Biologic Weaponsin War

The use of germs to kill, immobilize or demoralize the Enemy.

It WILL happen.

Again.

Vicken Y. Totten MD, MS

FACEP 1

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Warfare agentsProjectiles and explosives – physical injuries

incompatible with lifeChemical and nuclear – poisoning

incompatible with lifeEco devastation – the environment will no

longer sustain human lifeCarthage

Genetic imperialismRape and forced impregnation change a genome

“Germ Warfare”

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Purpose of bioterrorism

To instill fear, change lifestylesImmobilize populationsWaste resources Occupy trained personnelWeaken the Enemy

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Germ Warfare (BioWar)

Different agents have different infectious dose, germ survival in the environment, effectiveness, availability & LD-50, but: all should be feared.

Psychological impact almost as lethal as their physical effects.

Hot zones where contracting these germs means sure but slow! and contagious! death.

1 to 2 weeks turn your body into liquefied, virus - infected tissue culture. You

Hemorrhage virus infected blood: potential to wipe out 20-99% of population

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The Salt Lake Tribune (5/12, May)

“ if "a killer flu strikes, with several thousand sick or injured and no room to spare in understaffed hospitals, care will be denied to the sickest adults and children."

Individuals "who are severely burned, have incurable and spreading cancer, fatal genetic diseases, end-stage multiple sclerosis or severe dementia will be turned away.

They can be sent elsewhere for comfort care, such as painkillers, but they will not be treated for the flu, according to the guidelines.

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BioWeapons = Germ Warfare

Not new: used for thousands of yearsWhat’s new is “Weaponizing”

increases virulenceAssists in spread by technology

Biologic capability is relatively inexpensive and widespread.

Risk of a serious bioterrorism incident.

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Serendipitous and deliberate

Zoonoses in the “New World”Deliberate small pox in the New WorldActual infection is not even required:

post attack, US anthrax hoaxes had many of the effects hoped-for from actual infections: Disrupting business, life styles and demoralizing the Enemy.

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Ashdod of the Philistines1320-1000 BC

I Samuel: The Philistines stole the Israelites’ Ark of the Covenant.

Rats (mice) appeared, then “the Lord’s hand on the people of Ashdod and its vicinity, throwing [the city] into a great panic. He afflicted the people of the city, both young and old, with an outbreak of tumors (emerods) in the groin.”

As a result, the Philistines returned the Ark of the Covenant with “five golden emerods and five golden mice.”

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Plague of Athens (430-426 BCE)

Thucydides’ “The Peloponnesian War” attributed the success of the war to the plague.

The plague arrived in the first days of summer, during the second year of the war, at the same time as Archidamus, son of the king of Lacedaemon.

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Plague of Athens

Spartans besieging the city were not affected by the disease.

Many Athenians died, and eventually capitulated.

Plague probably came by boat with the alleys up from Egypt, with immune soldiers.

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14th and 15th century Europe.

Armies would fling diseased and decaying cadavers (especially of slaughtered enemy soldiers) over protective town walls to demoralize and sicken the besieged cities.

1346 -1347. Tartars defeated Genoese army by catapulting plague-dead soldiers over the walls into Kaffa (Caffa), by the Black Sea

1422. Lithuanians flung dead soldiers and 2000 cart loads of excrement into Carolstein.

These battles contributed to the 25 million victims of the European Black Plague

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THE BLACK DEATH PANDEMIC

Worst from 1346 and 1352 with outbreaks till 1800s

Killed 25 million people(1/3 of the world’s population at that time)

30-60% of the populations of large cities died from the disease

final “foray” occurred in Marseilles in 1720.

Still around13

World War II British

tested anthrax in Gruinard Island off the coasts of Scotland.

Anthrax can live decades in soil.Cleaning the Island years later was very

costly.

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United States, Post WWII

1950, Germany accuses US of releasing Colorado beetles over German crops.

China, North Korea, and the Soviet Union accused the US of using biological weapons during the Korean War.

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Second Sino-Japanese War

The Imperial Japanese Army bombed Ningbo with fleas carrying bubonic plague.

1941. More plague-contaminated fleas airdropped by 40 planes onto Changde.

These operations caused epidemic plague outbreaks.

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United States 1980s

September 1984, The Dalles, OR, dozens got food poisoning: Salmonella enterica typhimurium.

1st: Shakey’s Pizza. Later, 10 more restaurants.More than 700 ill; the only hospital ran out of

beds. CDC involved. Deliberate contamination was

proved; the Rajneesh cult was suspected but never convicted.

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Weaponized Super-Germs vs common organisms

Small inoculums will infect large populations (highly infectious)

Easily transmitted from person to person: airborne better than contact.

Either lethal or prolonged illness with lasting morbidity (ties up Enemy resources and diverts them from War Effort; demoralizes)

Treatment: none

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Properties for “Maximum Credible Threat”

highly lethal & toxiceasily produced in large quantities.environmental & aerosol stabilityDispersal capability to (1 mm to 5 mm

particle size) person to person communicationno treatment or vaccine.

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Potential human biological pathogens.

NATO handbook lists 39 agents including bacteria, viruses, rickettsiae, and toxins.

Biologic agents spread on their own; therefore, the “dose” needed is less.

Highly toxic poision, Ricin: 8 metric tons vs 1 kg anthrax for same number casualties

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Comparison

Agent   Type Untreated

Mortality %

 Relative Infectivity

Dose

 Incubation Period

 Treatment

Anthrax Bact-eria

80 1000+ Spores

1-4 Days Pre Exposure Antibiotics*

Botulism Virus 40-90 Moderate 2-7 Days Some Antibiotics

Plague Bact-eria

90 10 Organisms

2-3 Days Antibiotics

Smallpox Virus 75 High 7-14 Days Vaccine

Tular-emia

Bact-eria

30 25 Organisms

2-4 Days Antibiotics

V.H.F. Virus 50-90 High 2-7 Days Antibiotics

* Not effective after symptoms develop 21

Anthrax, Plague and Smallpox: best candidates

Highly lethal: Anthrax, untreated anthrax > 80% die; Variola Major:

30% of unvaccinated patients die; Septicemic Plague 100%

All can be produced in quantity Plague available world wide; no need to raid

containment facilitiesAnthrax & Smallpox stable for aerosol

transmission; Anthrax spores survive for decades; smallpox can be freeze-dried.

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All Weaponized.

Iraq produced anthrax for use in Scud missiles; former Soviet Union produced smallpox virus by

the ton; Japanese weaponized plagueAll uncommon diseases with non-specific initial

presentationDelayed recognition will allow for secondary

spreadVaccines poor or limited in availability.

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Treaties: honored in the breach

1972 Biological Weapons Convention Soviet Union in 1979 accidentally

released anthraxIraq in 1995 had anthrax, botulinum

toxin, and aflatoxin

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United States 1969 stockpile:

Bacillus anthracis, botulinum toxin, Francisella tularensis, Brucella suis, Venezuelan equine encephalitis virus, staphylococcal enterotoxin BCoxiella burnetti (9).

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Soviet Union stockpile:

smallpox, plague, anthrax, botulinum toxin,equine

encephalitis viruses,

tularemia, Q feverMarburgmelioidosis Typhus

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More details about:

Plague (Yersinia pestis), Smallpox (Variola major and minor)Anthrax (Bacillus anthracis), Tularemia (Francisella tularensis)Influenza is seldom mentioned but would be

an excellent BioWeaponMany diseases have been accused of being

BioWeapons, including SARS, Swine Flu and HIV

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Plague

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Plague (Yersinia pestis),

gram-negative, anaerobic coccobacillus. transmitted to humans through fleas,

rodents, or droplet infection. Human-to-human transmission quick Called “Black death” because the septic

shock causes cyanosis, & peripheral gangrene

“Blackening”29

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Rodents and fleasEndemic in rodents; fleas transmit but

don’t sicken. The next mammal is the next victim. 10,000 years of human garbage attracting

flea-ridden rats. Less a disease of nomads.

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Plague – mode of transmissionNatural: Fleas from

infected rodents BioWar: aerosolized Large aerosol

droplets contain 100-500 organisms

Person-to-person transmission

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Plague

Worldwide: one of most feared diseases throughout history

As many as 200 million deaths in last 1000 years.

Not gone! India had outbreak in 1994. Endemic in US Southwest in rodents

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Plague: Clinical Manifestations

Cervical bubo Ecchymosis, septicemia Gangrene, septicemia

Inglesby T, et al. JAMA 2000;383:2281

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Plague

3 forms: bubonic, pneumonic and septicemic; Bubonic is classic.

infected individuals die within 2 -3 daysBubonic has a mortality of 30 - 75 %;

pneumonic & septicemic forms have mortality of 90 - 100 % respectively

Septicemic plague usually occurs secondary to bubonic or pneumonic plague.

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Plague:

Black lesions & bubos

(fingers & toes, penis &

nose)

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Symptoms: Bubonic Plague

AMS: Hallucinations, headache, fever, chills.

semiconscious to lethargic.

" Madness” (agitated delirium)

Hematemesis, bloody diarrhea

Lymphadenopathy: swollen, tender lymph nodes (buboes) in armpits, groin; even supra-clavicular and cervical buboes rupture & suppurate

Black blisters and hematemesis

Recovered victims disabled: muscular tremors, “withered thighs and tongues“

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Plague bubo

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Plague Septicemia

Non-specific gram-negative septicemic symptoms:

Flu-like illness rapidly progresses to pneumonia, hemoptysis.

Blood cultures +, but no lymphadenopathy; respiratory contagion at 2 to 5 feet.

Pneumonic plague is 100% fatal unless treatment is given with 24 hours of the onset of symptoms.

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Pneumonic Plague

Most contagious and deadly: pneumonic plague

Airborne person-to-person airborne spread.

Y. pestis is not spore forming, and is viable for only 60 minutes as an aerosol.

Doesn’t live long on surfaces.

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Pneumonic Plague: CXR

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Plague Diagnosis and Treatment

CXR nonspecificSuspicion, setting, environmentStandard treatment of bubonic, septicemic, or

pneumonic plague is streptomycin, 30mg/kg IM q 12 h x 10 days.

alternatives: chloramphenicol, gentamicin, or doxycycline.

Chemoprophylaxis includes treatment with tetracycline or doxycycline.

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Plague Vaccine

Not a generally viable optionThe Greer vaccine is an inactivated form

of the disease, and requires a course of injections over 6 months.

A recombinant sub-unit vaccine is being investigated.

Outbreak would spur vaccine development – too late

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Smallpox

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Smallpox Communicability

Contact: fomites, person to personAerosol: communicability by aerosol

requires negative-pressure isolation.One single case -> 10 to 20 others. No more than 20% of the population has

any immunity from prior vaccination No acceptable treatment

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Smallpox: Mode of transmissionPatient-to-patient transmission likely

Droplets, Large & Small

More infectious if coughing or bleeding

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Smallpox – the Virus

2 Wild typesVariola major Variola minor

Variola called "smallpox" to distinguish it from Syphilis, the "great pox"

Smallpox is believed to have emerged in human populations about 10,000 BC.

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Pustules up close. Note: thick covering of skin. not like typical blisters.

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Small Pox Symptoms:

Maculopapular rash, then Raised fluid-filled blisterscharacteristic scars, commonly on the face,

which occur in 65–85% of survivors.Blindness resulting from corneal ulceration and

scarring; Limb deformities due to arthritis and osteomyelitis are less common complications, 2–5% of cases.

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Variola DiseasesV. major produces a more serious

disease than V. minor V. major mortality 30–35% V. minor causes a milder form of disease

(also known as alastrim, cottonpox, milkpox, whitepox, and Cuban itch; kills about 1% of its victims.

?Protective immunity?

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Smallpox versus

chicken pox

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Smallpox

Lesions progress simultan-eously; in Chicken pox they come in crops

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Biological Warfare Using Smallpox

Ravaged Europe; surviving population relatively immune

Frequently used against American Indians:

The British: June 24 1763, William Trent, a local trader, wrote, “…we gave them two Blankets and an Handkerchief out of the Small Pox Hospital. I hope it will have the desired effect.“

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Diagnosis

Clinical setting: classic syndrome & rash is enough to make the diagnosis

Electron Microscopy of vesicle; see Orthopox virus; does not prove variola

Culture definitive but SLOW. Chick membrane or cell culture

PCR (ref lab) is faster

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TreatmentIsolation!!Supportive care

Fluid balanceElectrolytesHemodynamic supportRespiratory support if needed

No proven effective antiviralsAntibiotics for secondary infections

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Smallpox Infection Control

Strict Universal PrecautionsPrevent inhalation of particles 5µ or

smallerTransfer to appropriate isolation roomIn large epidemic, may cohort patientsLimit transportation

(but use mask on patient if necessary)

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Post-Exposure ProphylaxisVaccine

Partially effective up to 3 days s/p exposureReduces incidence 2-3 foldDecreases mortality by ~50%

Plus Vaccinia immune globulin (VIG)3 fold decrease in incidence and mortalityPassive immunity for 2 weeks

(?) Cidofovir – antiviral agent is effective in animals against other poxviruses

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Smallpox prevention

No more wild smallpox Vaccine available

Last case 20 years agoImmunization may NOT

confer lifelong immunity.CDC has 10-15M doses

of vaccine, can produce more fairly quickly

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Reactions to Smallpox Vaccine

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More reactions

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Anthrax and tularemia (rabbit fever)

Most infectious in aerosolcause the highest number of dead and

incapacitatedgreatest downwind spread

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Anthrax &Tularemia (rabbit fever)

These are the most infectious aerosolsAerosols cause the highest number of

dead and incapacitatedSpread downwind & person to personAvailable in the wildWeaponized versions are Abx resistant

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Anthrax

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Anthrax history

Biblical Egyptian plague. Bacillus anthracis, a gram-positive, spore

forming bacillus. Transmission by inhalation, ingestion, or

skin breaks from infected animals or their products, or from terror attack.

Often associated with sheep and wool

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Cutaneous lesions are black

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Anthrax as BioWeapon

Anthrax as a Biological Weapon, 2002: Updated recommendations for management

JAMA. 2002;287(17):2236-2252 (doi:10.1001/jama.287.17.2236)

Thomas V. Inglesby; Tara O'Toole; Donald A. Henderson; et al.

http://jama.ama-assn.org/cgi/content/full/287/17/2236

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Lesion of Cutaneous Anthrax Associated With Microangiopathic Hemolytic Anemia and Coagulopathy in

a 7-Month-Old Infant

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Infant w Cutaneous Anthrax

Previous slide photo was from hospital day 12, when 2-cm black eschar was present in the center of the cutaneous lesion.

Reprinted from Freedman et al.

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BioWar Anthrax not newAerosol technologies for large-scale

dissemination are developed and testedBrits weaponized Anthrax pre-WWII1995, Iraq acknowledged producing

weaponized AnthraxSoviet Union & at least 13 other

countries: Clear evidence of offensive biological weapons programs.

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US: 2001 Anthrax AttacksPowder containing Anthrax spores in at

least 5 letters to Florida, New York City, and Washington, DC.

22 confirmed or suspected Anthrax cases B anthracis spores in all the letters were

“Ames strain” a research strainAerosol release of B anthracis would be

odorless and invisible and would have the potential to travel many kilometers before dissipating.

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Types of Anthrax

cutaneous, (Woolsorter's disease), gastrointestinalinhalationalCNS (meningitis)Anthrax invades the lymphatic system

and causes hemorrhages, sepsis, produces necrotizing toxins & death

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Cutaneous anthrax stemming from wearing contaminated wool scarf

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Cutaneous anthrax

inoculation of spores through open skin lesions. Painless, pruritic papules appear w/i 5 d. Papules develop into vesiclesBy 7 days, central necrosis develops Necrosis progresses to black eschar that

eventually sloughs off. Cutaneous: Not usually fatalHalf the victims of mailed powdered anthrax

2001 got cutaneous anthrax.

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Cutaneous Anthrax EscharRaised, vesiculated edge, inflamed, and with a black base to the ulcer

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Cutaneous anthrax ulcer

Antibiotics reduce systemic symptoms

Antibiotics don’t alter lesion course

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Gastrointestinal Anthrax

Seen in poor, developing countries with food shortages or inadequate food inspection. Sub-Saharan Africa, Central Asia, Russia, India, and Thailand

Usually have concurrent cutaneous cases from butchering the affected animal or handling the infected meat

Probable frequency: one outbreak per 64 infected animals eaten.

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Gastrointestinal anthrax

From eating contaminated meat:Starts with pharyngeal ulcers and edema. Hemorrhagic mesenteric adenitis, ascites,

hematemesis, and melena may occur.Morbidity from loss of blood, fluids,

electrolytes. Subsequent shock. Death from intestinal perforation or anthrax

toxemia. Symptoms subside in 10 to 14 days in survivors

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Inhalational Anthrax

Sudden, severe, acute febrile illness in persons at risk following a specific attack

Fulminant course and death or acute febrile illness

Example: from 2001 attacks: postal workers, members of the news media, and politicians and their staff

Half got inhalational anthrax

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Inhalation anthraxUsually fatal. Infective dose is 8,000-15,000 spores. Flu-like symptoms for 4 days. Primary pulmonary infection rare. Endospores are engulfed by alveolar macrophages,

get transported to the mediastinal and hilar lymph nodes, germinate and multiply in lymph nodes.

Hemorrhagic mediastinitis, peribronchial hemorrhagic lymphadenitis, Lymphatic drainage blocked.

Pulmonary edema. Toxin released into circulation.Death from septicemia, toxemia, or pulmonary

bleeding/edema.

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Anthrax CXRCXR: widened mediastinum (classic

but not so common), infiltrates, pleural effusion

Chest CT: hyperdense hilar and mediastinal nodes, mediastinal edema, infiltrates, pleural effusion

Hemorrhagic mediastinitis, hemorrhagic thoracic lymphadenitis, hemorrhagic meningitis;

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Diagnostic tests Toxin: ELISA Peripheral blood smear & culture: gram-

positive bacilli CXR: classically, “widened mediastinum”

pleural effusion, mediastinal edema (boards question)

Chest CT scan: hyper-dense mediastinal and hilar lymph nodes

Thoracocentesis: hemorrhagic pleural effusions

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DiagnosisDFA stain of infected tissuesThoracentesis: hemorrhagic pleural

effusionsPeripheral blood smear: gram-

positive bacilli on blood smearBlood culture: large gram-positive

bacilli with preliminary identification of “Bacillus species”

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Treatment:Natural strains sensitive to penicillinDoxycycline (preferred) of tetracyclinesFluroquinolones should have equivalent

efficacy; Penicillin, doxycycline, & ciprofloxacin are FDA approved for inhalational anthrax.

Other drugs: clindamycin, rifampin, imipenem, aminoglycosides, chloramphenicol, vancomycin, cefazolin, tetracycline, linezolid, and the macrolides.

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Anthrax Prophylaxis

Natural anthrax is PCN & TCN sensitive; weaponized Anthrax is resistant.

CDC recommends: Oral ciprofloxacin 500 mg q 12 hours. Prophylaxis for 60 days (unless exposure

has been excluded) because disease can present 50 days or more after exposure.

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Anthrax VaccinePoor, many side effects & limited availability.1997: all U.S. military personnel are required

to receive it. Anthrax vaccine adsorbed (AVA): inactivated

cell-free product, produced by Bioport Corp, Lansing, Mich.

6-dose SC series: 0, 2, & 4 weeks; then 6, 12, & 18 months; annual boosters.

Peacetime / civilian safety has been questioned.

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Weaponizing Anthrax B anthracis engineered to resist tetracycline

and penicillin. 1999 study induced in vitro Ofloxacin resistance

Assume PCN & TCN resistance if terrorist attack

Fluroquinolones 1st choice. Maybe.Once susceptibility known, use most widely

available, efficacious, and least toxic antibiotic

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Francisella tularensis

aerobic, gram-negative, intracellular coccobacillus

found in the water, soil, and vegetation. Natural reservoir: small mammals such

as rabbits, squirrels, and mice In many ways, similar to Plague

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Tularemia Disease

3 types: Ulcero-glandular, Oro-glandular, Pneumonic.

Usual humans infections from insect bites, contact with (skinning) infected rabbits or other small mammals, inhalation, & contact with contaminated environments

The last 2 modes of transmission are what makes F. tularensis an ideal agent for BioWar.

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Ulceroglandular Tularemia

Most common. It occurs after a bite from an infected arthropod or from handling an infected mammal.

Symptoms begin as flu-like and an ulcer appears at the site of infection.

Regional lymph nodes enlarge and may resemble buboes.

The patient may become bacteremic. Low mortality rate, but may take quite a long

time for recovery.

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Oro-glandular Tularemia Usually after ingestion of contaminated raw

meat, contaminated water; occasionally from inhalation.

Symptoms: stomatitis, exudative Pharyngitis or tonsillitis.

Cervical or retropharyngeal lymphadenopathy will occur and also may resemble buboes.

Bacteremic possible; low mortality rate, but long recovery.

Immunity ?

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Pneumonic Tularemia

Most severe form Inhalation of aerosolized bacteria. Or secondary to

hematogenous spread from cutaneous or oral lesions. Symptoms: fever, non-productive cough, pleuritic chest

pain, chills, headache, and malaise. It may resemble community-acquired pneumonia.

No person to person spread; no isolation needed. Mortality rate of 30-60%.

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Tularemia Chest x-ray May show infiltrates, hilar adenopathy, or

pleural effusion. Can have TB-like miliary infiltrates.Sometimes caseating granulomas found on lung

biopsy.Culture of F. tularensis will grow in about 24-

48 hours, and can make the definitive diagnosisPCR or ELISA may also be used to aid in the

diagnosis.

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Treatment of Tularemia

Streptomycin 30mg/kg IM q 12 h x 10-14 days. Alternative gentamicin 5mg/kg IM or IV q day

x 10-14 days. Vaccination is not recommended as a post-

exposure prophylaxis. No live attenuated vaccine against tularemia

yet. Weaponised Tularemia: oral doxycycline or

ciprofloxacin are recommended as post-exposure prophylaxis.

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Viral Hemorrhagic FeversRNA viruses: highly lethal, high infectivity

by aerosol route. 90- 100% mortality Sx: febrile illness, liver failure, DIC,

hypotension, death. Highly contagious.Dx: Setting, environment, H&P Confirm: viral serologies or culture

(difficult)Available in the wild; hard to handle. Weaponizable when techniques for tissue

culture mature.

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The Viral Hemorrhagic FeversEbola Hemorrhagic Fever and Marburg

Disease from the Filoviridae family.Lassa Fever from the Arenaviridae familyRift Valley Fever & Crimean Congo

Hemorrhagic Fever, from the Bunyaviridae family

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Clinical Hallmarks of Ebola

Bleeding everywhere:

DIC, capillary leaks,“bleeding eyes”Nose, GI tract…

Highly Infective

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VHR Patient Isolator

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Treating in Isolator Difficult

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VHF - Treatment

Mostly supportive and ineffectiveIn a mass casualty situation, Triage (in

the harshest sense of the word)For lesser numbers, consider antiviralsRibavirin for Lassa, CCHF, Rift Valley

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Personal Protective Equipment (PPE)

No universal standard of PPE for health care providers in BioWar.

Health Care workers will be among the first infected secondarily

Fear of contamination or infection may prevent some physicians from going to work

At a minimum: mask, gown, gloves. Complete change of clothes and shower BEFORE LEAVING FACILITY.

HCW may be isolated into workplace 105

Decontamination in hospitalDecontamination PRIOR TO patient arrival,

and AWAY from hospital ventilation ducts. Do you know where the UH decon room is?BioAgent: undress, & mask the patient. For

most agents, this would be enough.Anthrax: washing the patient with soap and

water reduces the likelihood of secondary aerosolization of the spores.

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Mass Casualty Wet decontamination (undress completely, shower &

with soap/detergent, contain effluent.) Isolate & decontaminate all clothing & patient goods Dilute bleach solution: hypochlorite can render a

biological agent harmless, is safe for equipment and most fabrics

(hypochlorite is contraindicated for open wounds) Heat and radiation for durable equipment: Autoclaving and dry heat at 100 C x 2 hours Solar UV radiation and desiccation to inactivate

biological agents.

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