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Bioterrorism Summaries from Annual Session 2002

Course Title: Vaccines: the Front-line Defense Against Bioterrorism
Section: Disaster Preparedness
Faculty Member: Gregory Poland, MD, FACP
Date/Time: 13 April 2002/2:00 PM
Course Number: MTP 137

Introduction

Bioterrorism is defined as the use of a biologic agent against humans, animals, or plant life to induce a state of fear or terror, as a means of intimidation or coercion, especially as a political or religious weapon. Bioterrorism, which is sometimes referred to as "strategic psychobiologic warfare," differs from conventional terrorism in that the latter involves calculated levels of violence against human life, rather than to induction of fear.

There are four main components of a biologic weapon: the payload (biologic agent); a munition that keeps the payload intact, virulent, and dry; a delivery system (typically a conventional explosive); and a dispersal mechanism. For example, the anthrax attacks during October and November of 2001 used an envelope as the munition and the U.S. Mail as the delivery system.

Before October 2001, it was believed that bioterrorism would not occur on a large scale in the United States. However, those events should be seen as evidence that terrorists do have the means and technology to perpetrate a biologic attack, and that preparedness is an important political and public health concern. To this end, current vaccines against biologic agents are limited. For example, the anthrax vaccine is not presently available for widespread civilian use, manufacture of the vaccine against plague was ceased in 1999, and a new smallpox vaccine is only under development.

This session addresses strategies for recognizing and preventing casualties from bioterror attacks that use anthrax, smallpox, and plague. These three diseases are the bioweapons of choice for terrorists, because they are odorless, tasteless, and highly lethal; stable for transmission in aerosol form; can be produced on a large scale; have a delayed onset of symptoms and disease recognition; have devastating psychological effects and induce panic; and have the ability to induce outbreaks over large geographic areas. In addition, vaccines to prevent disease are in low supply.

Clinical Questions

  • What is bioterrorism?
  • What are the clinical syndromes produced by anthrax, smallpox, and plague?
  • How can vaccines be used to prevent these diseases?

Discussion

Anthrax

Anthrax results from infection with the gram-positive bacteria Bacillus anthracis, which forms extremely long-living and durable spores. The three primary syndromes associated with anthrax are cutaneous, inhalational, and gastrointestinal forms. Although no documented cases of gastrointestinal anthrax have been reported in the United States, it is not uncommon in parts of Africa. Inhalational anthrax is essentially 100% fatal if untreated.

Pathogenesis

In inhalational anthrax, the spores enter the lungs, are ingested by macrophages, and migrate to regional lymph nodes. Once in the lymph nodes, the spores germinate, multiply, and produce toxins that cause the primary disease syndrome. Three important proteins are produced by this bacteria: 1) protective antigen, a binding protein that combines with 2) lethal factor to produce lethal toxin or with 3) edema factor to produce edema toxin. Lethal toxin and edema toxin enter cells and cause massive necrosis and edema. Anthrax vaccine, therefore, is derived from protective antigen, such that vaccinated persons produce antibody against protective antigen. Contrary to popular belief, bioengineered strains of anthrax are not a current threat because mutations to protective antigen render it unable to combine with lethal factor or edema factor and, therefore, unable to cause disease.

Characteristics of Spores

Anthrax bacteria being manufactured for use as a weapon must be exposed a stressor (eg, heat) for spore development to occur. Once formed, anthrax spores have a electrostatic charge that makes them extremely adhesive to surfaces and one another. To be inhaled into the terminal alveoli and cause damage, anthrax spores must be refined to a size of 1 to 5 microns (for comparison, the diameter of a human hair is about 25 microns).

Clinical Signs and Symptoms

Inhalational anthrax caused by these toxins did not resemble textbook examples, as was demonstrated by the attacks of October and November, 2001. Incubation typically lasts 1 to 6 days, after which victims develop an abrupt respiratory distress or flu-like syndrome. Patients may improve after a few days of symptoms, but this improvement is followed by eschars on the skin, shock, massive edema, hemorrhage, and death 24 to 36 hours later. This bimodal illness was not seen in the recent anthrax attacks.

Although inhalational anthrax shares clinical signs and symptoms with influenza, the two diseases can be fairly easily distinguished (Table 1). Anthrax victims often have drenching sweats, nausea, vomiting, shortness of breath, substernal pain, and chest discomfort, but do not show symptoms of viral upper respiratory infections (eg, sore throat, rhinorrhea, purulent sputum). Clinical findings include mild fever, tachycardia that is disproportionate to the fever, and a mildly elevated leukocyte count with a marked left shift. In addition, patients have abnormal chest radiographs that show a widened superior mediastinum, which often is followed by pleural effusion. In some cases, pulmonary infiltrates and consolidations also may be seen.

The black eschar that appears on the skin of victims with cutaneous anthrax is quite distinctive, with nonhealing ulcers and elevated edges. These skin lesions also have a propensity for hematogenous dissemination, which often carries the bacteria to the brain and can lead to brain hematomas and hemorrhagic meningitis.

Vaccination and Prevention

Anthrax vaccine is a toxoid vaccine, similar to tetanus vaccine. It contains no live organisms, and its principal component is protective antigen. Like all vaccines, anthrax vaccine has been tested for potency, sterility, purity, and safety. It has been approved for use in the United States since 1970, and its safety and efficacy were reaffirmed in 1985. Therefore, contrary to popular belief, anthrax is not an experimental vaccine, although experimental regimens were tested after the attacks of last year.

Anthrax vaccine is administered subcutaneously in 6 doses over 18 months (at 0, 2, and 4 weeks, and at 6, 12, and 18 months, with an annual booster), which accounts for its lack of use in the civilian population. However, the subcutaneous route of administration is associated with an excess of local reactions, which should not be confused with increased risk of systemic reactions. Local reactions are more common in women than men, possibly because men have less deltoid fat tissue.

Contraindications to use of anthrax vaccine include allergic reaction to a previous dose, severe systemic reactions that occur in temporal association with the dose, pregnancy, and previous severe local reactions. In a 5-year study of reactions to anthrax vaccine in nearly 7000 subjects by Brachman et al, 20% had a mild local reaction (ie, erythema, edema, induration <30 mm), 3% had a moderate local reaction (ie, induration 30-120 mm), and 1% had a severe local reaction (ie, induration >120 mm); only 0.06% had systemic reactions (eg, fever, malaise, chills, nausea). These data are similar to those seen from other, similar trials as well as data regarding use of other vaccines. Effects on pregnancy include a small, but statistically significant, number of birth defects in children of women who received at least 1 dose during the first trimester reported by Wiesen and Littel, whereas no effect was reported by a CDC report.

Patients also can be treated with anthrax vaccine postexposure in a 3-dose regiment that includes antibiotics, although this regimen is experimental and under investigation. This approach was used in treating individuals infected in Washington, DC, following the October, 2001, attacks.

The Efficacy Controversy

The efficacy of anthrax vaccine has been surrounded by tremendous controversy. However, the Institute of Medicine has recently gathered non-Department of Defense experts to review all available data on anthrax vaccination (Joellenbeck et al). The committee concluded that anthrax vaccine as licensed is effective at protecting humans against anthrax, including inhalational anthrax. The committee also concluded that the vaccine is reasonably safe, such that immediate and systemic reactions occur at a rate comparable with that of other vaccines, and that there is no evidence to suggest that vaccinated individuals face an increased risk of developing adverse health effects.

Despite these conclusions, common clinical experience with anthrax vaccine remains low and it is little understood. But there are no reliable data linking anthrax vaccine to maladies such as Gulf War Syndrome. It is exceedingly difficult to dissuade the general public-as well as many physicians-that temporal associations between systemic reactions and vaccination should not be equated with a cause-and-effect relationship.

Smallpox

Unlike anthrax, smallpox is a highly transmissible virus that can be spread from person to person. About one third of individuals exposed to smallpox die, and there is yet no cure or specific treatment. Some variants of smallpox (eg, hemorrhagic) are extremely contagious and lethal. By the end of the second millennium, smallpox had killed, blinded, crippled, or disfigured one tenth of all humans who had ever lived. Use of smallpox vaccination has eliminated the natural occurrence of the disease. However, there is reliable evidence that Russia shared its stores of smallpox with enemies of the United States. Routine smallpox vaccination in the United States was stopped in 1972.

Clinical Features

Clinical features include the very abrupt onset of high fever, headache, backache, malaise, which occur 2 to 3 days before the onset of a macular-papular rash. The rash begins on the oral mucosa, face, arms, and possibly the palms of the hands and soles of the feet, and the lesions develop synchronously. By contrast, the rash caused by varicella infection typically begins on the trunk and develops asynchronously. The lesions of smallpox are full-skin thickness and are described as feeling like a dried pea or pellet beneath the skin. They progress to vesicles, pustules, then crust and scar, with several days between each stage. Smallpox lesions become umbilicated and can cover up to 98% of the surface area of the skin.

Diagnostic Criteria

The Centers for Disease Control and Prevention (CDC) has published major and minor criteria for the diagnosis of smallpox. Major criteria are summarized in Table 2. Minor criteria include centrifugal distribution (with the greatest concentration of lesions on the face and distal parts of the extremities), first appearance of lesions of the oral mucosa or face, toxic or moribund appearance, slow evolution or rash, and lesions on the palms or soles.

Vaccination

Beginning with Jenner's experiments in the 19th century, the efficacy of smallpox vaccination has been demonstrated. However, the vaccine is no longer manufactured in the United States. Although the CDC has about 15 million doses, they are roughly 20 years old and have lost some potency. In addition, because smallpox vaccine is a live viral vaccine, in some patients, and in unpredictable ways, it can disseminate. Patients developing disseminated disease can be treated with vaccinia immunoglobulin, but the solution is discolored and only exists in enough supply to treat 675 people. In 1991, the World Health Organization destroyed 200 million doses of smallpox vaccine, leaving only about 150 million doses worldwide. About half of the people in the United States have been vaccinated against smallpox, but only about 20% to 30% of those people still are believed to have some immunity.

The current smallpox vaccine has a side effect profile and reactogenicity that were factors in the decision to discontinue its routine civilian use. Reactions may occur more frequently in younger patients, and death may occur unpredictably in 1 to 2 persons per million primary vaccinees, but only about 0.1 per million persons who are revaccinated. In addition, autoinoculation may result from scratching the vaccination site. Other adverse events include generalized vaccinia, eczema vaccinatum, vaccinia gangrenosum (ie, progressive vaccinia), and postvaccinal encephalitis. These side effects are not unappreciable, so it would be very difficult to deploy this vaccine in the civilian population in the absence of a documented case of smallpox, despite the presence of threats. Contraindications for nonemergency use include any exfoliative skin disorder, immunosuppression, pregnancy, use in children, or a vaccine-component allergy.

Containment

The last modern outbreak of smallpox occurred in Yugoslavia in 1972, when a pilgrim returning from Iraq developed a mild illness, rash, and fever. Two weeks later, 11 people who had come into contact with him developed similar symptoms. None of these people knew each other, and one developed hemorrhagic smallpox and died; that person infected 38 other people. Four weeks after the initial patient became ill, the outbreak was recognized, which lead to the mandatory vaccination of 20 million people and quarantine of 10,000 contacts of the patient. The surrounding countries closed their borders to travel and commerce, and the outbreak ended 8 weeks later, with 175 known cases of smallpox and 35 deaths. It should be noted, however, that the initial patient was a hyperexcreter with hemorrhagic smallpox, which is the most severe and rare form.

Similar to the contamination of the outbreak in Yugoslavia, the CDC strategy for responding to smallpox outbreaks also involves ring vaccination, which relies on quarantining and vaccinating successively larger groups of people who may have come into contact with the infected individual. However, there are problems with such a strategy in that travel is restricted and vaccination is mandatory, and it is unlikely that this strategy would be effective against multiple, simultaneous outbreaks in highly populated areas. The strategy also has never been tested in an era in which there is no preexisting herd immunity. In addition, there are more people with a greater number of contraindications than in the past, and it is unclear how ring containment would be received by a free society. Finally, a government simulation that was undertaken in the summer of 2001 to test preparedness and the ring vaccination strategy was a complete failure. Despite the drawbacks of ring vaccination, however, it is the only viable strategy currently available from a public health standpoint.

Plague

Caused by infection with Yersinia pestis, plague is a nonmotile, gram-negative bacillus with bipolar, or safety-pin, staining. The three primary syndromes of plague are the following: 1) bubonic plague ("black death"), which manifests as severe destruction and necrosis of lymph nodes, bacteremia, septicemia, disseminated intravascular coagulation, coma, and death; 2) primary septicemic plague, which is septicemia that generally occurs without bubos and gangrene of the digits); and 3) pneumonic plague, which has a fulminant course and high mortality.

Clinical Features and Diagnosis

Clinical features of pneumonic plague, were it to be deployed as a weapon, include the sudden appearance of many people with fever, cough, apnea, and hemoptysis. Other features are gastrointestinal symptoms, tachypnea, dyspnea, cyanosis, pneumonic consolidation, sepsis, shock, and organ failure. Bubos are very uncommon in patients with pneumonic plague. Diagnosis cannot be based on chest radiography, which is nonspecific in infected patients.

Vaccination

The plague vaccine licensed in the United States was a killed, whole cell vaccine developed during the 1940s, but has not been manufactured since 1999. The administration regimen was complicated and immunity was short, with 1 mL given intramuscularly, followed by 0.2 mL intramuscularly at months 1, 3, 4, 5, and 6, with boosters at months 12 and 18 and annually thereafter. The reactogenicity is relatively benign and similar to that of other vaccines. Although it has not been investigated in randomized, controlled trials, data gathered during the Vietnam War suggest that the plague vaccine is effective in some circumstances, but is ineffective at protecting against pneumonic plague. Therefore, the current vaccine cannot be used for postexposure prophylaxis against pneumonic plague, and management would rely on recognition and antibiotic treatment.

Conclusion

The panic that ensued after the recent terrorist attacks can be quite powerful. Therefore, physicians should be aware of the signs and symptoms of biologic agents to quell the fears of their patients-because phycological infection is not unlike that produced by biologic warfare, and a person unnerved is a highly infectious carrier of fear, capable of spreading an epidemic of panic.

Q & A

Q: Can smallpox vaccine be diluted?
A: Yes. A recent study demonstrated immunogenicity at dilutions of 1:5 and 1:10 (Frey et al).

Q: How does the attack rate of smallpox differ from that of other viral infections?
A: The attack rate after exposure to smallpox is significantly lower than that for varicella and measles, which range from 80% to 100%. This is one of the main reasons why the CDC believes that ring vaccination will be effective.

Q: What are next-generation vaccines likely to look like?
A: Anthrax: a recombinant PA vaccine is under investigation that may be administered intramuscularly in fewer doses; vaccinia: tissue culture-derived, live viral vaccines; plague: preclinical work is being done on a non-whole cell killed vaccine.

References

Brachmann PS. Gold H, Plotkin SA, Fekety FR, Werrin M, Ingraham NR. Field evaluation of a human anthrax vaccine. Am J Public Health. 1962;52:632-45.

Centers for Disease Control and Prevention. Status of US Department of Defense preliminary evaluation of the association of anthrax vaccination and congenital anomalies. JAMA. Feb 2002;51(6):127.

Frey SE, Couch RB, Tacket, et al. Clinical responses to undiluted and diluted smallpox vaccine. N Engl J Med. 2002;346:1265-1274.

Henderson DA, Inglesby TV, Bartlett JG, et al. Smallpox as a biological weapon: medical and public health management. Working Group on Civilian Biodefense. JAMA. 2000;281:2127-37.

Inglesby TV, Dennis DT, Henderson DA, et al. Plague as a biological weapon: medical and public health management. Working Group on Civilian Biodefense. JAMA. 2000;283:2281-90.

Inglesby TV, Henderson DA, Bartlett JG, et al. Anthrax as a biological weapon: medical and public health management. Working Group on Civilian Biodefense. JAMA. 1999;281:1735-45.

Inglesby TV, O'Toole T, Henderson DA, et al. Anthrax as a biological weapon, 2002: updated recommendations for management. JAMA. 2002;287:2236-52.

Joellenbeck LM, Zwanziger LL, Durch JS, Strom BL. The anthrax vaccine: is it safe? does it work? Washington, DC: National Academies Press; 2002.

Wiesen AR, Littel CT. Relationship between prepregnancy anthrax vaccination and pregnancy and birth outcomes among US Army women. JAMA. 2002;287:1556-60.

Recommended Web Sites

Anthrax vaccine immunization program: the official Department of Defense anthrax information Web site. Available at: http://www.anthrax.osd.mil. Accessed 1 July 2002.

Centers for Disease Control and Prevention. Public health emergency preparedness & response. Available at: http://www.bt.cdc.gov. Accessed 1 July 2002.

Table 1 - Symptoms and signs of inhalational anthrax, laboratory-confirmed influenza, and influenza-like illness (ILI) from other causes

Table 2. CDC Major Clinical Criteria for Diagnosis of Smallpox

Febrile prodrome occurring 1-4 days before rash onset; temperature =101 F; and at least one of the following: prostration, headache, backache, chills, vomiting, severe abdominal pain

Classic smallpox lesions (ie, deep-seated, firm/hard, round, well-circumscribed vesicles or pustules) that may become umbilicated or confluent as they evolve

Lesions in the same stage of development (eg, all vesicles or pustules) on any one part of the body (eg, face or arm)

CDC, Centers for Disease Control and Prevention.

Table 3 - The "Flu" Versus Inhalational Anthrax

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