Bioterrorism Overview

Overview of Bioterrorism

• Deliberate attempts to induce infectious diseases date back to the Roman Empire
• Concerns about terrorist use of microbes or biological weapons programs have increased significantly in recent decades
• In the 1990s, biological agents of concern were grouped by the CDC into three tiered categories: A, B, and C
• Tier-specific assignment of organisms was based factors like dissemination, transmissibility, associated morbidity/mortality, and special preparedness needs
• The Department of Homeland Security (DHS) has developed a systematic framework to assess the risk of organisms, complementary to the CDC categories
• A subset of organisms is deemed a material threat to the national security of the United States
• In 2001, the dissemination of Bacillus anthracis spores through the U.S. postal system illustrated the potential havoc of bioterrorism
• Although only 22 people became ill from the Bacillus anthracis attack, apprehension extended nationally and internationally

What Is Bioterrorism?

• Bioterrorism involves the deliberate release of viruses, bacteria, or other germs (agents) to cause illness or death in people, animals, or plants
• These agents are often found in nature and can be altered to increase disease-causing ability, resist medicines, or spread more easily
• Biological agents can be spread through the air, water, or food
• Biological agents are difficult to detect and may not cause illness for hours to days
• Some bioterrorism agents like smallpox, can spread from person to person, while others, like anthrax, cannot

Bioterrorism Agent Categories

• Bioterrorism agents are separated into three categories based on ease of spread and severity of illness or death
• Category A agents pose the highest risk due to easy transmission, high death rates, potential for public health impact, and the possibility of public panic leading to special action for public health preparedness
• Category B agents are the second highest priority as they are moderately easy to spread causing moderate illness rates and lower mortality, requiring specific enhancements of the CDC's laboratory capacity and enhanced disease monitoring
• Category C agents are emerging pathogens that could be engineered for mass spread because they are easily available and can be easily produced/spread, and have a potential for high morbidity and mortality rates, as well as major health impacts

Category A Agents

• Anthrax (Bacillus anthracis)
• Botulism (Clostridium botulinum toxin)
• Plague (Yersinia pestis)
• Smallpox (variola)
• Tularemia (Francisella tularensis)
• Hemorrhagic fever viruses (e.g., Ebola)

Category B Agents

• Brucellosis (Brucella species)
• Epsilon toxin of Clostridium perfringens
• Food safety threats such as Salmonella
• Glanders (Burkholderia mallei)
• Melioidosis (Burkholderia pseudomallei)
• Psittacosis (Chlamydia psittaci)
• Q fever (Coxiella burnetii)
• Ricin toxin from Ricinus communis (castor beans)
• Staphylococcal enterotoxin B
• Typhus fever (Rickettsia prowazekii)
• Viral encephalitis like Venezuelan equine encephalitis
• Water safety threats like Vibrio cholerae

Category C Agents

• Emerging infectious disease threats, for example, Nipah virus and Hantavirus

Pathogens of Great Concern

• Smallpox
• Anthrax
• Botulism
• Glanders and Melioidosis
• Ebola and Marburg Hemorrhagic Fever
• Tularemia
• Epidemic Typhus
• Plague

Variola (Smallpox)

• The WHO General Assembly declared smallpox eradicated in 1980
• The destruction of remaining virus stocks has been delayed to allow for research to improve preparedness if smallpox recurs due to malevolent use
• The VECTOR laboratory and the CDC in Atlanta are the only two WHO-designated repositories for smallpox virus stocks
• The virus was mainly transmitted between humans through large-droplet respiratory particles inhaled by susceptible people due to prolonged face-to-face contact with someone infectious
• Less commonly, it spread through aerosol or direct contact with rash lesions or sloughed crusts
• The Variola major smallpox has four main clinical types

Clinical Types of Variola Major

• Ordinary smallpox (90% of cases) : viremia, fever, prostration, and rash are produced with mortality rates generally proportionate to the extent of the rash
  • Ranging from 10% for 'ordinary discrete' smallpox to 50-75% for a rarer presentation
• Vaccine modified smallpox (5% of cases): prodrome skin lesions are produced in previously vaccinated people with a mortality rate well under 10%
• Flat smallpox (5% of cases): slowly developing focal lesions with generalized infection leading to approximate 50% fatality are produced
• Hemorrhagic smallpox (Mortality invariably fatal within a week): caused bleeding into the skin and mucous membranes

Anthrax

• Anthrax is a worldwide disease that is found in domesticated and wild animals and secondarily may infect humans
• The WHO estimates between 2,000 and 20,000 human cases per year worldwide
• Anthrax remains enzootic in much of sub-Saharan Africa with more cases in wildlife, livestock, and humans than in most of the world
• Sub-Saharan Africa, Central/South America, and Eastern Europe tend to lack vaccination programs for livestock
• Bacillus anthracis is a gram-positive bacillus with rapid, nonhemolytic growth on blood agar and readily forms spores in the presence of oxygen
• Colonies have a characteristic "Medusa's head" appearance, also referred to as a "comet tail.”
• Bacillus anthracis is a Toxin producer with no human-to-human transmission

Diagnosis of Anthrax

• B/C (biopsy and culture) is the most useful routine lab test; growth at 6-24 hours
• Immunohistochemical staining, ELISA (titer >1:32), and PCR testing can identify Bacillus anthracis.
• A Gram stain and culture of vesicle content can identify Bacillus anthracis.
• A punch biopsy of the skin lesion can be used to confirm diagnosis.

Cutaneous Anthrax

• Cutaneous anthrax is the most common naturally occurring form, with approximately 2,000 cases reported yearly
• Incubation period is ~5 days (1-10 days)
• It initially presents as a pruritic macule and papule
• Formation of vesicles with serosanguineous fluid containing bacilli after the second day
• The infection progresses to a painless depressed black eschar that falls off in 1-2 weeks
• In untreated cases, mortality is around 20%
• It is often contracted through contact with animals or exposed skin that has made contact with contaminated products like wool

Pulmonary Anthrax

• Early phase manifests as vomiting, fever, cough, and chest pressure
• Second phase presents with tachypnea, stridor, shock, and bleeding
• Mediastinal lymphadenopathy and hemorrhagic necrosis are also present
• Mild cases do not exist and if left untreated the mortality rate is approximately 70%
• Occurs when you breathe in anthrax spores

Clinical Manifestations of Gastrointestinal Anthrax

• Responsible for approximately 1% of human cases Occurs typically 1 to 5 days after ingestion of contaminated meat

Clinical Manifestations of Anthrax Meningitis

• Secondary seeding of the meninges occurs during bacteremia in fulminant disease
• Death occurs within 24 hours in 75% of cases

Therapy for Anthrax

• Rapid antibiotic initiation is crucial
• Ciprofloxacin or doxycycline alone is used for cutaneous anthrax
• Pulmonary, gastrointestinal, and anthrax meningitis is treated with two bactericidal agents
  • Prefereably a quinolone like ciprofloxacin and a β-lactam like meropenem, combined with a protein synthesis inhibitor such as linezolid, clindamycin, rifampin, or chloramphenicol
• CNS penetration of antibiotics is important for treatment of potential meningitis

Botulism

• Botulism is a toxin-mediated paralytic illness caused by Clostridium botulinum
  • It causes muscle paralysis, breathing difficulty, and even death
• It is classified as:
  • foodborne botulism
  • infant botulism
  • wound botulism
  • iatrogenic botulism
  • botulism of undetermined etiology, or inhalational botulism
• Foodborne botulism occurs in outbreaks, whereas other forms are sporadic
• Foodborne botulism is associated with home-canned or fermented foods
• Infant botulism is historically associated with honey ingestion
• Wound botulism is associated with injection drug use of "black-tar" heroin
• Botulinum toxins A and B are used for therapeutic and cosmetic purposes and may cause iatrogenic botulism
• Botulism is a potential bioterrorism agent deployed by aerosol or ingestion
• Clostridium botulinum produces anaerobic spore forming gram-positive bacilli
• Is found in Soils, animals' intestines, marine, and fresh water
• It's spores tolerate 2 hours at 100°C (among the most potent neurotoxins, acetylcholine block)
• Type A, B, and E are found in almost all human cases
• Canned goods provide the perfect environment for spores to grow within anaerobic, low/high pH, low nutrient environments
• Toxin absorption is through mucosal membranes or wounds
• Within 24 to 72 hours of toxin exposure: cranial nerve dysfunction is followed by descending motor paralysis
• Sensation and sensorium are preserved
• With Food-borne botulism: Preformed toxin is ingested
• In food that is not properly prepared that is stored without adequate heat in ↑pH, low sugar, and O2 environments
• Supportive care remains the mainstay of botulism treatment
• Heptavalent botulinum antitoxin is available for non-infant botulism in the United States
• Human botulinum immune globulin (BabyBIG) is available for treating botulism in infants (younger than 1 year)
• Foodborne botulism can be prevented by proper food preparation
• There is no vaccine currently available

Tularemia

• Tularemia is a zoonotic disease caused by Francisella tularensis
• Tularemia is widely distributed but is primarily a disease of the Northern Hemisphere
• In 2010, most cases in the United States occurred in Arkansas, Missouri, Kansas, South Dakota, California, and Oklahoma
• Tularemia peaks in the late spring and summer in the United States
• Animal reservoirs include lagomorphs like rabbits/hares, and rodents
• Major transmission vectors are ticks and biting flies in the U.S., and mosquitos in Europe
• Transmission also occurs through aerosol droplets, contaminated mud or water, and animal bites
• High risk occupations for transmission include laboratory workers, farmers, landscapers, veterinarians, sheep workers, hunters/trappers, cooks, or meat handlers
• Tularemia begins abruptly with fever, chills, headache, anorexia, and fatigue following an average incubation of 3 to 5 days

Patterns of Tularemia

• Six major patterns of illness are: ulceroglandular, glandular, oculoglandular, pharyngeal, typhoidal, and pneumonic, with Secondary rashes being relatively common
• Pneumonic and typhoidal tularemia are expected to be the primary patterns of illness resulting from a bioterrorism event
  • Pneumonic tularemia occurs when you breathe in dust or aerosols containing the organism, or when other types like ulceroglandular tularemia spread to the lungs
• Lymph node suppuration and persistent debility are the most common complications of tularemia
• Diagnosis relies on clinical suspicion, lab personnel should be notified whenever tularemia is suspected, given its potential danger
• F. tularensis is a Tier 1 select agent, possession and shipment are tightly restricted
• Routine cultures and smears are often negative, and the diagnosis is usually confirmed serologically
• direct fluorescent antibody and polymerase chain reaction tests are available in specialized laboratories for rapid diagnosis
• Drugs of choice when therapizing tularemia is streptomycin and gentamicin are the preferred drugs, except meningitis
• Selected adults and children with mild to moderate disease may be treated with oral agents (Cipro/Doxycycline)
• Surgical therapy is limited to drainage of suppurated nodes or of empyemas
• Adults with suspected or proven high-risk exposure to F. tularensis should take either ciprofloxacin, 500 mg, or doxycycline, 100 mg, orally twice a day for 14 days
• Observation without prophylactic antibiotics is appropriate for exposed children (except during a bioterrorist event) and adults with lower risk exposures

Plague

• Yersinia pestis (Gram negative) causes plague
• Life cycle: Transmission through contact with wild rodents (work, hunting, camping), a major epidemic of Rattus species, and from Human respiratory exposure; also through flea bite and infected materials in Europe 14th century -The rodents were not the actual carriers, but the fleas
• Bubonic Plague: the most common form, exhibits an incubation period of 2-6 days which causes Fever, chills, malaise and headache, enlarged and tender lymph nodes (buboes) at ~ 24 hr, with necrosis and sero-sanguineous discharge
  • If untreated mortality is 60% but has with prompt treatment mortality is 5%
• Septicemic plague: the organism enters, and causes frequent GI symptoms gangrene of finger and nose tips (black death), and metastatic foci
  • if left untreated there is 100% mortality for septicemic plague
• Pneumonic plague: Highly contagious and most deadly.
  • if left untreated there is 100% mortality for Pneumonic Plague
  • the illness can result in The most fulminant (death within ~24 hrs) exhibits an Incubation period is 1 - 3 days
  • it's symptoms include Cough, chest pain, hypoxia, and hemoptysis, and readily spreads from person to person (only the form that infectious can spread droplets)

Diagnosing Plague

• Requires suspicion, that is brought about by exhibiting symptoms in those at risk must be initially suspected:
  • followed by a Gram-stain
• Diagnosis must be confirmed by analyzing Cultures
  • Performing fourfold agglutination tests
  • Or if Single antibody titer tests show titers of 1:128 (while not taking into account prior exposure/vaccinations)
• effective antibiotic therapy must be given as after obtaining diagnostic specimens!
• Since the 1940’s The choice of antibiotics has remained unchanged:
  • Streptomycin remains a choice of drug -Gentamicin is also proposed as an effective alternative -Doxycycline is now the choice of drug, for For those with contraindications aminoglycosides
• Recently the Federal Drug Administration (FDA) approved fluoroquinolone Levoflaxacin!
  -Based on animal rule, -Showed efficacy in vitro & shown within animal models, specifically African Green monkeys. -Treating Y. pestis Infections

Ebola & Marburg Hemorrhagic Fever

• Ebola and Marburg Hemorrhagic Fever are considered to be a significant threat for use as biological weapons due to the potential illness and death that is associated with them
• These viruses are highly infectious, easily spread from person to person and associated with high mortality
• There are no vaccines or treatments that have been shown to be safe and effective
• There were more than 27,000 confirmed or suspected instances of Ebola & Marburg Hemorrhagic Fever were reported by the World Health Organization
• Guinea, Liberia, and Sierra Leone had the most instances of Ebola & Marburg Hemorrhagic Fever
• This was the most complex and had the Largest of all Ebola epidemic has ever been recorded that the W.H.O. and contained more cases and deaths

Glanders & Melioidosis

• Glanders is caused by infection with the bacterium Burkholderia mallei, and melioidosis is caused by Burkholderia pseudomallei.
• Melioidosis is endemic in Southeast Asia and northern Australia
• The disease is associated with a high mortality rate due to the speed with which septicemia develops, particularly in immunocompromised hosts, and the inherent resistance to antibiotics
• Prolonged courses of antibiotics are required to treat melioidosis. Despite prolonged antimicrobial therapy, recurrent disease is common -Both Glanders and Melioidosis are primarily a zoonotic disease in Africa, Asia, the Middle East, and Central/South America.
• Human susceptibility has not been thoroughly studied, while *B. mallei infection however the organism is highly infectious in the laboratory setting
• As with melioidosis, prolonged antimicrobial therapy is required to treat to prevent relapse

Epidemic Typhus

• Epidemic typhus is caused by Rickettsia prowazekii, a bacterium carried and transmitted by body lice
• Associated with Naturally War, Famine and/or environments that are hygienic at best, that can lead to lice infestations (the bacteria is easily aerosolized)
• When Prompt antibiotics therapy is used the mortality is low but diagnosis can show non-specificity of the disease