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Bioterrorism Summaries from Annual Session 2002

Course Title: Bioterrorism
Section: Disaster Preparedness
Faculty Member: Richard P. Wenzel, MSc, MACP
Date/time: April 11, 2002, 10:45 a.m.-12:15 p.m.
Course Number: MTP 131
Reporter: Shannon Donovan, MA

Introduction

Timely recognition of symptoms and early treatment are key to the survival of victims of bioterror attacks. Physicians must be able to diagnose quickly the symptoms of such attacks.

Clinical Questions

  • What are the clinical characteristics of infection with various biological agents that may be used as weapons?
  • What is the pathogenesis of anthrax, smallpox, and botulism?
  • What measures can be taken to control the problem?

Key Points

  • Symptoms of anthrax are nonspecific: fever, chills, fatigue, and malaise.

  • Anthrax is characterized by hemorrhage and edema. Key symptoms of cutaneous anthrax are massive edema and painless ulcers (unlike those seen after brown recluse spider bites).

  • Only 8 anthrax spores have to reach the mediastinal nodes to cause pleural effusions, followed by bloodstream infection, sepsis and septic shock, and (in 50% of patients) meningitis.

  • Hemorrhagic meningitis occurs in 50% of patients and should be treated expectantly with antibiotics that cross the blood-brain barrier.

  • Gross pathologic examination of patients with anthrax reveals hemorrhage, edema, hemorrhagic necrosis of the thoracic lymph nodes, hemorrhagic mediastinitis, focal hemorrhage at portal of entry, and hematogenous spread (meningitis ["cardinal's cap"] and gastrointestinal tract infection)

  • Investigational treatments include peptide binders to protective antigen, soluble receptors to protective antigen, and monoclonal antibodies to protective antigen.

  • A quinolone should given for 8 weeks after exposure to anthrax.

  • Anthrax is very hardy; it has been grown from samples bottled 70 years previously.

  • The dose of anthrax in an exposure is inversely correlated with incubation time.

  • The variable number of nucleotide tandem repeats can distinguish one strain of anthrax from another, as can single-nucleotide polymorphisms.

  • Some strains of Bacillus anthracis are resistant to antibiotics. Most are resistant to penicillins and cephalosporins.

  • Early treatment with a quinolone seems beneficial.

  • Treatment with a cocktail of drugs is recommended: a quinolone, clarithromycin or clindamycin, and rifampin or trimethoprim-sulfamethoxazole.

  • The mortality rate of smallpox is 30%.

  • The hallmark symptom of smallpox versus chickenpox is consistently sized lesions of the same age and maturity in the former disease.

  • After incubation of 8 to 16 days, smallpox produces two to three days of nonspecific symptoms: malaise, fever, vomiting, and backache. Disease is contagious at this point and throughout the 2- to 3-week convalescence period. Vesicles initially form on the hands, feet, face, and forearms. Pulmonary edema occurs, especially with the hemorrhagic form of smallpox.

  • In the author's opinion, vaccination against smallpox should be given only if a credible threat is imminent, because rates of complications are somewhat high.

  • Childhood vaccination against smallpox may confer some immunity even 50 years later.

  • Cidofovir has been developed and may be useful to treat smallpox.

  • Monkeypox causes smallpox-like vesicles but also produces marked adenopathy of the neck and inguinal adenopathy.

  • The mortality rate of monkeypox is half that of smallpox (15% vs. 30%), and the secondary attack rate is one third to one fourth that of smallpox (10%).

  • Smallpox vaccination is thought to confer immunity to monkeypox.

  • Plague carries a worldwide mortality rate of 10% and of 22% in the United States.

  • Early symptoms of plague are nonspecific: high fever, dehydration, normal chest examination, and sometimes no adenopathy or prominent hilar nodes on chest radiography.

  • In plague, immunohistochemical staining of lung shows inflammation and many polymorphonuclear leukocytes. This finding, and the fact that plague is contagious from person to person, differentiates the disease from anthrax.

  • The social history is important in the diagnosis of plague.

  • Streptomycin or gentamicin is used to treat plague. Tetracycline, sulfa drugs, or chloramphenicol is given as prophylaxis. Quinolones may also be effective treatment; no clinical data are available. Penicillin and cephalosporins are not effective.

  • Bioterrorists could make plague strains that are resistant to current drugs and vaccines.

  • Infection with Burkholderia mallei causes necrosis of the tracheobronchial tree, skin necrosis, pustular skin lesions, pneumonia, and abscess. The social history is important in detecting the disease.

  • Most strains of Francisella tularensis are susceptible to streptomycin, tetracycline, chloramphenicol, rifampin, gentamicin, ciprofloxacin, and levofloxacin. They are resistant to beta-lactams and other drugs. Doxycycline and third-generation cephalosporins have also been recommended.

  • Synthesis of biological agents can have unintended environmental consequences. For example, a laboratory accident in Russia caused wild rodents to be exposed to tularemia, and disease was disseminated in the animals.

  • Food-borne botulism usually occurs when the pH of home-canned foods exceeds 4.6.

  • Wound-related botulism is most commonly caused by intramuscular or subcutaneous use of black tar heroin from Mexico.

  • Infant botulism is usually caused by feeding contaminated honey before 1 year of age.

  • Patients with botulism experience the following symptoms, in descending order of prevalence: dry mouth, nausea or vomiting, weakness, dysphagia, diplopia, respiratory impairment, dilated and fixed pupils, ptosis, and dizziness.

  • Botulism causes acute bilateral cranial neuropathies, symmetrical descending weakness, normal heart rate, no fever, no sensory defects, dry mucous membranes, and autonomic features. Patients are alert and responsive.

  • Chimeras are infectious agents that are the offspring of unlikely parents. Examples include smallpox viruses imbued with Venezuelan equine encephalitis (VEE pox) or with Ebola (Ebola pox or blackpox).

  • Adding certain genes affecting the immune system to a viral payload can turn a harmless virus into a lethal one.

  • Physicians have an obligation to recognize and treat unusual disease clusters early and to educate their colleagues and the public about control and prevention. Control measures ultimately based on ethical solutions will be difficult to achieve.

Discussion

A 1996 article in Scientific American listed at least 20 nations suspected of manufacturing biological weapons, according to the Office of Technology Assessment.

Anthrax

In November 2001, 11 cases of anthrax due to bioterrorism occurred in the United States. The index case of inhalational anthrax appeared in a Florida man who was treated appropriately, but the man died. In the 10 cases published first, the median incubation time between receipt of letters containing the disease and illness was 4 days.

Symptoms

All patients with anthrax had fever, chills, fatigue, and malaise, and most shared other nonspecific symptoms. The disease could have been mistaken for wintertime influenza. In the 11th case of inhalational anthrax, the mediastinal nodes in the chest showed many fragmented organisms on histochemical analysis.

Anthrax is characterized by hemorrhage and edema. Key symptoms of cutaneous anthrax are massive edema and painless ulcers (unlike those seen after brown recluse spider bites).

Pathogenesis of Inhalational Anthrax

If untreated, anthrax has a mortality rate of at least 30%. A 1966 study found that the LD50 of aerosolized bacillus anthracis in the cynomolgus monkey is 4130 spores. The LD50 for humans is estimated to be about 8000 spores.

Macrophages in the alveoli try to digest spores. Only 0.1% of spores reach the mediastinal nodes, where they multiply and cause hemorrhage and edema. Thus, only 8 spores (from the estimated LD50 for humans of 8000 spores) have to reach these nodes. The spores cause pleural effusions, then bloodstream infection, sepsis, and septic shock. Hemorrhagic meningitis occurs in 50% of patients and should be treated expectantly. Trismus is characteristic in some series.

Gross pathologic examination of patients with anthrax reveals the following characteristics:

  • hemorrhage and edema
  • hemorrhagic necrosis of the thoracic lymph nodes
  • hemorrhagic mediastinitis
  • focal hemorrhage at portal of entry
  • hematogenous spread (meningitis ["cardinal's cap"] and gastrointestinal
    tract infection)

The cardiac muscle of an animal with anthrax revealed edematous pericardium with no polymorphonuclear leukocytes. Anthrax is not an inflammatory disease. Rather, disease results from bacterial toxins. The genes on a plasmid called pX02 encode the polyglutamic acid capsule, and the genes on pX01 encode pag (protective antigen), cya (edema factor), and lef (lethal factor). Neither of these factors is harmful in itself, but when they mix, a lethal toxin is produced. Thus, anthrax is a classic AB (active and binding) toxin. The anthrax vaccine is derived from a capsule-free strain that contains mainly protective antigen.

In a cellular model, an enzyme cleaves the cap off of the protective antigen if it meets the receptor on the cell. It can then form a 7-member heptamer of itself, and edema factor or lethal factor can bind to each heptamer. The protective antigen ushers edema factor into a cellular endosome. The endosome is high in hydrogen and has a low pH, allowing the harmful factors to be released intracellularly. Edema factor is calcium-dependent adenyl cyclase. Edema factor causes massive edema in anthrax. Intracellular lethal factor cleaves five or six MAP kinase kinase enzymes. Intracellular signaling is therefore altered. Kinase interruptions cause a large outpouring of cytokines, resulting in septic shock.

New Therapies

Some investigators are examining the value of monoclonal antibodies against protective antigen. This prevents the heptamer from forming and thus interrupts the ability to usher in edema and lethal factors.

Another investigational approach is to fill the broken-off cap of the protective antigen with peptide binders, leaving no room for edema factor or lethal factor to hook on and enter the cell. Others are attempting to use the receptor domain of cell and make soluble receptors that compete for protective antigen. Finally, if protective antigen forms along with lethal factor, a mutation can result in one of the hectomers. Lethal factor can be carried into the cell but cannot be released.

History

In the former Soviet Union, anthrax was being manufactured on a large scale. After a laboratory accident, an unknown quantity of wind-borne anthrax entered a nearby city. Persons in a direct line of the wind developed anthrax. Symptoms and postmortem findings clearly matched the inhalational variety, in the face of government claims that the disease was acquired by ingestion of contaminated sausage. All patients had the key finding of cardinal's cap. Of 100 cases, 65 persons died, and the last case occurred 6 weeks after accident. Thus, quinolones should given for 8 weeks from exposure.

In reporting on biological warfare in World War I, the journal Nature described the discovery of sugar cubes containing vials of anthrax in Norway. The anthrax was intended to kill animals carrying British arms through Norway. Scientists who examined the broth with standard cultures and polymerase chain reaction were able to grow anthrax from the vials 70 years later.

Dose-Response Relation

The dose of anthrax is correlated inversely with incubation time. The median incubation time was 10 days among those who were very close to the accident and 3 weeks in those farther downstream. In the United States, the median incubation time after exposure to contaminated letters in 2001 was 4 days, meaning that the exposure dose must have been much larger.

Identification and Treatment of Strains

On microbiological fingerprinting of anthrax, all strains look the same. Large and small patterns must be used to identify different species and will be useful for finding the source of strains used for bioterrorism. The variable number of nucleotide tandem repeats can distinguish one strain from another, as can single-nucleotide polymorphisms.

Some strains of Bacillus anthracis are resistant to antibiotics. The cases seen in the United States had constitutive and inducible beta-lactamases. Penicillin does not work against these strains, but a beta-lactamase with a beta-lactamase inhibitor will be effective. Data from other countries have shown that in in vitro serial passages, one strain was susceptible to a quinolone (ofloxacin) and a strain with intermediate resistance to vancomycin was susceptible to a third-generation cephalosporin.

Some of the U.S. patients seen in the emergency department were given ciprofloxacin, when their cases of anthrax were thought to be bronchitis. These patients later returned with clear signs of anthrax and received full treatment. Of note, all of these patients survived, whereas those who presented with late anthrax requiring intubation and mechanical ventilation died, Thus, early therapy with quinolone seems beneficial.

Treatment with a cocktail of drugs is recommended: a quinolone; clarithromycin or clindamycin to interfere with protein synthesis and retard production of toxin; and rifampin or trimethoprim-sulfamethoxazole, because 50% of patients with inhalational anthrax develop meningitis and the other drugs do not cross the blood-brain barrier.

Pharmacodynamic studies of the best quinolone for anthrax found that the best predictor of outcome is the ratio of the area under the curve for 24 hours to the minimum inhibitory concentration. The ratio for ciprofloxacin, the drug approved by the U.S. Food and Drug Administration for treatment anthrax, is lower than that of levofloxacin, moxifloxacin, or gatifloxacin. The latter drugs may eventually be shown to be more effective than ciprofloxacin.

Smallpox

In the 20th century, smallpox killed 500 million people. The mortality rate of the disease is 30%.

Symptoms

The hallmark symptom of smallpox versus chickenpox is consistently sized lesions of the same age and maturity. In chickenpox, the size and maturity of lesions varies.

After incubation for 8 to 16 days, smallpox produces two to three days of nonspecific symptoms: malaise, fever, vomiting, and backache. Ten percent of patients have erythematous rather than vesicular rash, especially in axillary areas. Disease is contagious at this point and throughout the 2- to 3-week convalescence period. Vesicles initially form on the hands, feet, face, and forearms.

In large series, the rate of skin infection is only 3% to 5%; of blindness, 1%, and of corneal opacities, 2%. One of 500 patients dies of encephalitis. Viral bilateral arthritis of the elbows in 2% of patients. Pulmonary edema occurs, especially with the hemorrhagic form of smallpox.

Vaccination

A 1970 study found that rates of complications of smallpox vaccinations are somewhat high (generalized vaccinia, 242 cases per 1 million persons; eczema, 39 per 1 million persons; encephalitis, 12 per1 million persons; and death, 1 to 3 per 1 million persons). Vaccination should probably only be given if a credible threat is imminent.

An epidemiologic study of the effect of earlier childhood vaccination on mortality during the 1902-1903 smallpox epidemic in Liverpool was reviewed. No one younger than14 years of age who was vaccinated died; rates of death then increased steadily but slightly among those who were vaccinated as children. Thus, childhood vaccination seems to confer some resistance even 50 years later. In another study, immune memory in CD8 and CD4 cells to smallpox vaccine was observed 50 years later.

Treatment

Since 1972 (when the United States stopped vaccinating against smallpox), cidofovir has been developed. A single intravenous dose of this potent nucleoside analogue protects mice and primates against monkeypox and protect mice from aerosolized cowpox. An oral cidofovir derivative was announced recently to be active in vitro against smallpox animal studies. Thus, drugs might be used if not all persons can be vaccinated during an epidemic.

Monkeypox

Monkey resembles smallpox in that it causes vesicles that are all similar in size and shape. However, monkeypox produces marked adenopathy of the neck and inguinal adenopathy. Smallpox is thought to exist in two laboratories worldwide only, but monkeypox is found in nature. The mortality rate is half that of smallpox (15% vs. 30%), and the secondary attack rate is one third to one fourth that of smallpox (10%). Smallpox vaccination thought to confer immunity to monkeypox.

Plague

From 1980 to 1994, almost 19,000 cases of plague have occurred. The overall mortality rate is 10% and is 22% in United States. The disease reservoir is wild rodents that live in the western part of the United States.

Symptoms of plague can be nonspecific: high fever, dehydration, normal chest examination, and sometimes no adenopathy on chest radiography. Other patients may have adenopathy on examination and prominent hilar adenopathy on chest radiography. Patients progress to cyanosis, septic shock, and pneumonia. Immunohistochemical staining of lung shows inflammation and many polymorphonuclear leukocytes. This finding, and the fact that plague is contagious from person to person, differentiates the disease from anthrax.

A case report described a 31-year-old man died of plague that went unidentified. Before his symptoms developed, he had removed a dying cat from underneath his house. Thus, the social history is important in the diagnosis of plague.

Streptomycin or gentamicin is used to treat plague. Tetracycline, sulfa drugs, or chloramphenicol is given as prophylaxis. Quinolones may also be effective treatment; no clinical data are available. Penicillin and cephalosporins are not effective.

Multidrug-resistant strains of plague are found in nature. One strain was susceptible to trimethoprim and quinolones. Bioterrorists could make organisms that are resistant to our best drugs and vaccines.

Infection with Burkholderia mallei (Pseudomonas)

Infection with Burkholderia mallei causes glanders in horses. In people, this infection can cause necrosis of the tracheobronchial tree, necrosis, pustular skin lesions, pneumonia, and abscess. The Germans used Burkholderia mallei for biological warfare in World War I. The social history is important in detecting the disease.

Tularemia

In the United States, almost half of cases of tularemia are rabbit-related, 20% are tick-related, and 32% come from other animals. The infectious dose is 10 organisms subcutaneous or 10 to 50 aerosolized. Tick-borne tularemia causes a classic adenopathy.

Most strains of Francisella tularensis are susceptible to streptomycin, tetracycline, chloramphenicol, rifampin, gentamicin, ciprofloxacin, and levofloxacin. They are resistant to beta-lactams and other drugs. Doxycycline and third-generation cephalosporins have also been recommended.

Tularemia was manufactured in the Soviet Union from 1972 to 1992. A leak in the basement of the laboratory contaminated ground; wild rodents then picked up the disease and spread it throughout an area near Kirov. This highlights the fact that synthesis of such agents can have unintended environmental consequences.

Botulism

The term "botulism" comes from the Latin for "sausage." Botulism takes three forms: food-borne, wound-related, and infant. Food-borne botulism usually occurs when the pH of home-canned foods exceeds 4.6. Achlorhydria may also be a risk factor in individual patients.

Wound-related botulism is most commonly caused by intramuscular or subcutaneous use of black tar heroin from Mexico. Most cases are seen on the west coast of the United States. One study found that if antitoxin was given within 12 hours, 57% of patients with wound-related botulism required mechanical ventilation, compared with 87% of patients who received antitoxin after 12 hours. The time to discharge was 50 days in patients who went into respiratory failure and 4 in those who did not, and 80% of the former patients were discharged to a nursing home.

Infant botulism is usually caused by feeding contaminated honey before 1 year of age.

All forms of botulism are caused by protein neurotoxins. Zinc metalloproteases prevent release of acetylcholine at the peripheral neuromuscular junction and at autonomic synapses. The toxin is acted on by a bacterial protease that allows binding site and a light chain to attach to receptor (depending on the neurotoxin present); the toxin then enters by endocytosis and inhibits the synaptic vesicle, preventing release of acetylcholine.

Symptoms

The percentage of patients who experience symptoms is as follows:

  • Dry mouth, 93%
  • Nausea or vomiting, 90%
  • Weakness, 88%
  • Dysphagia, 81%
  • Diplopia, 76%
  • Respiratory impairment, 66%
  • Dilated, fixed pupils, 63%
  • Ptosis, 59%
  • Dizziness, 44%

Botulism causes the following clinical features.

  • Acute bilateral cranial neuropathies
  • Symmetrical descending weakness (unlike polio)
  • Responsive and normal heart rate
  • No fever (unlike polio)
  • No sensory defects (unlike Guillain-Barré syndrome)
  • Autonomic features (unlike myasthenia gravis and the Eaton-Lambert syndrome)
  • Alert and responsive
  • Dry mucous membranes

Tick paralysis, magnesium intoxication, and diphtheria must be ruled out. The Miller-Fisher variant of Guillain-Barré syndrome also causes oculomotor dysfunction, but unlike botulism, ot produces marked ataxia. Early treatment with antitoxin is useful.

Bioweapons

Ken Alibek was in charge of 32,000 Soviet-era Russian scientists who were engineering bioweapons. He invented a powder that allowed anthrax particles to not stick to each other and therefore infect four times as many people.

The Russians developed the Popp strain of Marburg for use in MIRV missiles. Dr. Nikolai Ustinov was working with Marburg strain when he pricked his finger. He went into isolation and wrote a firsthand account of the symptoms. By day three after the needlestick, he developed headache and conjunctivitis; by day 5, he was vomiting and sweating blood. Ustinov died on day 7 after exposure. Variant U of Marburg was found to have an ID100 of 1 to 5 particles.

Chimeras

Chimeras are the disease offspring of unlikely parents. Examples include smallpox viruses imbued with Venezuelan equine encephalitis (VEE pox) or with Ebola (Ebola pox or blackpox).

Engineered Mousepox Virus

In an attempt to control mice in Australia, scientists injected them with mousepox virus plus an eggshell protein, zona pellucida 3. It was expected that the recipients would develop antibodies to zona pellucida 3, which would prevent them from conceiving. The first batch worked well, but the second did not work in Black-6 mice. Immunologists suggested adding interleukin-4 gene to boost antibody response and turn off T cells. This manipulation killed all mice by destroying the liver, either quickly or by chronic abscess. The researchers debated whether to publish their findings, knowing that bioweaponeers might benefit from this information, but did publish eventually. Thus, adding certain genes to a payload can turn a harmless virus into a lethal one.

Estimates of Casualties in Biological Attack

The Centers for Disease Control and Prevention estimated the number of deaths that would result from release of 50 kg of various diseases by aircraft along a 2-km line, with a target population of 500,000. Results ranged from 400 with Rift Valley fever to 95,000 with tularemia, and the respective number of incapacitated persons was 35,000 to 125,000.

Conclusion

Physicians have an obligation to recognize and treat unusual disease cluster early and to educate their colleagues and the public about control and prevention. Control measures ultimately based on ethical solutions will be difficult to achieve.

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