# Presentation: 055997

## Overview of Bioterrorism Agents

**William Bower, MD**
**Commander United States Public Health Service**
**Division of Bioterrorism Preparedness and Response**
**Centers for Disease Control and Prevention**

**Notes:**
Today I’m going to try to provide an overview of bioterrorism by focusing on what’s known as the category A agents.

Bioterrorism is different from other forms of terrorism mainly because the event may be covert and early detection offers a window of opportunity to intervene.  There is no loud boom, bright light, funny smell, or immediate effects in a bioterrorism event.  In fact, unless a terrorist group actually claims that they have a released a BT agent, it may not be until days to weeks later before we realize that a bioterrorism event has taken place.

- Continuing Education Credits DISCLAIMER:In compliance with continuing education requirements, all presenters must disclose any financial or other relationships with the manufacturers of commercial products, suppliers of commercial services, or commercial supporters as well as any use of unlabeled product(s) or product(s) under investigational use. CDC, our planners, and the presenters for this seminar do not have financial or other relationships with the manufacturers of commercial products, suppliers of commercial services, or commercial supporters. This presentation does not involve the unlabeled use of a product or product under investigational use.

## Objectives
Identify the major biological threat agents
Describe the natural transmission of Category A biological agents
Describe clinical presentations of Category A biological agents
Describe available treatments and prophylaxis options 

- Identify the major biological threat agents
- Describe the natural transmission of Category A biological agents
- Describe clinical presentations of Category A biological agents
- Describe available treatments and prophylaxis options

- Overview of Bioterrorism Agents

## Ideal Qualities for a Biologic Terrorist Agent 
High rate of illness among those exposed 
High attack rate 
High rate of death among those who get ill 
High case fatality rate
Short time between onset of illness and death
Small window to start treatment
Low level of immunity in the population

- High rate of illness among those exposed
- High attack rate
- High rate of death among those who get ill
- High case fatality rate
- Short time between onset of illness and death
- Small window to start treatment
- Low level of immunity in the population

- Overview of Bioterrorism Agents

## Ideal Qualities for a Biologic Terrorist Agent (cont)
No effective or available treatment
Can be transmitted person to person
Easy to produce and disseminate
Difficult to diagnosis either clinically or diagnostically (i.e. laboratory identification)

- No effective or available treatment
- Can be transmitted person to person
- Easy to produce and disseminate
- Difficult to diagnosis either clinically or diagnostically (i.e. laboratory identification)

- Overview of Bioterrorism Agents

## Epidemiological CluesWhat we look for... 
Large outbreak with high illness and death rate
Single case of uncommon disease (e.g., Smallpox)
Unusual symptoms or severity of illness
Infection is non-endemic to region
Unusual seasonal distribution
Multiple simultaneous outbreaks in non-contiguous areas
Sick or dying animals

- Large outbreak with high illness and death rate
- Single case of uncommon disease (e.g., Smallpox)
- Unusual symptoms or severity of illness
- Infection is non-endemic to region
- Unusual seasonal distribution
- Multiple simultaneous outbreaks in non-contiguous areas
- Sick or dying animals

- Overview of Bioterrorism Agents

## Bioterrorism Threats:Priority Biological Agents 
Bacterial
Anthrax
Plague
Tularemia
Brucellosis
Q fever
Other
food borne pathogens
waterborne pathogens

- Bacterial
**Anthrax**
**Plague**
- Tularemia
- Brucellosis
- Q fever
- Other
- food borne pathogens
- waterborne pathogens

- Viral
**Smallpox**
**Viral Hemorrhagic Fevers**
- Viral Encephalitis
- Toxins
**Botulism**
- Staph Enterotoxin B
- Ricin toxin
- Tricothecene mycotoxins

- Overview of Bioterrorism Agents

**Notes:**
A panel of experts was convened to look at agents that could be used in a biological terrorism attack
Note many of these diseases are unfamiliar to residents of the US
The ones that are highlighted will be reviewed in this presentation. These pathogens have also been identified as likely agents for use as biological weapons based on their potential for massive numbers of casualties, ability to produce lengthy illness requiring prolonged and extensive care, presence of incubation periods and contagious potential, and their ability to produce non-specific symptoms that mimic endemic infectious disease and complicate the diagnostic process. 

Category A agents based on public health impact and not probability of use.

## Anthrax
Gram positive spore forming bacterium Bacillus anthracis
Primarily disease of herbivores which are infected by ingesting spores in soil
Natural transmission to humans by contact with infected animals or contaminated animal products
“Woolsorter’s disease”
Three forms of disease
Cutaneous
Inhalational
Gastrointestinal (GI)

- Gram positive spore forming bacterium *Bacillus anthracis*
- Primarily disease of herbivores which are infected by ingesting spores in soil
- Natural transmission to humans by contact with infected animals or contaminated animal products
- “Woolsorter’s disease”
- Three forms of disease
- Cutaneous
- Inhalational
- Gastrointestinal (GI)

**CDC: Gram stain of **
***B. anthracis***

- Overview of Bioterrorism Agents

**Notes:**
Anthrax is found most commonly among animals whose primary source of food is plants
Humans do get infected naturally with anthrax in the US, usually be coming into contact with infected animals or animal products
The three kinds of anthrax are:
Cutaneous, or skin
Inhalational, or the kind that gets in the lungs
Gastrointestinal, or the kind that infects the stomach and intestines

## Epidemiology of Transmission

**Direct contact**

**Cutaneous anthrax**

**Ingestion**

**Gastrointestinal anthrax**

**Inhalation**

**Pulmonary/mediastinal anthrax**

**Epidemiology of Transmission**

- Overview of Bioterrorism Agents

**Notes:**
Anthrax is contracted through contact with the reservoir, which is infected herbivores and the soil.  Cutaneous anthrax is the most common type, and is acquired through direct contact with spores that enter the skin through a cut or scrape.  This is commonly seen in people who butcher animals, or those that handle hides or skins of animals that are contaminated with anthrax spores.  Outbreaks of cutaneous anthrax have also occurred by transmission from fly bites.
If meat of an animal with anthrax infection is ingested, people can get the gastrointestinal form of the disease or, if the bacteria germinate in the throat, the oropharyngeal form.  
If spores of anthrax are inhaled, the spores can germinate in the lymph nodes of the mediastinum, causing a pulmonary or mediastinal anthrax infection. 

## Overview of Bioterrorism Agents

**Day 2-4**

**Day 6**

**Day 10**

**Eschar formation**

- Anthrax: Cutaneous
**Accounts for 80% of naturally occurring Anthrax cases**
**Enters through openings in skin from abrasions, lacerations**
**20% progress to systemic form if untreated**
**Most cases recover**

**Notes:**
Cutaneous anthrax is the most common presentation of anthrax, accounting for more than 80% of all naturally acquired cases.  Once a person has been exposed to the anthrax spores through a break in the skin, there is an incubation period that ranges from 1 to 12 days, depending on the size of the inoculum and the immune status of the patient.  After the incubation period, a papule will form that will break down into an ulcer after 1 to 3 days.  The ulcer may have surrounding vesicles. Over approximately 4 days, this ulcer will form a painless eschar that gradually heals over a week or longer.  Most cases of cutaneous anthrax recover, with approximately 20% progressing to a systemic form of the disease.  That rate drops to less than 1% if treated with antibiotics. Antibiotics do not change the progression of lesions of cutaneous anthrax.

## Overview of Bioterrorism Agents

- Inhalation of spores
- Incubation, 2-3 days (range up to 60 days)
- Spores engulfed by macrophages and transported to mediastinal and peribronchial lymph nodes
- Insidious onset:  malaise, low grade fever, nonproductive cough
- Abrupt development of respiratory distress
- Hemorrhagic mediastinitis
- Hematogenous spread
- Meningitis in 50%, usually fatal

## Anthrax: Pulmonary/Mediastinal

**Mediastinal widening from anthrax**

**Normal chest x-ray**

- Overview of Bioterrorism Agents

**Notes:**
One of the hallmark signs of pulmonary anthrax is evidence of mediastinal widening and pleural effusion.  Once inhaled, the spores are taken up by macrophages and brought to the closest lymph nodes, in this case, those in the mediastinum. There, the spores germinate and cause a hemorrhagic process in the lymph nodes, which is seen by chest x-ray and computerized tomography as widening in the mediastinum.  This is pathognomonic for mediastinal anthrax, and if seen on x-ray with the symptoms previously discussed, should be considered to be anthrax and immediately reported.  Pleural effusion is also common in this disease.

Absence of rhinorrhea or sore throat
Concomitant meningitis (often hemorrhagic)
History of drenching sweats
Prominence of dyspnea and chest pain
Absence of grossly purulent sputum
Pleural effusions (often hemorrhagic)
Radiographic evidence of mediastinal widening

## Patient Care Inhalational Anthrax

**400 mg intravenous every 12 hours for adults**
**10 -15 mg/kg intravenous every 12 hours for children**

_**Doxycycline**_
**100 mg intravenous every 12 hours for adults and children **_**>**_** 8 yr and > 45 kg**
**2.2mg/kg every 12 hours for children **
**< 8 yr (up to 200 mg/day)**

**PLUS**
**One or two additional anti-microbial agents effective against anthrax (*****e.g. *****imipenem, clindamycin, rifampin, macrolides) **
_**Additional issues**_
**Penicillin should never be used as a monotherapy**
**If meningitis is suspected, an antibiotic with good CSF penetration should also be administered (*****e.g.***** rifampin or chloramphenicol)**
**Supportive therapy for shock, fluid volume deficit and airway management may be needed.**
**Drainage of pleural effusions may improve clinical outcome**

**AND/OR**

**Anthrax Immune Globulin (AIG) can be used to neutralize anthrax toxin.**

**Patient Care Inhalational Anthrax**

- Overview of Bioterrorism Agents

**Notes:**
With any form of systemic anthrax disease including pulmonary, gastrointestinal, oropharyngeal or sepsis, intravenous antibiotics should be used.  Ciprofloxacin 400 milligrams every 12 hours for adults and 10 to 15 milligrams per kilogram every 12 hours, up to 1 gram per day, for children. Doxycycline is an alternative – use 100 milligrams every 12 hours for adults and children 8 years of age and older who weigh at least 45 kilograms, and 2.2 milligrams per kilogram every 12 hours for children less than 8 years of age, up to 200 milligrams per day.  For systemic illness, one or two anti-microbial agents that have good activity against anthrax, such as imipenem, clindamycin, rifampin or a macrolide, should be used in conjunction.  Penicillin can be used in conjunction with other antibiotics, but should never be used alone.  If meningitis is suspected, an antibiotic with good CSF penetration such as rifampin or chloramphenicol should also be administered.
Supportive care is also important and patients may need airway management, and care for fluid volume levels and shock.  In the anthrax cases in the US in 2001, drainage of pleural fluids in pulmonary cases appeared to improve the outcome.

## Anthrax: Post-Exposure Prophylaxis 
Start 60 days of oral antibiotics ASAP after exposure
Ciprofloxacin or Levofloxacin 
OR
Doxycycline
OR 
Amoxicillin or Penicillin (if known PCN sensitive)
Vaccine
Can be given post-exposure in conjunction with antibiotics

- Start 60 days of oral antibiotics ASAP after exposure
- Ciprofloxacin or Levofloxacin
**OR**
- Doxycycline
**OR**
- Amoxicillin or Penicillin (if known PCN sensitive)
- Vaccine
- Can be given post-exposure in conjunction with antibiotics

- Overview of Bioterrorism Agents

**Notes:**
[Go over slide]

## Smallpox
Variola virus, two forms of the disease:  minor and major
Spread via respiratory droplets or aerosols expelled from the oropharynx
May also spread via direct contact
Patients are most contagious during the time at which the skin rash is present
Approx. 30% of patients exposed go on to develop the disease
Approx. 30% mortality with ordinary smallpox

*Variola *virus, two forms of the disease:  minor and major
- Spread via respiratory droplets or aerosols expelled from the oropharynx
- May also spread via direct contact
- Patients are most contagious during the time at which the skin rash is present
- Approx. 30% of patients exposed go on to develop the disease
- Approx. 30% mortality with ordinary smallpox

- Overview of Bioterrorism Agents

**Notes:**
There are variants of the disease such as hemorrhagic and flat. Very difficult to recognize unless you are in the midst of an outbreak. Extremely high fatality rates.
Laundry personnel at risk from infected bed linens and clothes. Whether a person develops the disease may be dependent on baseline level of immunity from vaccination, type of contact whether it is incidental or face-to-face. Also makes it less contagious than measles and influenza.
Seasonal occurrence with rates highest in the winter and spring. 
Only a small number of virion are believed to be the infectious dose approximately 10-100 virion.

## Overview of Bioterrorism Agents

**Smallpox Characteristics**
**Febrile Syndrome** – occurring 1-4 days prior to rash.
**Classic Smallpox lesion** – deep-seated, firm/hard, round, well-circumscribed; lesion may become umbilicated or confluent.

## Overview of Bioterrorism Agents

**Smallpox Rash**

**Chickenpox Rash**

**Notes:**
Smallpox vs. Chickenpox:
Since the last case of smallpox in the US was in 1949
	-Many clinicians are unfamiliar with the disease
	-May be confused with a severe case of chickenpox
		-Most people in the room are probably familiar with the chickenpox (Varicella)
		-Receive a number of reports to CDC with suspicious rash illnesses

They are different disease with different stages of disease progression
	-This slide shows the differences in lesion appearance between smallpox and chickenpox
		-Smallpox: same stage of development 
			-Deep seeded rash (BB under the skin)
		-Chickenpox: different stages of development

Next Slide: Smallpox vs Chickenpox: Distribution

## Overview of Bioterrorism Agents

**Smallpox Characteristics**
**Febrile Syndrome** – occurring 1-4 days prior to rash.
**Classic Smallpox lesion** – deep-seated, firm/hard, round, well-circumscribed; lesion may become umbilicated or confluent.
**Lesion in Same Stage of Development **– Evolve from macules → papules → pustules at the same time.
**Centrifugal distribution **– First lesion on oral mucosa, face, or forearms.

## Overview of Bioterrorism Agents

_**Smallpox vs. Chickenpox: Distribution**_

**Notes:**
Smallpox vs Chickenpox: Distribution
Another difference is the distribution pattern of the diseases
	-Smallpox affects the head and extremities
	-Chickenpox lesions are generally more dense on the trunk

## Overview of Bioterrorism Agents

**Smallpox Characteristics**
**Febrile Syndrome** – occurring 1-4 days prior to rash.
**Classic Smallpox lesion** – deep-seated, firm/hard, round, well-circumscribed; lesion may become umbilicated or confluent.
**Lesion in Same Stage of Development **– Evolve from macules → papules → pustules at the same time.
**Centrifugal distribution **– First lesion on oral mucosa, face, or forearms.
**Lesion on palms and soles**

## Exposure

- Abrupt onset of fever >38.3°C
- Malaise/myalgia
- Headache
- Nausea/vomiting
- Backache
_***Usually NOT Infectious***_

**Incubation period **
**12 days (range 7-19 days)**
**NOT Infectious**

**Rash Phase**
**(21 days)**
**macules**
**papules**
**vesicles**
**pustules**
**scabs**
_***Infectious***_*** until all scabs fall off***

**Early Rash Phase**
** **Mucous membrane lesions
-  Small red spots on the tongue and throat
-  Lesions enlarge, ulcerate, then shed virus
_***Infectious 24 hours before visible skin rash***_

_**Clinical Timeline for Smallpox**_

- Overview of Bioterrorism Agents

**Notes:**
This slide shows the normal progression of smallpox.  
Following an exposure, there is an Incubation period ranging from 7 to 19 days, then the patient enters the Prodrome phase of 2 to 4 days where there is an abrupt onset of influenza-like symptoms that include a fever greater than 38.3°C, malaise, myalgia, headache, nausea, vomiting, backache, and will appear to be very sick.  The patient is not infectious to others during the Prodrome phase.  
The next phase is the Early Rash Phase.  The rash usually begins in the mucous membranes of the mouth as small red spots on the tongue and back of the throat.  The lesions enlarge and ulcerate allowing virus to be shed when the patient coughs.  The Early Rash Phase normally precedes the visible skin rash by about 24 hours meaning the patient is infectious to others before visible symptoms are evident.
The Rash Phase begins around the time the lesions in the mouth break down and last about 21 days.  The Rash Phase stages are shown in the last text box on this slide and will be further explained in the next slide.

## Smallpox Progression

**Smallpox Progression**

- Day 4

- Day 6

- Day 8

- Day 13

- Overview of Bioterrorism Agents

**Papules**

**Vesicles**

**Pustules**
**“****pocks”**

**Scabs**

**Notes:**
On the second day of rash, more papules appear. Although they differ somewhat in size, note that they all have a very similar appearance. By day 5, the fluid in the vesicles has become cloudy and looks like pus. At this stage, the pocks are called pustules. At this time, the fever usually rises and the patient feels more ill than before. On day 7, the rash is definitely pustular. Note that the pocks, although varying somewhat in size, all resemble each other in appearance. The rash is now so characteristic that there should be no mistake in diagnosis. Gradually the pustules dry up and dark scabs form. The scabs begin to appear between 10 and 14 days after the rash first develops. The scabs contain live smallpox virus. Until all scabs have fallen off, the patient may infect others. By day 20, the scabs have come off and light-coloured or depigmented areas are observed. Over a period of many weeks the skin gradually returns to its normal appearance. However, scars which last for life may remain on the face. Such scars are an indication of previous infection with smallpox.

## Smallpox:  Medical Management
Strict respiratory/contact isolation of patient
Patient infectious until all scabs have separated
Treatment is supportive care only
Antivirals are under evaluation
Cidofovir
ST246

- Strict respiratory/contact isolation of patient
_**Patient infectious until all scabs have separated**_
- Treatment is supportive care only
- Antivirals are under evaluation
- Cidofovir
- ST246

- Overview Bioterrorism Agents

**Notes:**
Currently no specific medical treatment for smallpox other than supportive care.

Isolate to prevent transmission

Identify and vaccinate contacts, watch for symptoms of illness

## Smallpox: Prevention and Control
Immediate vaccination of ALL close contacts (< 6 ft) and ALL contacts of patients contacts (Ring vaccination)
Vaccination within 4 days of exposure may prevent or lessen disease 
Mass vaccination may be necessary and/or everyone may want to be vaccinated

- Immediate vaccination of _ALL_ close contacts (_< _6 ft) and _ALL _contacts of patients contacts (Ring vaccination)
- Vaccination within 4 days of exposure _may_ prevent or lessen disease
- Mass vaccination may be necessary and/or everyone may want to be vaccinated

- Overview of Bioterrorism Agents

**Notes:**
Who to vaccinate
Spread most often by face-to-face contact
When to vaccinate
May prevent or at least lessen severity of disease if vaccinate within 4 days of exposure, may still lessen disease if vaccinate within 1 week of exposure
What to watch for
Consistent fever (2 consecutive measurements) or rash 

## Smallpox:  Current Vaccine
Live vaccinia virus
Because it is a live virus, there can be adverse events from vaccination
Occurs mostly in immunologically suppressed persons
Immunity is not life-long, but having been vaccinated in the past may reduce morbidity and mortality

- Live _vaccinia_ virus
- Because it is a live virus, there can be adverse events from vaccination
- Occurs mostly in immunologically suppressed persons
- Immunity is _**not**_ life-long, but having been vaccinated in the past may reduce morbidity and mortality

- WHO

- Overview of Bioterrorism Agents

**Notes:**
[go over current vaccine and how to vaccinate]

Certain type of site reaction indicates successful vaccination

Immunity wanes, really good for about 5 years if vaccinated only once, waning protection for up to 10 year

Longer protection if vaccinated more than once (longer lasting high neutralizing antibody titer)

## Plague

- Plague is a severe bacterial disease of humans and animals produced by the gram negative nonsporulating bacillus *Yersinia pestis*
- Bite of a rodent flea that is carrying the plague bacterium, or by handling an infected animal
- Hundreds of millions of people died when human dwellings were inhabited
- 	by flea-infested rats
- Modern antibiotics are effective, but without prompt treatment the disease can likely cause illness or death

- Overview of Bioterrorism Agents

**Notes:**
Plague is an infectious disease of animals and humans caused by a gram negative, non-sporulating, bacterium named Yersinia pestis.
People usually get plague from being bitten by a rodent flea that is carrying the plague bacterium or by handling an infected animal. Millions of people in Europe died from plague in the Middle Ages, when human homes and places of work were inhabited by flea-infested rats. Today, modern antibiotics are effective against plague, but if an infected person is not treated promptly, the disease is likely to cause illness or death.

Three plague pandemics have been recorded throughout history with an estimated 200 million deaths The first pandemic, known as the Plague of Justinian” started in Egypt beginning in 542 AD after arriving from Ethiopia. It quickly spread through the Middle East and Mediterranean basin. The Pandemic then spread throughout the “known world” and extended into Europe, Central Asia and Arabia (East Asia was largely unaffected). The case fatality rate among those infected was estimated to be between 15 and 40%, and for specific locations, an estimated population loss of 50-60% occurred between 541 and 700AD.  However its hard to ascribe al of this to plague alone, as other epidemics (like smallpox) also occurred during this time. This pandemic did have many economic, religious and political consequences including a weakening of the Byzantine Empire.

## Types of Plague
Three types:
Bubonic
Septicemic
Pneumonic

**Three types:**
**Bubonic**
**Septicemic**
**Pneumonic**

- Overview of Bioterrorism Agents

**Notes:**
There are three kinds of plague:
Bubonic, a kind that infects the glands causing a huge swelling
Septicemic, a kind that infects the blood system
Pneumonic, a kind that infects the lungs

Yersinia pestis used in an aerosol attack could cause cases of the pneumonic form of plague. One to six days after becoming infected with the bacteria, people would develop pneumonic plague. Once people have the disease, the bacteria can spread to others who have close contact with them. Because of the delay between being exposed to the bacteria and becoming sick, people could travel over a large area before becoming contagious and possibly infecting others. Controlling the disease would then be more difficult. A bioweapon carrying Y. pestis is possible because the bacterium occurs in nature and could be isolated and grown in quantity in a laboratory. Even so, manufacturing an effective weapon using Y. pestis would require advanced knowledge and technology.

## A

**Secondary**** plague ****cases**

**Primary ****pneumonic plague**

**A**

**Flea vector such as**
***Xenopsylla cheopis***** **

**Animal Reservoirs**

**Primary ****bubonic plague**

**Primary ****septicemic plague**

**A**

**B**

**B**

**C**

**C**

**D**

**D**

_**Routes of Plague Transmission**_
**A****= Bite of Flea**
**B**** = Contact with animal or carcass**
**C**** = Inhalation of respiratory droplets**
**D**** = Contact with sputum or fluid**

**Plague:  Epidemiology of Natural Transmission**

- Overview of Bioterrorism Agents

**Notes:**
Yersinia pestis is most commonly transmitted between animal reservoirs and to humans via bites of infected fleas. Primary Bubonic plague is transmitted from animal reservoirs to humans via bites from flea vectors (A), bites or scratches from infected animals such as cats, or direct contact with infected animal carcasses, such as rodents (especially marmots), rabbits, hares, carnivores (eg., wild cats, coyotes), and goats (B). Primary septicemic plague is defined as systemic toxicity caused by Y pestis infection but without apparent preceding lymph node involvement. This can also occur from bites from flea vectors (A) or bites, scratches or contact with infected animals or carcasses (B). Primary pneumonic plague is naturally acquired from the inhalation of respiratory droplets from infected animals such as cats. (C)

Secondary bubonic and septicemic plague cases may occur via person to person transmission that results from contact with infected sputum or fluid from a buboe (D). Secondary septicemic plague occurs commonly with either untreated bubonic or primary pneumonic plague (E). Secondary pneumonic plague occurs from the inhalation of respiratory droplets from a person with primary or secondary pneumonic plague (C) or through hematogenous spread as a complication of bubonic or septicemic plague (E). 

## Exposure

**Early Presentation**
** ****Abrupt onset of fever, malaise, headache, myalgia**
** ****Chest pain and dyspnea**
** ****Tachypnea (particularly in young children)**
** ****Productive cough (sputum may be purulent or ****   watery, frothy, blood-tinged)**
** ****Hemoptysis**

**Incubation****Period****1-6 days **

**Late Presentation**
** ****Rapid progression to pulmonary disease/ARDS**
** ****Pulmonary edema, dyspnea, cyanosis**
** ****Meningitis may be a complication**
** ****Hypotension, DIC, septicemia, and death **
** ****Lab findings -- bacterial infection and sepsis**
** ****Organism usually seen on sputum gram stain **
** ****Mortality approaches 100% if untreated in 24 hours**

**Antibiotic**
**therapy in the first 24 hours can prevent septicemia, cardio-respiratory failure, shock, and death!**

**Clinical Presentation of Pneumonic Plague**

- Overview of Bioterrorism Agents

**Notes:**
The next form of plague we’ll discuss is the pneumonic disease that is caused by either by direct inhalation of infective respiratory droplets or aerosolized bacteria, or by secondary spread of infection to the lungs from another anatomic site.  After inhalation, the incubation period is usually 1 to 6 days. The initial onset of disease involves non-specific signs and symptoms including the acute onset of fever, chills, malaise, and myalgias associated with progressive lethargy; associated chest pain and increasing dyspnea; and a productive cough of copious watery mucoid sputum that may be bloody. 

Without treatment the disease rapidly progresses to adult respiratory distress syndrome (ARDS) characterized by refractory pulmonary edema, may occur. Signs of shock, including hypotension and eventual multi-organ failure, may also occur. Without early detection and treatment in less than 24 hours, pneumonic plague is almost universally fatal. 

## Overview of Bioterrorism Agents

**Early antibiotic treatment* is paramount to patient survival**
**Adults****:  ****	**Streptomycin 1 gm IM b.i.d. for 10 days;
- 		Chloramphenicol 25 mg/kg IM or IV 4 times** **daily for 10 days
- 		Gentamicin 5 mg/kg IM or IV once daily for 10 days; 			Doxycycline 100 mg IV b.i.d. or 200 mg IV once daily for 10 days;
- 		Ciprofloxacin 400 mg IV b.i.d. for 10 days;
**Children****:****	**Streptomycin 15 mg/kg IM twice daily for 10 days (max 2 	gm/day);
- 		Chloramphenicol 25 mg/kg IV 4 times daily for 10 days (max 4 gm/day)
- 		Gentamicin 2.5 mg/kg IM or IV 3 times daily for 10 days;
- 		Doxycycline 2.2 mg/kg IV twice daily for 10 days (max dose 200mg/day);
- 		Ciprofloxacin 15 mg/kg IV twice daily for 10 days (max 1 gm/day)
*****CDC recommends initiating treatment with _two_ drugs believed effective against *Y. pestis* until antimicrobial susceptibility data is available on isolates.

**Notes:**
If you suspect a case of plague, it is important to start treatment immediately to prevent systemic disease. Traditionally, streptomycin, tetracycline, and doxycycline have been used for the treatment of plague and are approved by the United Stated Food and Drug Administration for this indication. Gentamicin also has been shown to be efficacious in the treatment of plague (although is not currently approved by the FDA) (Boulanger 2004, Crook 1992, Welty 1985). 

Recently the Workingroup on Civilian Biodefense in the United States recommended a treatment protocol for plague that involves Streptomycin and Gentomycin as the preferred choices of antibiotic therapy followed by Doxycycline, Ciprofloxacin and Chloramphenicol as alternative choices. Rifampin, aztreonam, ceftazidime, cefotetan, and cefazolin have been shown to not be efficacious and should not be used to treat plague. These recommendations are most appropriate for the setting where resources are adequate to treat all patients with intravenous antibiotics. In situations where the medical care delivery system is not able to meet the demands for patient care, oral antibiotics may need to be substituted for intravenous antibiotics for treatment of patients with plague. 

Supportive care of patients also is critical, including fluid management and hemodynamic monitoring. Many patients would require intensive care with respiratory support owing to complications of gram-negative sepsis (eg, shock, adult respiratory distress syndrome, multisystem failure, DIC). The possibility of a Y pestis strain resistant to conventional antibiotic therapy is of concern and should be considered, particularly if patients deteriorate despite early initiation of antibiotic therapy. Recently, a clinical isolate of Y pestis with plasmid-mediated multidrug resistance was identified in Madagascar. Studies from the Anti-Plague Institutes in Central Asia also suggest that greater strain diversity exists in Asia and Eastern Europe than is recognized in the West (Galimand 1997). 

## Plague:  Prophylaxis
Pneumonic plague contacts (transmitted via droplets)
Oral Doxycycline or Ciprofloxacin 
For 7 days after last exposure
Vaccine no longer manufactured

- Pneumonic plague contacts (transmitted via droplets)
- Oral Doxycycline or Ciprofloxacin
- For 7 days after last exposure
- Vaccine no longer manufactured

- Overview of Bioterrorism Agents

**Notes:**
Doxy prophylaxis for 7 days following last contact 

Vaccine no longer manufactured, was only protective against bubonic plague, not protective against pneumonic

## Botulism 
Caused by toxin from Clostridium botulinum
Colorless, odorless and tasteless
Lethal dose for 70kg human is 1ng/kg
Botulinum toxin is the most lethal neurotoxin known to man
Dispersal of aerosolized toxin, 1 gm of aerosolized toxin could kill up to 1.5 million people
Seven toxin types
Human disease: A, B, E, and F
Animal disease: C, D, and G

**Caused by toxin from *****Clostridium botulinum***
- Colorless, odorless and tasteless
- Lethal dose for 70kg human is 1ng/kg
- Botulinum toxin is the most lethal neurotoxin known to man
- Dispersal of aerosolized toxin, 1 gm of aerosolized toxin could kill up to 1.5 million people
- Seven toxin types
- Human disease: A, B, E, and F
- Animal disease: C, D, and G

- Overview of Bioterrorism Agents

**Notes:**
Botulinum toxin is the most lethal neurotoxin known and is colorless, odorless and tasteless. The lethal dose for a 70 kg human is approximately 1ng/kg.  Intravenous exposure poses the highest level of risk, whereas inhalational exposure is the least toxic. Aerosolized toxin particles are approximately 0.1 to 0.3 mcm and the toxins are inactivated by heating at temperatures greater or equal to 85 degrees Celsius for a minimum of 5 minutes.  There are seven types of botulinum toxin, Types A, B, C, D, E, F, G.  Types A, B, E, and F cause natural disease in humans while types C, D and G rarely cause disease in humans but rather cause natural disease in birds, horses, and cattle.  Type A is primarily found in North America, type B is primarily in Europe and type C is typically found in seafood and water environments.  When exposed to the right conditions, spores germinate to vegetative cells which release toxin by cell lysis.   

## Botulism:  Epidemiology of  Natural Transmission

**Botulism:  Epidemiology of  Natural Transmission**

- Overview of Bioterrorism Agents

**Notes:**
C. Botulinum can be found is soils, lake sediments, marine sediments, and in the guts of many animals.  It is transmitted to humans when food becomes contaminated, a wound becomes contaminated, or when the intestinal tracts of infants and adults become colonized. The mode of transmission denotes the clinical form of botulism: foodborne, wound, or intestinal. Unintentional botulism is caused by ingestion of botulinum toxin, by contamination of a wound with botulinum-toxin producing C. botulinum bacteria, and in infants by colonization of the intestine by toxin-producing C. botulinum. Botulism is not transmitted from person-to-person; a patient with botulism does not pose a threat to others.

A terrorist attack could take the form of food or beverage contamination with botulinum toxin or aerosolization and inhalation of botulinum toxin.

## Exposure

**Descending**
**Flaccid Paralysis**
**Symmetric Paralysis**
**Voluntary Muscles**
**1. Neck**
**2. Shoulders**
**3. Upper extremities**
**4. Lower extremities**
**BP often normal; Mental status normal**

**Cranial Nerve Palsies**
**Cranial Nerves ****III, IV, VI, VII, IX**
** ****Blurry vision**
** ****Diplopia**
** ****Ptosis**
** ****Expressionless Facies**
** ****Regurgitation**
** ****Dysarthria/Dysphagia**

**Incubation**
**Period**
**Inhalational**** **
**24-72 hours**
**Foodborne**** **
**18-36 hours**
**(range 2 hours to 8 days)   **
**Dependent on toxin dose**

**Clinical Presentation of Botulism**

- Overview of Bioterrorism Agents

**Notes:**
The time from exposure to clinical manifestation varies with each form of botulism.  For wound botulism, the incubation period is 4 to 14 days, for inhalational botulism the incubation period is 24 to 72 hours, for foodborne botulism the incubation period is typically 18 to 36 hours although can range from 2 hours to 8 days.  The length of incubation is directly related to the amount of toxin the individual is exposed to.  The disease generally begins with evidence of cranial nerve dysfunction – often including blurry vision, diplopia, ptosis, expressionless facies, regurgitation, and dysarthria/dysphagia, and then progresses to muscle weakness and perhaps symmetric, descending flaccid paralysis.

## Botulism: Medical Management
Early administration of antitoxin

Supportive care
Monitoring respiratory function
Providing mechanical ventilation
May be needed for weeks or months

**Early administration of antitoxin**
**Supportive care**
- Monitoring respiratory function
- Providing mechanical ventilation
**May be needed for weeks or months**

- Overview of Bioterrorism Agents

**Notes:**
The mainstays of therapy are rapid administration of botulinum antitoxin and meticulous intensive care, including careful monitoring of respiratory function and provision of mechanical ventilation when needed. Paralysis and ventilator dependency may last for weeks to months. In the case of wound botulism, the wound should be surgically debrided and patient should be given antibiotics, typically penicillin. Aminoglycoside antibiotics are contraindicated for treatment of secondary infections since they can exacerbate the neuromuscular blockade.  

## Botulism:  Antitoxin
Preferably within 24 hours of symptom onset
Type of antitoxin based on type of botulism
Bivalent antitoxin specific to serotype A and B,
Monovalent antitoxin specific to serotype E, and 
Heptavalent antitoxin specific against serotypes A, B, C, D, E, F, and G 
1 vial per person
Acts by binding free systemic toxin
Does not reverse paralysis already present

**Preferably within 24 hours of symptom onset**
**Type of antitoxin based on type of botulism**
**Bivalent antitoxin specific to serotype A and B,**
**Monovalent antitoxin specific to serotype E, and **
**Heptavalent antitoxin specific against serotypes A, B, C, D, E, F, and G**
**1 vial per person**
**Acts by binding free systemic toxin**
**Does **_**not**_** reverse paralysis already present**

- Overview of Bioterrorism Agents

**Notes:**
Rapid administration of antitoxin is very important and should be given to patients as soon as a diagnosis of botulism is suspected, since confirmation may take several days and antitoxin s most effective if given within 24 hours of symptom onset.  Originally two separate types of antitoxin were available, bivalent equine for types A and B and botulism antitoxin type E.  The type of antitoxin chosen should be based on the type of botulinum toxin responsible for disease.  Now a trivalent antitoxin is available and should be administered if the type of botulinum toxin is unknown. The vials should be diluted in 0.9% saline for intravenous infusion at a 1:10 dilution.  The preparation should be stored at ambient temperature before infusion and each diluted vial should be infused slowly, over a minimum of two minutes, according to the manufacturers instructions.  Hypersensitivity reactions are known to occur in some patients.  Therefore, if possible, skin testing should be performed on all patients before they receive antitoxin.  The best method is through a scratch test which is outlined in the package insert.  Even if the scratch test is positive, the patient can be desensitized over several hours  before the full dose of the antitoxin is administered.  Diphenhydramine and epinephrine should be available during administration of antitoxin and the patient should be kept under careful observation for 1 to 2 hours after receiving antitoxin and under close surveillance for 24 hours.  Antitoxin prevents progression of paralysis by binding free circulating toxin, but will not reverse paralysis already present.  

## Viral Hemorrhagic Fevers (VHF)
Hemorrhagic fever viruses (RNA) belong to four taxonomic families: 
Filoviridae (Ebola/Marburg)
Arenaviridae (Bolivian HF))
Bunyaviridae (Congo-Crimean HF)
Flaviviridae (Dengue)
Natural vectors – virus dependent
Rodents, mosquitoes, ticks
No natural occurrences in U.S.

**Hemorrhagic fever viruses (RNA) belong to four taxonomic families: **
- Filoviridae (Ebola/Marburg)
- Arenaviridae (Bolivian HF))
- Bunyaviridae (Congo-Crimean HF)
- Flaviviridae (Dengue)
**Natural vectors – virus dependent**
- Rodents, mosquitoes, ticks
_**No**_** natural occurrences in U.S.**

- Overview of Terrorism Agents

**Notes:**
The hemorrhagic fever viruses are, in fact, a diverse group within the enveloped, single-stranded RNA viruses, consisting of members of four separate taxonomic families.  (i) Members of the Family Filoviridae are Ebola and Marburg viruses, the etiologic agents of severe hemorrhagic fever with high mortality.  (ii) The arenaviridae includes the viruses causing Lassa fever, Argentine hemorrhagic fever and Bolivian hemorrhagic fever.  (iii) Within the Family Bunyaviridae are Crimean Congo hemorrhagic fever virus and a number of hantaviruses that cause hemorrhagic fever with renal syndrome.  (iv) Finally, Family Flaviviridae contains the most common cause of viral hemorrhagic fever, dengue virus, and the first described cause of hemorrhagic fever, yellow fever virus.  

## Overview of Bioterrorism Agents

**VHF as a Biological Weapon**
**These viruses are considered suitable weapons because:**
- they have a low infectious dose
- they cause high morbidity and mortality
- they cause fear and panic in the general public
- effective vaccines are either not available, or supplies are limited

**Notes:**
The hemorrhagic fever viruses possess many qualities considered desirable for biological weapons. Studies in animals and accidental laboratory infections in humans document that most hemorrhagic fever viruses are highly infectious in aerosol form.  They also tend to have a low infectious dose, have a high morbidity and mortality, have few effective medical countermeasures against them and have the propensity to cause public fear and panic in the presence of outbreaks. Animal studies using nonhuman primates, and laboratory accidents, have demonstrated that clinical infection can be caused by aerosolized preparation. 

## Exposure

**Later **
**Manifestations**
_**External /Internal Hemorrhage**_
** ****Ecchymosis**
** ****Petechiae**
** ****Bleeding from puncture site**
** ****Bleeding from nose and gums**
** ****Hemorrhagic conjunctivitis**
** ****Gastrointestinal bleeding**
** ****Severe vaginal bleeding**
** ****Pleural effusion**
** ****Renal Failure**
** ****Shock **
_**Laboratory Findings**_
** ****Leukopenia or leukocytosis **
** ****Thrombocytopenia**
** ****Elevated Liver Function Tests**
** ****Anemia or Hemoconcentration**
** ****Prolonged PT, PTT **

**Early Manifestations****	**
**In general:**
** ****High fever**
** ****Headache**
** ****Myalgia**
** ****Arthralgia**
** ****Anorexia**
** ****Varying degrees of  ****  nausea, vomiting and ****  diarrhea**

**Incubation****Period****2-21 days **
**(depending on the virus)**

- Overview of Bioterrorism Agents

**Clinical Timeline for VHF**

**Notes:**
The incubation period for viral hemorrhagic fevers varies.  Patients are not infectious during the incubation period.  In general, the clinical features of viral hemorrhagic fevers can be divided into two phases: early and late.  Early manifestations are non-specific, but a positive tourniquet test may provide a diagnostic clue.  Hemorrhagic manifestations occur later in the course of illness and are often accompanied by hypotension, shock, renal failure and capillary leak.

## Clinical Presentation of VHF

**Clinical Presentation of VHF**

- Overview of Bioterrorism Agents

**Melena**

**Notes:**
Cutaneous findings in viral hemorrhagic fevers range from flushing to small discrete petechiae to large eccyhmotic lesions.  These findings vary by severity of disease and by causative virus.  

## Aggressive supportive care with intravenous fluids, colloids, blood products as needed
Specific therapy (ribavirin) may be helpful in bunyaviruses and arenaviruses 
Avoid IM injections or invasive procedures (due to bleeding)
Strict aerosol precautions (i.e. respiratory isolation)

**Specific therapy (ribavirin) may be helpful in bunyaviruses and arenaviruses **
**Avoid IM injections or invasive procedures (due to bleeding)**
**Strict aerosol precautions (i.e. respiratory isolation)**

**VHF Clinical Management**

- Overview of Bioterrorism Agents

**Notes:**
Specific therapy exists for a minority of viral hemorrhagic fevers.  The antiviral nucleoside analog ribavirin can be effective in the treatment of viral hemorrhagic fever due to bunyaviruses and arenaviruses.  It substantially reduces mortality in cases of HFRS from Hantaan virus and is thought to reduce mortality in CCHF as well.  However, the intravenous formulation of ribavirin is not readily available.  
Intensive supportive care may improve outcome.  Aggressive fluid management algorithms using simple clinical parameters such as blood pressure and hematocrit have greatly reduced mortality in dengue hemorrhagic fever and may be effective in other viral hemorrhagic fevers. 

## Sources of Information
Centers for Disease Control (CDC)
www.cdc.gov
CDC Emergency Preparedness 
www.emergency.cdc.gov
CDC Quarantine and Isolation
www.cdc.gov/ncldod/dp/index.htm

- Centers for Disease Control (CDC)
- www.cdc.gov
- CDC Emergency Preparedness
- www.emergency.cdc.gov
- CDC Quarantine and Isolation
- www.cdc.gov/ncldod/dp/index.htm

- Overview of Bioterrorism Agents

## Overview of Bioterrorism Agents

- Questions?

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