Bioterrorism
Evidence Levels: A Double-blind study B Clinical trial ≥ 20 subjects C Clinical trial < 20 subjects D Series ≥ 5 subjects E Anecdotal case reports
Bioterrorism is defined as the use of viruses, bacteria, fungi, or toxins from living organisms to produce death or disease in humans, animals, or plants. The US Centers for Disease Control and Prevention (CDC) has designated several agents/diseases as category A agents that can be easily disseminated or transmitted, result in high mortality rates, have the potential for serious public health impact, and which would require special action for public health preparedness. The diseases that are of greatest concern are smallpox, anthrax, tularemia, plague, the hemorrhagic fevers, and botulism (which have no cutaneous features and will not be further discussed here). Dermatologists should familiarize themselves with these disorders, their recognition and treatment, and the measures that can be undertaken to limit the spread of disease. Several of the conditions discussed, including smallpox, pneumonic plague, and viral hemorrhagic fevers, are contagious to caregivers, so appropriate care must be taken to prevent the further transmission of disease.
Smallpox
The history of smallpox is fascinating, culminating in the public health achievement of worldwide eradication of this double stranded DNA virus. The virus now remains stored in secure laboratory facilities in the US and Russia. Its effect on the world was overwhelming with over 500 million deaths attributed to smallpox in the 20th century. After a worldwide vaccination campaign, the last natural case occurred in Somalia in 1977 and by 1980 the World Health Assembly declared smallpox eradicated.
Smallpox is a highly stable virus, spread by direct contact, short distance (6 feet) aerosol exposure, or, in rare cases, through fomites. The incubation period ranges from 7 to 19 days, followed by a prodrome of 2 to 4 days which includes high fever (101–104°F), prostration, malaise, and myalgias. During this time smallpox becomes communicable after the appearance of an enanthem, including macules, papules, and ulcers on the tongue and mouth, and remains so for about 3 to 4 weeks, until the disappearance of all scabs. After the prodrome, an exanthem appears with a mostly centrifugal distribution. Lesions progress in a synchronous fashion from macule (day 0–1), papule (day 2–3), deep tense umbilicated vesicle (day 3–5), deep round tense pustule (day 6–12), crust formation (day 13–20), crust separation (day 21–28), and resulting depressed scars. Complications of smallpox include sepsis and toxemia, encephalitis, and blindness.
The differential diagnosis for smallpox includes varicella and disseminated herpes simplex or zoster, molluscum contagiosum, erythema multiforme, pustular drug eruption, purpura fulminans, hand, foot, and mouth disease, and monkeypox. Varicella has a relatively benign prodrome, with more superficial lesions in a centripetal distribution with asynchronous evolution and crusting in 4 to 7 days.
Smallpox vaccination with the scarification technique using the live vaccinia virus can cause adverse reactions in those vaccinated as well as their close contacts. Contraindications to non-emergency vaccination include immunodeficiency states, immunomodulating medications, allergic reactions, pregnancy, cardiovascular diseases, and epidermal-disrupting diseases such as atopic dermatitis, pemphigus, or Darier disease in vaccine recipients or family members. Localized skin reactions include a robust primary reaction at the site, autoinoculation or contact transmission of the vaccinia, and ocular vaccinia. Generalized skin reactions with systemic symptoms can also occur, including, generalized vaccinia (distant site viremic spread), erythema multiforme major, progressive vaccinia (progressive necrosis at the site), and eczema vaccinatum (localized or systemic dissemination) as seen in those with atopic dermatitis or other skin diseases. Other adverse reactions of vaccination include post-vaccinial encephalopathy and encephalomyelitis and myopericarditis. New generation vaccines, including non-replicating attenuated modified Vaccinia Ankara, are being investigated to see if adverse reactions can be minimized and for use in atopics.
Management strategy
The management of smallpox includes the recognition, diagnosis, and isolation of index cases, notification of public health authorities, vaccination, treatment, and supportive care of the cases, and vaccination and isolation of those who were in contact with the cases. Although there is no specific treatment for smallpox, there are several investigational antiviral candidates undergoing study for both treatment of disease and for adverse events associated with vaccination. Vaccinia immune globulin is also available from the CDC to treat specific adverse events. In an outbreak scenario a ‘ring vaccination’ strategy, as used in the eradication program, would be used initially whereby the case would be vaccinated, as well as those exposed to the case and those exposed to the exposed, in an expanding ring fashion. Vaccination should be effective in limiting the disease if given within 3 to 4 days of exposure.
Specific investigations
Laboratory diagnosis to differentiate smallpox, vaccinia, and other vesicular/pustular illnesses.
Besser JM, Crouch NA, Sullivan M. J Lab Clin Med 2003; 142; 246–51.
Patients who are at risk should have laboratory testing to include electron microscopy, PCR, orthopox virus culture, and variola serology performed at designated laboratories. Tzanck smears, real-time PCR assays for HSV and VZV can be performed at standard reference laboratories.
Cutaneous manifestations of category A bioweapons.
Aquino LL, Wu JJ. J Am Acad Dermatol 2011; 65: 1213.e1–15.
Reviews the diagnosis and treatment of diseases caused by potential biowarfare agents that produce cutaneous manifestations, and also provides information regarding reporting and containment of possible bioterrorism-related diseases.
Development and experience with an algorithm to evaluate suspected smallpox cases in the United States, 2002–2004.
Seward JF, Galil K, Damon I, Norton SA, Rotz L, Schmid S, et al. Clin Infect Dis 2004; 39; 1477–83.
Diagnostic criteria and a CDC algorithm to evaluate and manage suspected cases of smallpox. Three categories (i.e., low, moderate, or high risk of actually having smallpox) dictate subsequent diagnostic strategies. Specific variola laboratory testing is reserved for high-risk persons. An interactive version of the algorithm is available online at http://www.bt.cdc.gov/agent/smallpox/diagnosis/riskalgorithm/index.asp.
First-line therapies
Countermeasures and vaccination against terrorism using smallpox: pre-event and post-event smallpox vaccination and its contraindications.
Sato H. Environ Health Prev Med 2011; 16: 281–9.
Core components of the public health management of a terrorist attack using smallpox are: vaccination (ring vaccination and mass vaccination), adverse event monitoring, confirmed and suspected smallpox case management, contact management, identifying, tracing, monitoring contacts, and quarantine.
Inactivation of poxviruses by upper-room UVC light in a simulated hospital room environment.
McDevitt JJ, Milton DK, Rudnick SN, First MW. PLoS ONE 2008; 3; e3186.
A reduction in airborne Vaccinia concentrations can be obtained by combining UV light, upper-room 254 nm germicidal UVC, with air mixing using a conventional ceiling fan. While the greatest risk for an aerosol attack with smallpox is during the winter, protective measures using UVC would be best suited during winter due to the increased survival at baseline and greater UVC susceptibility of Vaccinia under winter conditions.
Progressive vaccinia in a military smallpox vaccinee: United States, 2009.
MMWR Morb Mortal Wkly Rep 58: 532–6.
This report summarizes the patient’s clinical course and medical management. This is the first confirmed case of progressive vaccinia in the US since 1987. Therapy included imiquimod, VIG, oral and topical ST-246 (a smallpox drug candidate with anti-orthopox activity inhibiting virus maturation), and oral CMX001 (a lipid conjugate of cidofovir) under emergency investigational new drug protocols.
Household transmission of vaccinia virus from contact with a military smallpox vaccinee: Illinois and Indiana, 2007.
MMWR Morb Mortal Wkly Rep 56: 478–81.
This case highlights the need for clinicians to maintain a high index of suspicion when evaluating recently vaccinated patients and their family members with vesiculopustular rash. This is the first eczema vaccinatum case reported in the US since 1988. Therapy included cidofovir, VIG, and oral ST-246 under emergency investigational new drug protocols.
A randomized, double-blind, dose-finding phase II study to evaluate immunogenicity and safety of the third generation smallpox vaccine candidate IMVAMUNE.
von Krempelhuber A, Vollmar J, Pokorny R, Rapp P, Wulff N, Petzold B, et al. Vaccine 2010; 28: 1209–16.
IMVAMUNE is a modified Vaccinia Ankara-based virus that is being developed as a safer third-generation smallpox vaccine, especially in those for whom traditional smallpox vaccines are contraindicated, such as the immunocompromised and those with eczema or dermatitis. IMVAMUNE has displayed a favorable safety profile, with local reactions as the most frequent observation.
Adverse events following smallpox vaccination with ACAM2000 in a military population.
Beachkofsky TM, Carrizales SC, Bidinger JJ, Hrncir DE, Whittemore DE, Hivnor CM. Arch Dermatol 2010; 146; 656–61.
Presentation of the first confirmed case of generalized vaccinia following immunization with the second-generation smallpox vaccine ACAM2000. In addition, there’s a description of seven cases of benign, acral, papulovesicular eruptions thought to be associated with ACAM2000 administration.
Clinical efficacy of intramuscular Vaccinia immune globulin: a literature review.
Hopkins RJ, Lane JM. Clin Infect Dis 2004; 39; 819–26.
VIG reduces the morbidity and mortality associated with progressive vaccinia (vaccinia necrosum) and eczema vaccinatum. Indications for treatment include generalized vaccinia, progressive vaccinia, eczema vaccinatum, and some accidental implantations. The use of intramuscular administration of VIG to prevent smallpox in contacts of patients with documented cases of smallpox is also discussed.
Ocular complications in the Department of Defense Smallpox Vaccination Program.
Fillmore GL, Ward TP, Bower KS, Dudenhoefer EJ, Grabenstein JD, Berry GK, et al. Ophthalmology 2004; 111; 2086–93.
In a Department of Defense vaccination campaign, patients experienced complications 3–24 days after inoculation or contact. These complications consisted of eyelid pustules, blepharitis, periorbital cellulitis, conjunctivitis, conjunctival ulcers, conjunctival membranes, limbal pustules, corneal infiltrates, and iritis. Treatment for most cases was topical trifluridine 1%. VIG was used in one case, and all patients recovered without significant visual sequelae.
Pregnancy discovered after smallpox vaccination: is vaccinia immune globulin appropriate?
Napolitano PG, Ryan MA, Grabenstein JD. Am J Obstet Gynecol 2004; 191; 1863–7.
VIG is not approved for use in fetal vaccinia complications and a risk of teratogenicity from mercury in the thimerosal preservative has been cited. Fetal vaccinia is a rare complication of smallpox vaccination during pregnancy and, although some have suggested that therapeutic treatment with VIG can prevent fetal vaccinia, VIG should only be given if a pregnant woman develops a condition in which VIG is indicated (e.g., eczema vaccinatum, progressive vaccinia, or serious generalized vaccinia).
Myopericarditis following smallpox vaccination among vaccinia-naive US military personnel.
Halsell JS, Riddle JR, Atwood JE, Gardner P, Shope R, Poland GA, et al. JAMA 2003; 289; 3283–9.
Myopericarditis occurred in military personnel at a rate of slightly less than one in 10 000 during primary vaccination. Chest pain four to 30 days following smallpox vaccination should prompt clinicians to consider this diagnosis.
Mucosal immunization induces a higher level of lasting neutralizing antibody response in mice by a replication-competent smallpox vaccine: vaccinia Tiantan strain.
Lu B, Yu W, Huang X, Wang H, Liu L, Chen ZJ. Biomed Biotechnol 2011; 970424.
In this study, intranasal and intraoral vaccinations induced better protections against homologous or alternating mucosal routes of viral challenges 6 months post vaccination. Data has implications for understanding the potential application of mucosal smallpox vaccination.
Traditional smallpox vaccination with reduced risk of inadvertent contact spread by administration of povidone iodine ointment.
Hammarlund E, Lewis MW, Hanifin JM, Simpson EL, Carlson NE, Slifka MK. Vaccine 17. 2008; 26: 430–9.
This ointment rapidly inactivated virus on the skin without reducing neutralizing antibody titers or antiviral T cell responses. Moreover, there was no delay in healing/eschar separation following povidone-iodine application