Bioterrorism Agents: An Overview for Physicians and Hospitals
Epidemiology & Assessment

Orange County Health Care Agency
Public Health

Table of Contents

Bioterrorism: Introduction, physician role, response

• Anthrax

• Smallpox

• Plague

• Tularemia

• Viral Hemorrhagic Fevers

• Botulism

• Web Resources

Bioterrorism (BT)—Definition

Biological terrorism is the use of microorganisms (bacteria, viruses, and fungi) or toxins from living organisms to produce death or disease in humans, animals, and plants.

BT—General Properties

• Inhalation likely to have the greatest consequences for morbidity and mortality

• Must be dispersed as an aerosol—1 to 5 microns ideal size

• Other potential routes of entry, depending on the agent and the target:

  • Oral

  • Dermal abrasion

  • Percutaneous

Ideal BT Agent

• Can be delivered as an aerosol

• High disease/infection ratio

• Maintains viability/infectivity in environment

• Vaccine or prophylaxis to protect in manufacture and delivery

Environmental Constraints

• Sunlight—UV light kills many bacteria

• Wind—spreads biological agents

• Temperature—heat inactivates many biological agents; most are resistant to freezing

• Desiccation—may inactivate or inhibit growth

Identifying Suspicious Letters or Packages

• Excessive postage

• Handwritten or poorly typed addresses

• Incorrect titles

• Title, but no name

• Misspellings of common words

• Oily stains, discolorations or odor

• No return address

• Excessive weight

• Lopsided or uneven envelope

• Protruding wires or aluminum foil

• Excessive security material such as masking tape, string, etc.

• Shows a city or state in the postmark that does not match the return address

Response to Suspicious Powder or Package

• Call law enforcement

• Law enforcement performs threat assessment and contacts FBI as needed

• If no credible threat exists, incident is closed without further testing.

• If credible threat exists, FBI arranges for laboratory testing of specimen (and environment, if indicated)

• If tests are indicative of anthrax, Public Health is notified

• Public Health performs epidemiologic investigation

• makes recommendations for testing and prophylaxis of those exposed

Bioterrorism—Physicians on the front line

Provisional diagnosis needs to be made quickly

• High index of suspicion that BT agents have been used

• No time to wait on laboratory results to establish a definitive diagnosis

Bioterrorism Response

• Most important for physicians:

• Preparation

• Familiarity with agents of BT

• Personal/office disaster preparedness

• Hospital preparedness

• Recognition

• Reporting to Orange County Public Health

this will activate the response system

• Also notify hospital infection control, laboratory, and administration

How to report

• During regular business hours

• Call Epidemiology & Assessment

• (714) 834-8180

• After hours, weekends and holidays

• County Communications

• (714) 628-7008

• Ask for Public Health Official on call

Orange County Health Care Agency Response

• Case investigation and case finding

• Establish diagnosis

• Activate Orange County emergency plans

• Notify:

• California Dept of Health Services

• Centers for Disease Control & Prevention

• FBI and local law enforcement

Orange County Health Care Agency Response, cont.

• Recommend treatment and infection control measures

• Establish exposure date(s) and location(s)

• Identify exposed persons

• Follow-up cases and contacts

• Provide mass prophylaxis (if indicated)

What to report?

Worrisome Clinical Setting
(Epidemiological clues to a BT outbreak)

• Large numbers of cases of unexplained diseases or deaths

• Higher morbidity and mortality in association with a common disease or syndrome, or failure of such patients to respond to usual therapy

• Many ill persons seeking treatment at about the same time

• Illness associated with a ventilation system

• Worrisome Clinical Setting, cont.

• A disease that is unusual:

• for a given geographic area

• occurs outside the normal transmission season

• occurs in the absence of the normal vector for transmission

• Illness that is unusual (or atypical) for a given population or age group

• Unusual patterns of death or illness among animals that precedes or accompanies illness or death in humans

Worrisome Clinical Syndromes

• Acute severe pneumonia or respiratory disease

• Encephalitis syndrome

• Unexplained rash with fever

• Fever with mucous membrane bleeding

• Unexplained death or paralysis

• Septicemia/toxic shock

Agents of BT—Top Suspects

• Anthrax (Bacillus anthracis)

• Smallpox (Variola major)

• Plague (Yersinia pestis)

• Tularemia (Francisella tularensis)

• Botulism (Botulinum toxin)

• Viral hemorrhagic fevers (Filoviruses and Arenaviruses )

BT—Clinical Information

• Travel history

• Infectious contacts

• Employment history

• Activities over the preceding 3 to 5 days

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Anthrax

Anthrax—Microbiology

• Bacillus anthracis—gram +, spore-forming, bacillus

• Spores may remain infectious in environment for as long as 50 years

• Endemic infection in animals

• Spores enter host, germinate in a macrophage and are transported to regional lymph nodes where local toxins cause edema and death of tissue

• Humans develop infection naturally from handling contaminated fluids or hides ("Woolsorters Disease") or eating contaminated raw or undercooked meat

Anthrax—Microbiology

• Inoculation, ingestion, or inhalation of spores

• Inhalation route has highest mortality

• Untreated skin infection—20% mortality due to sepsis; treated <1% mortality

• Between 80 to 90% mortality if inhaled or ingested despite treatment

• Inhaled anthrax causes a mediastinitis

• Pleural effusions may be present

• Pneumonia is rare

Inhalational Anthrax

• 1-7 days (and possibly as long as 60 days) incubation period followed by fever, myalgias, cough, and fatigue

• Initial improvement followed by abrupt onset of respiratory distress, shock, and death in 24 to 36 hours

• Chest X-ray—may show widened mediastinum with or without a bloody pleural effusion

• 50% of cases have associated hemorrhagic meningitis

Anthrax: Cutaneous

• Incubation 1-12 days

• Skin lesion evolves:

• Macule or papule Ú vesicular Ú ulcer Ú depressed black eschar

• Usually painless

• Vesicles may surround ulcer

• Edema usually develops

• May have fever, malaise, headache, regional lymphangitis, painful lymphadenopathy

Anthrax—Prevention

• No documented cases of person-to-person transmission of inhalational anthrax has ever occurred

• Standard precautions required

Anthrax: Patient requests for testing

• There are no screening tests for anthrax

• Nasal swabs are

• A research tool

• ONLY used as part of an epidemiological investigation of KNOWN anthrax exposure

• Are not used to determine who should be treated or prophylaxed

• Should only be done at the request of Public Health

Anthrax: Patient requests for testing, cont.

• Asymptomatic patient WITHOUT known exposure:

• Reassurance

• No lab tests

• Asymptomatic patient WITH suspected (as determined by law enforcement/FBI) or known exposure:

• Consult with Public Health for recommendations

Anthrax: Patient requests for testing, cont.

• Patient with non-specific symptoms who reports having had an exposure to unknown substance which was not evaluated by law enforcement:

• Reassurance about rarity of infection

• Evaluate for symptoms c/w anthrax

• If afebrile, instruct patient to monitor for fever and other symptoms

Anthrax—Diagnosis

• Inhalational:

• Clinical picture of sudden onset of respiratory distress with mediastinal widening on X-ray

• Gram stain of blood and blood cultures

• Cutaneous

• Gram stain and culture of vesicular fluid

• Skin biopsy—immunohistochemical staining by CDC

• ELISA, PCR and other research tests may confirm diagnosis—contact Orange County Public Health to request

Inhalational Anthrax—Treatment

• Usually unsuccessful in severe disease

• Published recommendations based on animal studies

• Ciprofloxacin—400 mg IV q 8 to 12 hr

• Doxycycline—100 mg IV q 12 hr

• Naturally occurring strains usually sensitive to penicillin

• If vaccine available, begin vaccination at the start of drug therapy and treat for 30 days

• Vaccine not available: treat for 60 days

Anthrax—Treatment Recommendations

• In an actual BT event response, treatment recommendations may differ from published recommendations due to:

• Suspected or demonstrated antimicrobial resistance

• Availability of parenteral medications

• Experience during the incident

Anthrax—Pediatric Treatment

Prophylaxis

• Penicillin

• Doxycycline

IV Therapy

• Penicillin

• Doxycycline

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Smallpox

• Last naturally acquired case 1977, Somalia

• Laboratory-acquired case in 1978

• Declared eradicated 1980

• Vaccination program dismantled

• U.S. recommendations for routine vaccination

rescinded for

• children in 1971

• health care workers rescinded in 1976

• military in 1990

• Vaccination no longer required for international travelers as of Jan. 1982

• Only the U.S. and Russia possess repositories of the virus

Smallpox—Epidemiology

• Transmission: person-to-person primarily via direct respiratory droplet (face-to-face)

• Most communicable from onset of rash (after onset of prodrome) through first 7 days of rash

• Oral mucosa lesions ulcerate and release large amounts of virus into saliva

• Incubation averages 12 days (range 7-17)

• Attack rate ~30%

Smallpox: Clinical Types

• Variola major: classic smallpox (30% mortality)

• Variola minor: milder disease (1% mortality)

• Flat-type (2%-5%): severe toxicity, flat, soft lesions (95% mortality)

• Hemorrahagic (<3%): extensive petechiae

Clinical—Classic Smallpox

• Prodrome (2-3 days): Acute onset with high fever, malaise, and prostration with severe headache and backache; +/- erythematous rash

• Lesions appear over 1-2 day period

• Spread of rash to lower extremities, then centrally; lesions more abundant on face and extremities; may be present on palms and soles

Classic Smallpox

• Evolution of lesions:

• Maculopapular

• Vesicular (4^th-5^thday of rash)

• Pustular (7^th day)

• Scab (14^th day)

• Lesions on various parts of body generally synchronous in stage

• Lesions deeply embedded in dermis

Smallpox vs. Chickenpox

Smallpox

• Laboratory

• Demonstrate virus from vesicular sampling via electron microscopy

• Confirmation by tissue culture

• All contacts are quarantined for at least 17 days

• Infectious until all scabs have separated (3-4 weeks)

Smallpox—Treatment

Smallpox—Vaccine

• Current supplies limited

• Used only for laboratory personnel working with certain smallpox-like viruses

• Administered with bifurcated needle

• Side effects and complications (per million primary doses)

• Inadvertent inoculation—509

• Postvaccinial encephalitis—12.3

• Progressive vaccinia—1.5

• Can prevent or decrease severity if given within 3-4 days of exposure

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Plague

• Enzootic in rats, ground squirrels, prairie dogs, other rodents

• All continents except Australia

• Average 1700 cases/year worldwide

• U.S.—390 human cases from 1947-1996

• Most occurred in NM, AZ, CO, CA

• Last case of person-to-person transmission in U.S.—Los Angeles, 1924

Plague in California

• Occurs in foothills, plateaus, mountains and coastal areas

• Wild rodents in rural areas are major source

• Role of pets—cats especially sensitive and can transmit to humans

• 1990s: 9 human plague cases

• 1 fatal

• 4 cases from Kern County

Clinical forms of plague

• Bubonic

• Most common form—80%-90% of U.S. cases

• Case fatality rate ~14% (treated)

• Septicemic

• 10% of U.S. cases

• Case fatality rate ~50%

• Pneumonic

• 2% of U.S. cases

• Case fatality rate ~57%

• Other

Bubonic plague

• Usually transmitted by infected fleas

• Flea bite inoculates organisms into skin

• Bacteria migrate through cutaneous lymph nodes

• Symptoms begin 2-8 days after bite

• Sudden onset fever, chills, weakness

Differential Diagnosis—Bubo Formation

• Staph-Strep lymphdenitis

• Cat-scratch fever

• Tularemia

Bubo aspiration and gram stain is helpful in making diagnosis.

Pneumonic Plague—Signs & Symptoms

• 2 to 3 day incubation period followed by high fever, myalgias, chills, HA, and cough with bloody sputum

• In contrast to anthrax, pneumonia and sepsis develop acutely and may be fulminant with patients developing dyspnea, stridor, cyanosis, and circulatory collapse

• Patchy infiltrates or consolidation seen on chest x-ray

Acral Gangrene

Pneumonic Plague—Prevention

• Secondary transmission is possible

Plague—Diagnosis

• Gram stain and culture of lymph node aspirates, sputum, or CSF samples

• Bipolar staining; "safety pin" may be present

• Immunoassays are also available

Pneumonic Plague—Treatment

• Standard plus droplet precautions during first 48 hours of antibiotic treatment and until clinical improvement occurs

• Antibiotics must be started within 24 hours of symptoms to impact survival

• Streptomycin (15 mg/kg/day IM q 12 hrs for 10 days)

• Alternatives: Gentamicin, cipro, doxy

• Chloramphenicol for plague meningitis

Plague—Pediatric Treatment

Prophylaxis

• Doxycycline

• Trimethoprim/Sulfamethoxazole

IV Therapy

• Streptomycin (over 1 year of age)

• Gentamicin

• Chloramphenicol

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Tularemia

Tularemia—Description and Epidemiology

• Francisella tularensis—gram(-), non-motile, cocco-bacillus zoonotic disease (most common in rabbits)

• Humans become infected by handling contaminated animal fluids or being bitten by ticks, deer flies, or mosquitoes

• Upon infection, bacteria spread to regional lymph nodes and reticuloendothelial system, leading to bacteremia.

Tularemia—Description and Epidemiology

• Francisella tularensis—resistant to freezing temperatures, sensitive to heat and disinfectants

• Almost all of those exposed will become infected; low infectious dose (10-50 organisms)

• Person-to-person transmission does not occur

• 5% of treated victims die, untreated mortality rate is 20 - 30%

• Recovery is usually followed by permanent immunity

Tularemia: Inoculation or Ingestion

• Inoculatation:

• Painful and tender regional lymphadenopathy with or without skin ulcers

• Ulcer begins as papule, is tender, usually indolent, may develop eschar

• Ingestion:

• Oropharyngeal—exudative pharyngitis or tonsilitis, +/- ulceration

Tularemia—Localized Disease

• Ulceroglandular—skin inoculation

• Oropharyngeal—ingestion

• Glandular—adenopathy, no skin lesion

• Oculoglandular—painful, purulent conjunctivitis with adenopathy

Tularemia—Systemic Disease

• 2 to 10 days after inhalational exposure, patients develop abrupt onset of high fever, chills, headache, rigors, myalgias (especially low back), coryza, sore throat, dry or slightly productive cough. GI symptoms may occur.

• Pneumonia may or may not be present, especially in first few days of illness.

• Pharyngitis, bronchiolitis, pneumonitis, pleuritis, hilar lymphadenitis may occur.

Tularemia

• Diagnosis

• Notify lab if tularemia is suspected—potentially hazardous to lab workers, difficult to culture

• Culture/Gram stain blood, tissue (Gram-negative)

• DFA of sputum and cultures at PH reference Lab

• Serology at PH reference lab (retrospectively)

• Isolation: Standard precautions

• Treatment:

• Streptomycin, gentamicin, doxycycline

• Prophylaxis:

• Doxycycline x 2 wks

Tularemia—Pediatric Treatment and Prophylaxis

• Streptomycin 15 mg/kg IM bid (not to exceed 2 g/d)

• Gentamicin 2.5 mg/kg IM or IV tid

• Alternatives: doxycycline, chloramphenicol, ciprofloxacin

• Doxycycline or ciprofloxacin

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Viral Hemorrhagic Fevers

Viral Hemorrhagic Fevers (VHF)
Examples

• Ebola

• Marburg

• Arenaviruses

• Old World - Lassa

• New World

• Junin, Machupo, Tacaribe

• Dengue

• Yellow fever

• Congo-Crimean fever

Viral Hemorrhagic Fevers (VHF)

• RNA viruses causing high fevers and generalized vascular damage

• May be spread by aerosol or fomite, oral and subconjunctival in animals

• Human infections by contact with blood and body fluids

VHF—Pathological

• Not all infected patients develop classical VHF signs.

• Disease depends on various host factors, differences between virus strains, and other immunologic factors.

• Target organ is the vascular bed.

VHF—Signs & Symptoms

• Fever, myalgia, prostration

• Full-blown cases evolve into shock and generalized mucous membrane hemorrhage, with involvement of the respiratory, hematopoietic, and central nervous systems

• Conjunctival injection, petechial hemorrhage, and hypotension

• Abnormal renal function and LFTs—poor prognosis

• Mortality varies

VHF—Prevention

• Transmitted by body fluids

• Isolate patients in single room with an adjoining anteroom stocked with PPE; animal studies indicate aerosol transmission possible

• Negative air pressure if possible

• Strict barrier-nursing techniques

• Limit patient transfers—may increase risk for secondary transmission

• Easily killed with soap, detergents, and disinfectants

VHF—Diagnosis

• Travel history?

• Acute febrile illness

• Decreased platelets

• Diffuse vascular involvement—shock

VHF—Treatment

• Largely supportive with ICU monitoring

• Comfort measures (sedation, pain Rx)

• Blood replacement products as necessary (DIC)

• Ribavirin for treatment and prophylaxis (Lassa fever, CCHF)

• Vaccine available only for yellow fever

Biological Toxins

BT Toxins
General Characteristics

• Naturally produced poisons

• More toxic per weight than chemical agents

• Non-volatile

• Minimal absorption through intact skin

• Not prone to person-to-person transmission

• Sudden onset with prostration or death

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Botulism

Botulinum Toxin—Pathogenesis

• Neurotoxin produced by Clostridium botulinum

• Most lethal compound per weight (15,000 times more toxic than the nerve agent VX)

• Similar effects whether inhaled or ingested

• Blocks the release of acetylcholine at 3 places in the presynaptic terminal of the neuromuscular junction and autonomic nervous system

Botulism

• Clinical features:

• Incubation: 12 hrs to several days

• Initial symptoms: Cranial nerve palsies (ptosis, diplopia, dysphagia)

• Symmetrical descending weakness that may progress to flaccid paralysis

• Death due to respiratory failure

• Afebrile, alert and oriented

• Sensation intact

Botulism: Differential Diagnosis

• Miller-Fisher variant of Guillain-Barré

• Myasthenia gravis

• Botulism

Botulism

• Diagnosis

• Clinical signs and symptoms

• LP—Normal CSF protein (unlike GBS)

• Tensilon test to R/O myasthenia gravis

• EMG—augmentation of muscle action potential w/ repetitive nerve stimulation at 20-30 Hz c/w botulism

• Toxin assay—definitive diagnosis

• Mouse bioassay

• Only available at certain public health

• Takes days to weeks

Botulism

• Isolation: Standard precautions

• Treatment:

• Ventilatory support (if needed)

• Botulinum antitoxin (equine)

• Requires approval of Orange County Public Health and California Department of Health Services

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Web Resources

Disclaimer / about downloading files

• CDC Bioterrorism site:
  www.bt.cdc.gov

• List of reportable diseases:
  www.ochealthinfo.com/docs/public/epi/forms/diseases.pdf

• Confidential morbidity form
  www.ochealthinfo.com/docs/public/epi/forms/morbidrep.pdf

• CDC recommendations:
  www.cdc.gov/mmwr/PDF/wk/mm5041.pdf

• JAMA articles on bioterrorism (scroll down):
  www.jama.ama-assn.org/