccinations

**Notes:**
A recent article, summarizing all previous reports of secondary transmission, notes that cases arising from contact transmission resulted in either eczema vaccinatum or inadvertent inoculation.  These cases occurred approximately 5-19 days after suspected exposure with the index case(s).  There were no reports of secondary transmission of progressive vaccinia or post-vaccinial encephalopathy and encephalomyelitis in this case series or other literature that is deemed reliable.

The author suggests that vaccinia transmission may occur by aerosolization, but no data exists to support this hypothesis.  Although one study reported successful recovery of the vaccinia virus from the oropharynx of a minority of childhood vaccinees receiving European vaccine strains, droplet infection has not been epidemiologically implicated in transmission of vaccinia.  An unpublished study from the 1960s was unable to recover the NYCBOH vaccinia strain from the nasal swabs of healthy vaccinees.

The overall transmission of contact vaccinia in the 1960s occurred in the range of 2 to 6 per 100,000 first-time vaccinations (5) Infection control precautions should be taken to reduce this likelihood.  
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References:[i] Sepkowitz K.  Current Concepts:  How contagious is vaccinia?  NEJM 2003; 348(5):need pages – this was the web prerelease version
[ii] Gurvich EB, Braginskaya VP, Shenkman LS, Sokolova AF, Davydova AV.  Isolation of vaccinia virus from the pharynx of children vaccinated against smallpox.  Journal of Hygiene, Epidemiology, Microbiology and Immunology 1974; 18(1):69-78. 
[iii] J. Michael Lane, personal communication, 2002.

## Prevention of Contact Transmission

- Proper hand-hygiene
- Healthcare Setting
- Cover with gauze
- Cover gauze with semi-permeable dressing
- Until scab separates
- Non-Healthcare Setting
- Cover with gauze
- Wear sleeve over site

**Notes:**
The most critical measure in preventing inadvertent inoculation and contact transmission is proper hand-hygiene after changing bandages, or after any other contact with the vaccination site.  In contrast to the historical recommendation that the vaccination site be left uncovered, the Advisory Committee on Immunization Practices  (ACIP) recommends that to prevent nosocomial transmission, health-care workers involved in direct patient care should keep their vaccination sites covered with gauze or a similar absorbent material in order to absorb exudates that contain vaccinia.  This dressing should, in turn, be covered with a semi-permeable dressing to provide a barrier to vaccinia virus. Use of a semi-permeable dressing alone is not recommended because it may cause maceration of the vaccination site and increased prolonged irritation and itching at the site, which subsequently leads to increased touching, scratching, and contamination of the hands.   The vaccination site should be covered during direct patient care until the scab separates. 

Transmission of vaccinia is also possible in other settings when close personal contact with children or other persons occurs.  In these situations, the vaccination site should be covered with gauze or a similar absorbent material, and long-sleeved clothing should be worn, with careful attention to hand washing.  Hand washing should be done with soapy warm water or 60% based alcoholic hand rub solutions.  Historically, the home was the setting where most contact transmission occurred, presumably due to intimate contact and relaxed infection control measures.

If maceration of the vaccination site occurs, the lesion should be left open to air to allow the vaccination site to dry during a period when there will be no direct contact with patients or other persons.  Administrative leave should be considered for health care workers who are unable to adhere to the recommended infection control measures, which require that vaccination sites be covered during patient care duties. 
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Reference:
[i] World Health Organization: Smallpox Eradication: Report of a WHO Scientific Group. Geneva: WHO Techn. Rep. No. 393, 1968, pp. 30-31.

## Adverse Events Associated with Smallpox Vaccine

- Inadvertent inoculation
- Ocular vaccinia
- Generalized vaccinia
- Eczema vaccinatum
- Progressive vaccinia
- Post-vaccinial Encephalopathy
- Encephalomyelitis
- Fetal Vaccinia

**Notes:**
Adverse events associated with smallpox vaccination range from mild and self-limited to severe and life threatening.  Smallpox vaccination may be associated with adverse events common to other vaccines such as high fever, anaphylaxis, and erythema multiforme.  Adverse events unique to smallpox vaccination include inadvertent inoculation, ocular vaccinia, generalized vaccinia, eczema vaccinatum, progressive vaccinia, post-vaccinial encephalopathy and encephalomyelitis, and fetal vaccinia. Vaccinia–specific complications may occur in vaccinees or their contacts that have been inadvertently inoculated with vaccinia.   
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References:[i] Neff JM, Levine RH, Lane JM, Ager EA, et al. Complications of smallpox vaccination. United States 1963. Results obtained by four statewide surveys. Pediatrics. 1967;39:916-923.
[ii] Lane JM, Ruben FL, Abrutyn, Miller JD.  Deaths attributable to smallpox vaccination, 1959 to 1966 and 1968.  JAMA 1970:212.
[iii] CDC. Contact spread of vaccinia from a recently vaccinated Marine-Louisiana. MMWR 1984; 33:37-38.
[iv] CDC. Contact spread of vaccinia from a National Guard vaccinee-Wisconsin. MMWR 1985; 34:182-183.
[v] CDC. Vaccinia outbreak-Newfoundland. MMWR 1981; 30:453-455.

## Pregnant Women
Eczema or Atopic Dermatitis
Immunosuppression
Skin Conditions (burns, herpes, shingles, etc.)
Allergic to vaccine components

- Eczema or Atopic Dermatitis
- Immunosuppression
- Skin Conditions (burns, herpes, shingles, etc.)
- Allergic to vaccine components

**Contraindications to Smallpox Vaccine**

**Notes:**
Information presented in this report is primarily based upon reports from the 1960s.  Although the vaccine remains unchanged, supportive care and therapeutic care options have improved.  The US population has also changed, and now has a higher proportion of persons with contraindications to smallpox vaccination that are at risk for adverse events.  This group includes:  pregnant women (or those who desire to become pregnant in the 4 weeks following vaccination), persons with atopic dermatitis (commonly referred to as eczema), or persons who are immunocompromised due to cancer, radiation, autoimmune conditions, or immunomodulating therapies.  Updated reports on the current frequency of adverse events will be issued as data become available 

These guidelines for evaluation and treatment of patients with complications from smallpox vaccination are provided in the absence of circulating smallpox virus.  In the event smallpox is reintroduced, smallpox vaccine should be administered prophylactically to exposed persons to lessen their risk of contracting smallpox.  Should these persons develop a macular and/or papular eruption following vaccination, it will be necessary to determine whether the rash is early smallpox disease, or an adverse reaction to vaccinia vaccine.  Such patients should be presumed to be highly infectious and be placed in contact and respiratory isolation immediately until a diagnosis is made.  Appropriate local, state, federal health and security officials should be contacted. 

## Treatments for Adverse Events

- VIG
- Cidofovir
- Ophthalmic antivirals

**Notes:**
Treatments available for specific complications of smallpox vaccination include VIG, cidofovir, and ophthalmic antivirals.  Vaccinia immune globulin has been used since the 1960’s to treat vaccinia-related adverse events, and therefore is the first therapeutic of choice.  It is available in intravenous and intramuscular preparations under IND through the CDC.  Cidofovir is a nephrotoxic, carcinogenic, anti-viral medication licensed for the treatment of cytomegalovirus retinitis in patients with Acquired Immunodeficiency Syndrome (AIDS).  Cidofovir has never been used to treat vaccinia infections in humans, but has shown promise in animal models.  It is available under IND from the CDC as a second-line treatment for vaccinia complications.

We will discuss these treatments more, later.
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References: [i] De Clercq E. Cidofovir in the treatment of poxvirus infections.  Antiviral Research 2002; 55(1-13).

## Rates of Adverse Events1968

|  | National Survey |  | Ten-State Survey |  |
| --- | --- | --- | --- | --- |
|  | All primary vaccinees | Vaccines 1 yr old | All primary vaccines | Vaccinees 1 yr old |
| Serious, but not life-threatening |  |  |  |  |
| Inadvertent Inoculation | 25.4 | 27.1 | 529.2 | 532.0 |
| Generalized Vaccinia | 23.4 | 17.7 | 241.5 | 222.8 |
| Erythema Multiforme | NA | NA | 164.6 | 131.3 |
| Total | 48.8 |  | 935.3 |  |
| Life-threatening reactions |  |  |  |  |
| Postvaccinial Encephalitis/
Encephalomyelitis | 2.9 | 2.4 | 12.3 | 8.6 |
| Progressive Vaccinia | 0.9 | 1.0 | 1.5 | 1.7 |
| Eczema Vaccinatum | 10.4 | 10.6 | 38.5 | 41.5 |
| Total | 14.2 |  | 52.3 |  |
| Deaths | 1.1 | 0.6 | 1.5 | None |

## Rates of Adverse EventsToday

- May be higher today
- More persons at risk from immune suppression
- Cancer
- Cancer therapy
- Radiation
- Organ Transplantation
- HIV/AIDS
- Eczema or Atopic Dermatitis

**Notes:**
Adverse event rates in the United States today may be higher than those previously reported because there are currently more persons at risk from immune suppression due to cancer, cancer therapy, radiation, immunomodulating medications, organ transplantation and other illnesses, such as human immunodeficiency virus (HIV) or AIDS, and eczema or atopic dermatitis. The outcomes associated with adverse events may be better than previously reported because of advances in medical care. Rates for all adverse events may be lower for persons previously vaccinated, who may have some residual immunity.  There are estimations that approximately two-thirds of complications following smallpox vaccination were theoretically preventable and could have been avoided with better screening.  Therefore, rates may be lower today than in the 1960s because more stringent screening and infection control measures will be used.  
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Reference:
[i] Haim M, Gdalevich M, Mimouni D, Ashkenazi I, Shemer J. Adverse Reactions to Smallpox Vaccine: The Israel Defense Force Experience, 1991 to 1996. A Comparison with Previous Surveys. Military Medicine 2000; 165(4):287-289.

## Local Skin ReactionsIrritation from Adhesive Dressing

**Notes:**
Local skin reactions may occur following smallpox vaccination.  These include allergic reactions to bandage and tape adhesives, large vaccination reactions, sometimes referred to as robust takes (RT), and less commonly, bacterial infections of the vaccination site.  
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Annotation:  Erythema due to irritation from adhesive dressing:  post vaccination Day 7 in vaccinia naïve volunteer.  Patient 1.
Source:  “Vaccination reactions in vaccinia-naïve volunteers in a clinical study of diluted Dryvax smallpox vaccine enrolled at the NIAID-supported Vaccine Treatment and Evaluation Units at Saint Louise University, University of Maryland and University of Rochester and the Respiratory Pathogens Unit at Baylor College of Medicine in 2001.”

## Local Skin ReactionsIrritation from Adhesive Dressing

**Notes:**
Reactions to adhesives usually result in sharply demarcated lines of erythema that correspond to the placement of adhesive tape.  Patients have local pruritis but no systemic symptoms and are otherwise well.  Treatment includes oral nonsteroidal anti-inflammatory (NSAIDS) agents and oral antipruritic agents.  Frequent bandage changes, bandage holiday (leaving the vaccination site open to air) or a change to paper tape may alleviate symptoms. Care should be used to vary the positioning of tape or bandages.  This condition is self-limited and resolves when bandages are no longer needed.  Topical and oral steroid treatment for this reaction should be avoided since the site contains live vaccinia virus.  Salves or ointments, including topical antibiotics, should not be applied to the vaccination site.   
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Annotation:  Erythema due to irritation from adhesive dressing:  post vaccination Day 7 in vaccinia naïve volunteer.  Patient 2.
Source:  “Vaccination reactions in vaccinia-naïve volunteers in a clinical study of diluted Dryvax smallpox vaccine enrolled at the NIAID-supported Vaccine Treatment and Evaluation Units at Saint Louise University, University of Maryland and University of Rochester and the Respiratory Pathogens Unit at Baylor College of Medicine in 2001.”

## Local Skin ReactionsSecondary Reaction to Adhesive Dressing

**Notes:**
Note how the lesions in this picture correspond to the edge of the adhesive dressing.  No vaccinia virus was detected in these lesions.  Thus the lesions appear to be a secondary reaction to the dressing.
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Annotation:  Note the vesicle at the edge of the adhesive dressing.  Viral culture did not detect the presence of vaccinia virus and the lesions did not progress to a pustular stage.  These lesions appear to be a secondary reaction to the dressing.
Source:  “Vaccination reactions in vaccinia-naïve volunteers in a clinical study of diluted Dryvax smallpox vaccine enrolled at the NIAID-supported Vaccine Treatment and Evaluation Units at Saint Louise University, University of Maryland and University of Rochester and the Respiratory Pathogens Unit at Baylor College of Medicine in 2001.”

## Non-Specific RashesErythematous Patches

**Notes:**
Common nonspecific rashes associated with smallpox vaccination include nonspecific fine reticular maculopapular rashes, lymphangitic streaking, generalized urticaria, and broad, flat, roseola-like erythematous macules and patches.  Erythematous or urticarial rashes may occur approximately 10 days (range 4-17 days) after first-time vaccination. The vaccinee is usually afebrile, and the rash resolves spontaneously within 2 to 4 days.  In general, nonspecific rashes are self-limited.  These individuals appear well and benefit from simple supportive care measures such as oral NSAIDS and oral anti-pruritic agents.
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Annotation:  Examples of non-specific rashes.  This is a 14-month-old infant with a vaccination site on the small of his back.  He has extensive erythematous patches over his entire body except for relative sparing of the soles of the feet.
Source:  J. Michael Lane, Teaching Slide set.  J.M. Lane, M.D.

## Non-Specific RashesMaculopapular Rash

**Notes:**
Here is another example of a non-specific rash in a first-time vaccinee.
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Annotation:  Non-Specific Rashes.  Note the nonspecific maculopapular rash in a first-time vaccinee.
Source:  “Vaccination reactions in vaccinia-naïve volunteers in a clinical study of diluted Dryvax smallpox vaccine enrolled at the NIAID-supported Vaccine Treatment and Evaluation Units at Saint Louise University, University of Maryland and University of Rochester and the Respiratory Pathogens Unit at Baylor College of Medicine in 2001.”