Bioterrorism

Published on 19/03/2015 by admin

Filed under Dermatology

Last modified 22/04/2025

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Bioterrorism

Boris D. Lushniak and Cody R. Thornton

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

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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

First-line therapies

Third-line therapies

Anthrax

Anthrax is caused by spores from the Gram-positive, non-motile Bacillus anthracis. Although more commonly an animal disease it can be found in humans exposed to spores, resulting in cutaneous, inhalational or rarely gastrointestinal anthrax. Farm workers or processors of wool, hair, or hides are at risk. After a livestock vaccination campaign in the 1950s, anthrax became a very rare disease in the US with only 409 cases (of which 18 were inhalational, the remainder cutaneous) described from 1951–2000. In 2001 anthrax spores were disseminated in a bioterrorist incident through the US mail system resulting in 11 inhalational cases (five deaths) and 11 cutaneous cases.

Cutaneous anthrax is the form most commonly encountered in naturally occurring cases. A non-tender pruritic macule then papule develops one to 12 days after skin exposure and inoculation of spores (see Figure). Within 48 hours this lesion develops into a vesicle or bulla which then ruptures forming a depressed black necrotic ulcer (black eschar) within an edematous, erythematous plaque. The greatest concern in a bioterrorist event would be inhalational anthrax which can occur one to over 40 days after exposure. The initial prodrome is a viral-like illness with myalgias, fatigue, and fever followed by hypoxia and dyspnea (with evidence of radiographic mediastinal widening), and respiratory failure. After the initial infection the spores produce toxins which do not respond to antibiotics. Historically inhalation anthrax resulted in a high fatality rate.

The diagnosis of any form of anthrax especially in non-rural areas requires a high index of suspicion and would mandate a notification of public health authorities. The varied differential diagnosis of cutaneous anthrax includes insect bite, brown recluse spider bite, tularemia, the tache noir of rickettsial diseases, ecthyma gangrenosum, staphylococcal or streptococcal ecthyma, cat scratch disease, orf, and other conditions with eschar or an ulceroglandular presentation. Initial differentiation of pulmonary anthrax from other community-acquired pneumonias would be difficult and may include evidence of radiographic mediastinal widening.

Management strategy

Universal precautions should be maintained in evaluating a patient with suspected cutaneous anthrax. Ciprofloxacin or doxycycline are the mainstays of therapy. The need for post-exposure prophylaxis with antibiotics would be determined by public health officials based upon the epidemiologic investigation and the likelihood of exposure to spores. The duration of treatment and post-exposure prophylaxis may be up to 60 days.

The vaccine, Anthrax Vaccine Adsorbed (AVA), induces immunity to a protein in the toxins. The regimen consists of six injections at 0, 2, and 4 weeks, followed by doses at 6, 12, and 18 months plus annual boosters. Vaccination is only indicated for at-risk laboratory workers, select emergency responders, and military personnel. In combination with antibiotics, post-exposure vaccination may be effective in preventing disease after exposure to B. anthracis spores.

Specific investigations

First-line therapies

Oral antibiotics are used for cutaneous anthrax below the head and neck if systemic symptoms and malignant edema are absent. If they are present, intravenous antibiotics are used.

Third-line therapies

Prophylaxis

Tularemia

Tularemia is caused by the very infectious (as few as 10–50 organisms can cause disease) Gram-negative coccobacillus Francisella tularensis, found in rodents, rabbits, and hares. Tularemia can have a variety of clinical manifestations related to the route of exposure, dose, and the virulence of the specific subspecies. Exposure can occur through insect bites (usually infected ticks or deerflies), handling of infected animal carcasses, eating or drinking contaminated food or water, or through inhalation. Symptoms can appear one to 14 days after exposure and person to person transmission is not seen. Inhalational (pneumonic) tularemia would most likely be the chief concern in a bioterrorist event. It starts abruptly as a flu-like illness or atypical pneumonia with fever, chills, headaches, sore throat, and myalgia. Pulmonary symptoms can include a dry cough and pleuritic chest pain, and if untreated can escalate to severe bronchopneumonia, hemoptysis, and respiratory failure, with marked hilar lymphadenitis. There is no specific skin rash with pulmonary tularemia, but potential sepsis can result in disseminated intravascular coagulation and purpura.

Ulceroglandular tularemia presents with a painful papule at the site of inoculation. The papule progresses to a pustule and then to a tender ulcer with eschar formation. Regional lymph nodes become enlarged and tender (buboes) usually within a few days after the appearance of the papule. Affected nodes could become fluctuant and rupture. Oculoglandular tularemia presents with conjunctival ulcerations and purulent conjunctivitis, periorbital edema, and nodules of the conjunctivae, along with tender preauricular or cervical lymphadenopathy. Glandular tularemia is marked by lymphadenopathy with no ulcer formation. Oropharyngeal tularemia presents with gastrointestinal symptoms, stomatitis, and exudative pharyngitis or tonsillitis, sometimes with ulceration and pronounced cervical or retropharyngeal lymphadenopathy. Typhoidal tularemia is a systemic illness with chills, abdominal pain, nausea, vomiting, and diarrhea with no other anatomical localization of infection.

The varied clinical manifestations of tularemia may show exanthems which may be macular, papular, papulovesicular, pustular, or petechial, and are most prominent on the face and extremities. Erythema nodosum, erythema multiforme, and Sweet syndrome have also been described.

Although a high level of suspicion would be necessary, ulceroglandular or oculoglandular disease has a rather straightforward presentation. However, pneumonic tularemia has variable pulmonary symptoms.

Management strategy

The organism can be cultured and detected in secretions, exudates, or biopsy specimens by direct fluorescent antibody or immunohistochemical techniques. Antigen detection assays, polymerase chain reaction (PCR), enzyme-linked immunoassays (ELISA), and other specialized techniques may be used. Serum antibody titers could be helpful but not until 10 days into the disease course.

For severe disease, parenteral therapy is indicated. Streptomycin has been used successfully for many years for tularemia but it is not widely available and has been replaced by gentamicin. Steptomycin is ototoxic and nephrotoxic to patients, and if administered to pregnant women can cause fetal hearing loss and kidney damage. Oral ciprofloxacin and doxycycline have proven effective in the treatment of tularemia. There is no vaccine currently available.

Specific investigations

Second-line therapies

Plague

Plague, caused by the Gram-negative bacillus Yersinia pestis, is a disease of rodents and their fleas. The three main presentations are bubonic, pneumonic, and septicemic plague. Bubonic plague usually occurs after a bite and begins with fever and flu-like symptoms. Then swollen, tender lymph nodes (buboes) develop near the site of the infected bite, most often in the cervical, axillary, femoral, or inguinal areas. Vesicles, pustules, eschars, or ulcerations can appear at the site of the bite. Without antibiotic treatment, secondary pneumonia or septicemia may follow. Highly contagious pneumonic plague can be primary and spread from person to person (or even cat to person), or may develop secondarily from bubonic or septicemic plague. One to six days after exposure, patients with pneumonic plague present with fever, headache, weakness, gastrointestinal symptoms, and rapidly developing pneumonia with dyspnea, chest pain, productive cough, and hemoptysis, and can progress to respiratory failure and sepsis. The pneumonic form has no specific skin manifestations, but septicemic plague can cause vasculitis and disseminated intravascular coagulation, with cyanosis, purpura, and acral gangrene.

Management strategy

Early diagnosis mandates a high level of suspicion. Diagnostic tools include antigen detection, immunoassays, immunostaining, and PCR. Cultures and staining of sputum, blood, or lymph node aspirate will assist in the diagnosis. Cases should be reported immediately to public health authorities. Drainage and secretion precautions are indicated for buboes, and strict respiratory isolation and respiratory droplet precautions are mandatory for the first 48 hours of therapy of pneumonic plague. Post-exposure prophylactic treatment of at-risk contacts is mandatory.

Streptomycin is the drug of choice for plague but has limited availability. It is ototoxic and nephrotoxic to patients, and if administered to pregnant women can cause fetal hearing loss and kidney damage. Gentamicin is also used for plague and is favored in pregnancy. Doxycycline, ciprofloxacin, and chloramphenicol can also be used in treatment. All are highly effective if used early. Vaccines are not available.

Specific investigations

Viral hemorrhagic fevers

The viral hemorrhagic fevers are a group of febrile illnesses associated with a bleeding diathesis that are caused by viruses of four distinct families: arenaviruses, filoviruses, bunyaviruses, and flaviviruses. They are all RNA viruses and are found in animal or insect hosts which can infect humans. In some cases human to human spread through bodily fluids is possible as in Ebola, Marburg, Lassa, and Crimean-Congo hemorrhagic fevers. The mode of transmission, clinical course, and mortality of these illnesses vary with the specific virus involved, but each is capable of causing a hemorrhagic fever syndrome. Symptoms include fever, fatigue, dizziness, myalgias, exhaustion, and hemorrhagic manifestations, such as hemorrhagic or purpuric skin lesions, epistaxis, hematemesis, hemoptysis, and blood in stools.

Specific investigations

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