Bioterrorism and Biological Weapons

Overview

• Deliberate attempts to induce infectious diseases date back to at least the Roman Empire.
• Concerns have increased over recent decades regarding the use of microbes by terrorists or countries with biological weapons programs.
• In the 1990s, the CDC grouped biological agents of concern into three tiered categories: A, B, and C.
• Tier-specific assignment was based on factors like dissemination, transmissibility, morbidity, mortality, and preparedness needs, including laboratory preparedness.
• Complementary to the CDC categories, the Department of Homeland Security (DHS) developed a risk assessment framework.
• A subset of organisms poses a material threat to U.S. national security.
• In 2001, an attack using Bacillus anthracis spores disseminated via the U.S. postal system illustrated the potential havoc.
• While only 22 people became ill across five states, fear and apprehension spread nationally and internationally.

What is Bioterrorism?

• A bioterrorism attack involves the deliberate release of viruses, bacteria, or other germs (agents) to cause illness or death in people, animals, or plants.
• Agents can be altered to enhance their ability to cause disease, resist medicines, or spread more easily.
• Biological agents can be spread through air, water, or food.
• Terrorists might use biological agents because they are difficult to detect and have a delayed effect.
• Some bioterrorism agents, like smallpox, can spread between people, while others, like anthrax, cannot.

Bioterrorism Agent Categories

• Bioterrorism agents are separated into three risk-based categories based on ease of spread and severity.
• Category A poses the highest risk.
• Category B is the second highest risk.
• Category C agents are emerging threats.

Category A Agents

• These high-priority agents pose the highest risk to public and national security because:
  • They can be easily spread person to person.
  • They result in high death rates.
  • They might cause public panic and social disruption.
  • They require special action for public health preparedness.
• Examples
  • Anthrax (Bacillus anthracis)
  • Botulism (Clostridium botulinum toxin)
  • Plague (Yersinia pestis)
  • Smallpox (variola)
  • Tularemia (Francisella tularensis)
  • Hemorrhagic fever viruses (Ebola)

Category B Agents

• These agents are the second highest priority because:
  • They are moderately easy to spread.
  • They result in moderate illness rates and low death rates.
  • They require specific enhancements of CDC's laboratory capacity and enhanced disease monitoring.
• Examples
  • Brucellosis (Brucella species)
  • Epsilon toxin of Clostridium perfringens
  • Food safety threats (e.g., 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 (e.g., Venezuelan equine encephalitis)
  • Water safety threats (e.g., Vibrio cholerae)

Category C Agents

• These third-highest priority agents include emerging pathogens that could be engineered for mass spread in the future
  • They are easily available.
  • They are easily produced and spread.
  • They have potential for high morbidity and mortality rates and major health impact.
• Examples
  • Nipah virus
  • Hantavirus

Pathogens of Great Concern

• These are Smallpox, Antrax, Botulism, Glanders and Melloidosis, Ebola and Marburg Hemorragic Fever, Tularemia, Epidemic Typhus and Plague.

Variola (Smallpox)

• In 1980, the WHO declared smallpox eradicated
• Scheduled destruction of remaining virus stocks has been delayed to allow research for improved preparedness.
• The VECTOR laboratory and the CDC in Atlanta are the only WHO-designated repositories for smallpox virus stocks.
• The virus was most often transmitted between humans via large-droplet respiratory particles inhaled by susceptible persons who had:
  • Prolonged close face-to-face contact with an infectious person.
  • Spread less commonly via aerosol.
  • Direct contact with the rash lesion or sloughed crust material from the scab.
• Variola major smallpox was differentiated into four main clinical types:
  • Ordinary smallpox (90% of cases) produced viremia, fever, prostration, and rash, with mortality rates proportionate to the extent of rash and ranged from <10% to 50-75%.
  • (Vaccine)-modified smallpox (5% of cases) produced a mild prodrome with a mortality rate well under 10%.
  • Flat smallpox (5% of cases) produced slowly developing focal lesions with generalized infection and an approximate 50% fatality rate.
  • Hemorrhagic smallpox (<1% of cases) induced bleeding into the skin and mucous membranes and was invariably fatal within a week of onset.

Anthrax

• Anthrax is a worldwide disease of domesticated and wild animals that secondarily may infect humans.
• The World Health Organization (WHO) estimates 2,000 to 20,000 human cases per year.
• Anthrax remains enzootic in much of sub-Saharan Africa; humans have more reported cases than in most of the rest of the world.
• Bacillus anthracis is a gram-positive bacillus with rapid, nonhemolytic growth on blood agar that readily forms spores in the presence of oxygen.
• Colonies have a characteristic "Medusa's head" appearance, sometimes referred to as a "comet tail," appearing slightly curled at the periphery.
• Anthrax is a toxin producer.
• There is no human to human transmission.
• B/C is the most useful routine laboratory test; growth at 6 – 24 hours.
• Immunohistochemical staining, ELISA (titer >1:32), PCR can be used for diagnosis.
• Gram stain and culture of vesicle content can be used for diagnosis
• Punch biopsy of the skin lesion can be used for diagnosis.

Cutaneous Anthrax

• This is the most common naturally occurring form, with 2000 cases reported per year.
• The incubation period is ~5 days (1-10).
• Symptoms include pruritic macule and papule.
• Vesicles appear after the 2nd day (serosanguineous fluid with bacilli); round ulcer appears.
• A painless depressed black eschar falls off in 1-2 weeks.
• The mortality rate is 20% if left untreated.

Pulmonary Anthrax

• These are the Stages
  • Early phase: vomiting, fever, cough, chest pressure.
  • 2nd phase: tachypnea, stridor, shock and bleeding.
• Results in Mediastinal lymphadenopathy and hemorrhagic necrosis.
• Mild cases do not exist.
• Mortality is ~70% with treatment.

Clinical Manifestations: Gastrointestinal Anthrax

• It accounts for ~1% of human cases.
• This typically occurs 1-5 days after ingestion of contaminated meat.

Clinical Manifestations: Anthrax Meningitis

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

Therapy

• Rapid initiation of antibiotics for all stages is crucial.
• A single drug, ciprofloxacin or doxycycline, is used for cutaneous anthrax.
• Pulmonary, gastrointestinal, and anthrax meningitis needs treatment with two bactericidal agents, preferably a quinolone like ciprofloxacin.
  • Combine it with a β-lactam such as meropenem, combined with a protein synthesis inhibitor such as linezolid, clindamycin, rifampin, or chloramphenicol.
• Important to consider central nervous system penetration of antibiotics for the treatment of potential meningitis.

Botulism

• Botulism is a toxin-mediated paralytic illness caused by Clostridium botulinum, causing muscle paralysis, breathing difficulty, and even death
• Botulism is classified as:
  • Foodborne botulism.
  • Infant botulism.
  • Wound botulism.
  • Iatrogenic botulism.
  • Botulism of undetermined etiology.
  • Inhalational botulism.
• Foodborne botulism occurs in outbreaks, whereas other forms are sporadic.
• Foodborne botulism is associated with home-canned or fermented foods.
• Infant botulism historically is 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/cosmetic purposes and my cause iatrogenic botulism.
• Botulism is a potential bioterrorism agent deployed by aerosol or ingestion.
• Clostridium botulinum is an anaerobic spore-forming gram-positive bacilli.
• Its found in Soils, animals intestines, marine ,and fresh water .
• Spores tolerate 2 hours at 100°C and the spores contain potent neurotoxin acetylcholine block.
• Types A, B, and E are in almost all human cases.
• Canned goods provide the perfect environment for spores to grow.
• Canned goods provide the ideal environment for spores to grow, anaerobic, low/high pH, low nutrient environments.

Pathogenesis and Clinical Manifestations

• Toxin absorption occurs through mucosal membranes or wounds.
• Within 24-72 hours of toxin exposure there is cranial nerve dysfunction; followed by descending motor paralysis.
• During infection, the sensorium and sensation are preserved.

Clinical Manifestations: Food-borne

• Preformed toxin ingestion can cause botulism.
• Especially if Food is prepared without adequate heat and is stored in ↑pH, low sugar, ↓O2 environment

Therapy

• Supportive care remains the mainstay of botulism treatment.
• Heptavalent botulinum antitoxin is available for noninfant botulism in the United States.
• Human botulinum immune globulin (BabyBIG) is available for the treatment of infant botulism.
• Proper food preparation prevents foodborne botulism.
• There is currently no available vaccine.

Tularemia

• Tularemia is a zoonotic disease caused by Francisella tularensis.
• The Northern Hemisphere has a wide distribution of Tularemia
• In the US the majority of cases reported in 2020 occurred in Arkansas, Missouri, Kansas, South Dakota, California, and Oklahoma.
• Tularemia mainly appears in the late Spring and Summer in the United States.

Transmission of Tularemia

• Lagomorphs and rodents are animals reservoirs
• Major vectors of transmission include ticks and biting flies in the US and mosquitoes in Europe.
• Other routes are aerosol droplets, contaminated mud or water, and animal bites.
• Occupations with increased risk include laboratory workers, farmer, landscapers, veterinarian, sheep worker, hunter or trapper, and cook or meat handlers.

Clinical Manifestations

• It begins abruptly with fever, chills, headache, anorexia, and fatigue, with an average incubation period of 3 to 5 days.
• There are six major patterns of the illness: ulceroglandular, glandular, oculoglandular, pharyngeal, typhoidal, and pneumonic . Secondary rashes are relatively common.
• Pneumonia and Typhoid will result from bioterrorism
• The most common complications of tularemia result in lymph node suppuration and persistent debility.

Diagnosis

• Diagnosis rests on clinical suspicion and laboratory personnel need immediate notification to prevent the spread.
• F. tularensis is a Tier 1 select agent, and its possession and shipment are restricted.
• Routine cultures and smears are often negative, and is often confirmed serologically.
• Direct fluorescent antibody and polymerase chain reaction tests for rapid diagnosis are available in specialized laboratories.

Therapy

• Streptomycin and gentamicin are the drugs of choice for all forms 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 exposure to F. tularensis should take Ciprofloxacin 500mg or Doxycycline 100mg orally twice daily for 14 days.
• Observation without antibiotics can be appropriate for exposed children (except during a bioterrorist event) and for adults with low exposure risk.

Plague

• Plague is caused by GN cocobacillus (Yersinia pestis).
• Life cycle includes wild rodent contact during work, hunting, camping, and epidemics upon Rattus species invasion.
• The fleas are the actual carriers.
• A major outbreak killed 75millions in 14th century Europe (Black Death).
• Human to Human transmissions via respiratory exposure exist via flea bites and infected materials.

Bubonic Plague

• It's the most common form.
• It's incubation period is 2-6 days.
• Symptons are fever, chills, malaise and headache.
• Enlarged, tender lymph nodes commonly called buboes.
• This leads to Necrosis and sero-sanguineous discharge.
• Mortality lies at Rx = 5%; Mortality without Rx = 60%.

Septicemia Plague

• Organisms enters the blood.
• There are frequent GI symptoms.
• Gangrene of fingers and nose tips presents (black death).
• Causes Metastatic foci
• Mortality rate without treatment is 100%.

Pneumonic Plague

• It has a Very High mortality within 24 hours
• It has an incubation of 1-3 days
• Some symptons are Coughing, Chest pain, Hypoxia and Hemoptysis.
• Its only spread directly through droplets person to Person by infectious

Diagnosis

• A clinical diagnosis is Suspected based on:
  • Symptoms in a person at risk
  • Gram-stain results
• Plague is confirmed with:
  • Cultures.
  • Fourfold agglutination test.
  • Diagnosed with A single antibody titer of 1:128 for patients with pre exposure.

Therapy

• Effective antibiotic therapy should be given immediately after obtaining diagnostic specimens.
• Streptomycin has been considered the drug of choice since its introduction in the 1940s
  • Prompt administration can reduce the mortality rate in bubonic plague to 5% or less.
• Gentamicin has been proposed as an acceptable alternative Where streptomycin is not available
• For patients with contraindications to aminoglycosides, doxycycline is the agent of choice.
• The FDA approved levofloxacin for the treatment of Y. pestis infection.
• It's based on "animal rule," series of efficacy including monkeys.

Ebola & Marburg Hemorrhagic Fever

• Ebola and Marburg hemorrhagic fever viruses are a significant threat for weaponization for severe illness and death.
• There are only a few cases of it.
• They are both highly infectious and spreads easily from person to person and comes from high mortality.
• There are no shown treatments and vaccines available.
• There are >27,000 cases with more than 11,000 deaths. Guiana, Liberia and Sierra Leone have the most severe.
• Ebola epidemic is complex and recorded death is more than ebola combined.

Glanders & Melioidosis

• Glanders is caused by infection with the bacterium Burkholderia mallei
• Melioidosis is caused by Burkholderia pseudomallei.
• Melioidosis is endemic in Southeast Asia and northern Australia.
• The disease has a high mortality due to the speed of septicemia and antibiotic resistance
• Prolonged courses of antibiotics are required to treat melioidosis.
• Glanders is primarily a zoonotic disease in Africa, Asia, the Middle East and Central/South America.
• Human susceptibility to B. mallei infection in laboratories isn't studied but highly infectious there
• The aim is to prolong it to treat and not revert.

Epidemic Typhus

• Epidemic typhus is caused by Rickettsia prowazekii spread via by body lice.
• Occurs, with war, famine, not enough clean hygiene do to lies spreading the bacteria
• Antibiotics can treat with Low Mortality but its is nonspecific and can be hard to classify.