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Eczema Vaccinatum (smallpox vaccine)
- Vaccinia virus (smallpox vaccine)
- Eczema vaccinatum (EV) pathophysiology: autoinoculation from hosts vaccination site or from close contact w/ implantation in eczema site or healed lesion.
- Work in murine model suggests that NK cells are present in lower numbers; inhibition of IL-17 allowed the development of severe skin lesions.
- Source in half of cases in 1960s was a household contact.
- Most common sites: face, flexor surfaces.
- Lesions look like vaccination site but confluent + systemic illness +/- bacterial superinfection.
- See CDC training module for photos and recommendations.
- Ddx: smallpox, generalized vaccinia (no eczema), chickenpox, herpes viruses, Kaposi varicelliform eruption (due to HSV, enteroviruses in those with preexisting dermatosis), erythema multiforme.
- DX: multiple vaccinia skin lesions outside vaccination site + exposure to vaccinia + current eczema or hx of eczema.
- Eczema vaccinatum appears like the vaccination site, but confluent and with systemic illness.
- Eczema and atopic dermatitis are interchangeable terms.
- Relevance: most common contraindication to smallpox vaccination.
- Risk applies to vaccine candidate AND any household contacts with active eczema or eczema hx.
- Eczema pathophysiology: T cell immune defect + atopy with high IgE (85%).
- Prevalence: 6-22% of general population has eczema or prior hx; many more misdiagnosed.
- Eczema dx in this context: clinical (history and exam) rather than lab-based diagnosis. Skin biopsies rarely pursued. High IgE levels or eosinophilia may be seen.
- Pruritis (dominant symptom)
- Dermatitis - flexor surfaces
- Dermatitis is chronic or recurrent
- Family hx atopy
- Onset by age 7
- Skin changes:
- Children: pruritic, red patches + scaling; face, scalp, extremities, trunk may be involved.
- Adults: lichenification of flexor surfaces.
- Recommended screening test questions (ACIP recommendation):
- Have you or family member
- Ever had eczema/atopic dermatitis dx?
- A itchy, red, scaly rash lasting over 2 wks?
- Have you or family member
- Vaccinia immune globulin (VIG): only available from CDC but considered experimental, so needs IND protocol: T (404) 639-3356
- EV is clear indication for urgent use. Early treatment may be life-saving.
- Dose: 0.6-1.0 mL/kg IM = 40ml IM
- Severe/extensive lesions: up to 5-10 mL/kg in divided doses over several days has been used.
- Currently only available as IM. Intravenous preparation may be available in the future.
- Bacterial superinfections: common and should be treated to cover anticipated pathogens such as streptococci, staphylococci or Gram negatives.
- Septic shock may complicate. Usual supportive care recommended.
- Note: severe case of contact eczema vaccinatum reported in 2008. Child treated with vaccinia IVIG, cidofovir, ST-246 [oral, experimental anti-pox compound] and skin grafts.
- Eczema is most common contraindication to vaccine and was most common cause of vaccine mortality in 1960s.
- Best prevention of EV: careful history to assess for current or prior hx of eczema/atopic dermatitis.
- VIG is brutal due to large IM volume; IV form is in production
- GREATEST RISKS: age < 1yr, active eczema, primary vaccination.
Basis for recommendation
- CDC. Smallpox vaccine and Adverse Events Training Module. http://emergency.cdc.gov/training/smallpoxvaccine/reactions/default.htm (accessed 5/26/16)
Comment: Helpful images and directions regarding immunization with vaccinia (currently ACAM2000) regarding diagnosis and managment. Many photos.
- Said MA, Haile C, Palabindala V, et al. Transmission of vaccinia virus, possibly through sexual contact, to a woman at high risk for adverse complications. Mil Med. 2013;178(12):e1375-8. [PMID:24306023]
Comment: Report of EV in a non-vaccinee who had atopic dermatitis and likely acquired from a sexual encounter with a recently immunized military person.
- Kawakami Y, Tomimori Y, Yumoto K, et al. Inhibition of NK cell activity by IL-17 allows vaccinia virus to induce severe skin lesions in a mouse model of eczema vaccinatum. J Exp Med. 2009;206(6):1219-25. [PMID:19468065]
Comment: In this murine model, blocking IL-17 appeared to replicate severe skin lesions which these authors say implicates a role for NK cells in the pathogenesis potentially in humans with atopy, etc.
- Vora S, Damon I, Fulginiti V, et al. Severe eczema vaccinatum in a household contact of a smallpox vaccinee. Clin Infect Dis. 2008;46(10):1555-61. [PMID:18419490]
Comment: Severe case of eczema vaccinatum in child of vaccinated Iraq soldier on leave after smallpox vaccination. Child had eczema and was critically but survived with vaccinia IG, cidofovir, ST-246 and skin grafts.
- Reif DM, McKinney BA, Motsinger AA, et al. Genetic basis for adverse events after smallpox vaccination. J Infect Dis. 2008;198(1):16-22. [PMID:18454680]
Comment: Genotyping of patients with severe reactions to smallpox vaccination showed single nucleotide polymorphisms in the interferon regulatory factor-1 gene in those with severe reactions.
- Greenberg RN, Kennedy JS. ACAM2000: a newly licensed cell culture-based live vaccinia smallpox vaccine. Expert Opin Investig Drugs. 2008;17(4):555-64. [PMID:18363519]
Comment: Review of ACAM 2000 which was FDA approved as a suitable replacement for Dryvax in the event of bioterrorism in 2007.
- Centers for Disease Control and Prevention (CDC). Secondary and tertiary transfer of vaccinia virus among U.S. military personnel--United States and worldwide, 2002-2004. MMWR Morb Mortal Wkly Rep. 2004;53(5):103-5. [PMID:14961003]
Comment: Among 407,923 there were 30 reported cases of contact vaccinia. Most were "bed partners" - 12 spouses and 8 adult friends. There were no transmissions to health care workers or pts. The rate with primary vaccinees was 7.4/100,000 and for secondary vaccinees it was 5.2/100,000 (this may be underreporting, but the data may be better in the military population and the paucity of children compared to prior experience is striking).
- Naleway AL, Belongia EA, Greenlee RT, et al. Eczematous skin disease and recall of past diagnoses: implications for smallpox vaccination. Ann Intern Med. 2003;139(1):1-7. [PMID:12834312]
Comment: The frequency of atopic dermatitis is 0.8% involving 2.3% of households. History will miss 30-40%.
- Engler RJ, Kenner J, Leung DY. Smallpox vaccination: Risk considerations for patients with atopic dermatitis. J Allergy Clin Immunol. 2002;110(3):357-65. [PMID:12209080]
Comment: Authors review and emphasize the need to exclude patients with active or quiescent atopic dermatitis.
- Neff JM, Lane JM, Fulginiti VA, et al. Contact vaccinia--transmission of vaccinia from smallpox vaccination. JAMA. 2002;288(15):1901-5. [PMID:12377090]
Comment: Review of contact vaccinia, which is transmission of this virus to others. Risk is close contact nearly always household contact, occasionally in hospitals. Frequency from 1960's was 20-60/mil vaccinees. Disease in recipient depends on host-the greatest risks are vaccinia necrosum in persons w/T cell, cell defects & eczema. Vaccination in persons w/eczema was a major risk. This accounted for most vaccine associated deaths and most uses of VIG. Greatest risks were young age & primary vaccination. The risk of EV is thought to be substantially increased due to increased rate of atopic dermatitis.
- Smee DF, Bailey KW, Sidwell RW. Treatment of lethal cowpox virus respiratory infections in mice with 2-amino-7-[(1,3-dihydroxy-2-propoxy)methyl]purine and its orally active diacetate ester prodrug. Antiviral Res. 2002;54(2):113-20. [PMID:12062396]
Comment: The authors tested this acyclic purine nucleoside and its orally active diacetate ester prodrug for activity in vitro and in vivo vs. cowpox. Both drugs were active, but less active than cidofovir. The enthusiasm for HOE961 is the fact that, despite the reduced in vivo activity, it is orally absorbed.
- De Clercq E. Cidofovir in the treatment of poxvirus infections. Antiviral Res. 2002;55(1):1-13. [PMID:12076747]
Comment: Cidofovir is active in vitro vs. vaccinia and all other poxviruses. Clinical data are limited to case reports of treatment of molluscum contagiosum and orf.
- Breman JG, Henderson DA. Diagnosis and management of smallpox. N Engl J Med. 2002;346(17):1300-8. [PMID:11923491]
Comment: Review of the disease. Last case was 1977; last in U.S. was 1949. SP vaccination stopped in US in 1971 so few (<30yrs have been vaccinated). Vaccine is highly effective for 5-10yrs. Disease is acquired by inhalation. Contagious primarily at rash stage or about 3wks.
- Smee DF, Bailey KW, Sidwell RW. Treatment of lethal vaccinia virus respiratory infections in mice with cidofovir. Antivir Chem Chemother. 2001;12(1):71-6. [PMID:11437324]
Comment: Mice were challenged with cowpox and treated with cidofovir that was 100% effective at 30mg/kg/d.
- Laughter D, Istvan JA, Tofte SJ, et al. The prevalence of atopic dermatitis in Oregon schoolchildren. J Am Acad Dermatol. 2000;43(4):649-55. [PMID:11004621]
Comment: This study showed a prevalence of atopic dermatitis to be 7-17%.
- Nettleton PF, Gilray JA, Reid HW, et al. Parapoxviruses are strongly inhibited in vitro by cidofovir. Antiviral Res. 2000;48(3):205-8. [PMID:11164507]
Comment: The MIC50 for cidofovir vs. vaccinia was 1.32 mcg/ml.
- Habbick BF, Pizzichini MM, Taylor B, et al. Prevalence of asthma, rhinitis and eczema among children in 2 Canadian cities: the International Study of Asthma and Allergies in Childhood. CMAJ. 1999;160(13):1824-8. [PMID:10405666]
Comment: A Canadian study that showed the lifetime prevalence of atopic dermatitis in children was 14-22%.
- Schultz Larsen F, Hanifin JM. Secular change in the occurrence of atopic dermatitis. Acta Derm Venereol Suppl (Stockh). 1992;176:7-12. [PMID:1476042]
Comment: Authors emphasize characteristic feature of atopic dermatitis - Pruritis, chronic or recurrent dermatitis, family hx of atopy and early age of onset (by 5-7yrs). The distribution of skin lesions is more important than their appearance. Other features: xerosis, infraorbital skin folds, periorbital darkening, hyperlinear palms and keratosis pilaris.
- Cooper KD, Kazmierowski JA, Wuepper KD, et al. Immunoregulation in atopic dermatitis: functional analysis of T-B cell interactions and the enumeration of Fc receptor-bearing T cells. J Invest Dermatol. 1983;80(3):139-45. [PMID:6219166]
Comment: Atopic dermatitis is associated with reduced CMI, defective antibody dependent cellular cytotoxicity, reduced immunoregulatory T cells, elevated IgE, and high incidence of IgE mediated responses to skin tests to common inhaled antigens.
- Shirasawa K, Akai K, Kawaguchi Y, et al. Widespread eczema vaccinatum acquired by contacts. A report of an autopsy case. Acta Pathol Jpn. 1979;29(3):435-55. [PMID:377910]
Comment: Case report of lethal EV in a 4 month old with "allergic dermatitis". Skin lesions showed vaccinia was cytoplasm of cells at the stratum malpighii of the dermis + neutrophils and macrophages. The virus was also cultivated.
- Hanifin JM, Rajka G; Diagnostic features of atopic dermatitis; Acta Dermatol Venerol; Vol. 92; pp. 44;
Comment: Authors define criteria of diagnosis of atopic dermatitis which includes 3 of 4 major criteria: 1) Pruritis, 2) Dermatitis affecting flexural surfaces in adults & face & extensors in infants; 3) chronic or relapsing course and 4) personal or family history of atopy.
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