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Biosecurity & Bioterrorism: Containing and Preventing Biological Threats
Chapter 4
Category B Diseases and Agents
Learning Objectives
Key Terminology
HHS Category B - Criteria
Moderately easy to disseminate
Result in moderate morbidity rates and low mortality rates
Require specific enhancements for diagnostic capacity and disease surveillance
Category B Agents and Diseases
| Disease | Agent | Type of Agent | Zoonoses | Contagious Person-to-Person |
| Brucellosis | Brucella species | Bacteria | Yes | No |
| Glanders | Burkholderia mallei | Bacteria | Yes | No |
| Melioidosis | Burkholderia pseudomallei | Bacteria | Yes | No |
| Q Fever | Coxiella burnetii | Rickettsia | Yes | No |
| Psittacosis | Chlamydophila psittacii | Bacteria | Yes | No |
| Food and Water Safety Threats* | Salmonella species; Shigella dysenteriae Type 1; Escherichia coli O157:H7; Vibrio cholerae; Typhi | Bacteria | No | No |
| Viral Encephalitis | Several Arboviruses (e.g., VEE, WEE, EEE, SLE) | Virus | Yes | No |
| Epsilon Toxin Poisoning* | Clostridium perfringens Epsilon Toxin | Bacteria-derived toxin | No | No |
| SEB Poisoning* | Staphylococcal Enterotoxin B (SEB) | Bacteria-derived toxin | No | No |
| Ricin Poisoning | Ricin toxin from Ricinus communis | Plant-derived toxin | No | No |
Brucellosis
Malta fever
Undulant Fever
Bang’s Disease
Image courtesy of CDC PHIL
Brucella spp.
Gram negative, coccobacilli bacteria
Facultative, intracellular organism
Environmental persistence
Temp, pH, humidity
Frozen and aborted materials
Multiple species
Image courtesy of CDC PHIL
7
Malta Fever
450 BC: Described by Hippocrates
1905: Introduction into the U.S.
1914: B. suis Indiana, United States
1953: B. ovis New Zealand, Australia
1966: B. canis in dogs, caribou and reindeer
8
History
Alice Evans, American bacteriologist
Credited with linking the organisms
Similar morphology and pathology between:
Bang’s Bacterium abortus
Bruce’s Micrococcus melitensis
Nomenclature today credited to Sir David Bruce
Brucella abortus and Brucella melitensis
9
Brucella species summary
| Species | Biovar/Serovar | Natural Host | Human Pathogen |
| B. abortus | 1-6, 9 | cattle | yes |
| B.melitensis | 1-3 | goats, sheep | yes |
| B. suis | 1, 3 | swine | yes |
| 2 | hares | yes | |
| 4 | reindeer, caribou | yes | |
| 5 | rodents | yes | |
| B. canis | none | dogs, other canids | yes |
| B. ovis | none | sheep | no |
| B. neotomae | none | Desert wood rat | no |
| B. maris | marine mammals | unknown |
10
Brucella melitensis
Latin America, Middle East, Mediterranean, eastern Europe, Asia, and parts of Africa
Accounts for most human cases
In the Mediterranean and Middle East
Up to 78 cases/100,000 people/year
Arabic Peninsula 20% seroprevalence
Recent emergence in cattle on Middle Eastern intensive dairy farms
11
Brucella abortus
Worldwide
Some countries have eradicated
Notifiable disease in many countries
Poor surveillance and reporting due to lack of recognition
Fever of Unknown Origin (FUO)
12
Brucella suis
Biovars 1 and 3
Worldwide problems where swine are raised
Free
United Kingdom, Canada
Eradicated
Holland, Denmark
Low Incidence
Middle East, North Africa
13
Transmission to Humans
Conjunctiva or broken skin contacting infected tissues
Blood, urine, vaginal discharges, aborted fetuses, placentas
Ingestion
Raw milk & unpasteurized dairy products
Rarely through undercooked meat
14
Transmission to Humans
Inhalation of infectious aerosols
Pens, stables, slaughter houses
Inoculation with vaccines
B. abortus strain 19, RB-51
B. melitensis Rev-1
Conjunctival splashes, injection
Person-to-person transmission is very rare
Incubation varies
7-21 days to several months
15
Transmission in Animals
Ingestion of infected tissues or body fluids
Contact with infected tissues or body fluids
Mucous membranes, injections
Venereal
Swine, sheep, goats, dogs
16
Who is at Risk Normally?
Occupational Disease
Cattle ranchers/ dairy farmers
Veterinarians
Abattoir workers
Meat inspectors
Lab workers
Hunters
Travelers
17
Brucellosis
United States
Approximately 100 cases per year
Less than 0.5 cases/100,000 people
Mostly California, Florida, Texas, Virginia
Many cases associated with consumption of foreign cheeses
18
Image courtesy of CDC
Human Disease
Can affect any organ or organ system
All patients have a cyclical fever
Variability in clinical signs
Headache, weakness, arthralgia, depression, weight loss, fatigue, liver dysfunction
20
Human Disease
20-60% of cases
Osteoarticular complications
Arthritis, spondylitis, osteomyelitis
Hepatomegaly may occur
Gastrointestinal complications
2-20% of cases
Genitourinary involvement
Orchitis and epididymitis most common
21
Human Disease
Neurological
Depression, mental fatigue
Cardiovascular
Endocarditis resulting in death
Chronic brucellosis is hard to define
Length, type and response to treatment variable
Localized infection
Blood donations of infected should not be accepted
22
Diagnosis in Humans
Isolation of organism
Blood, bone marrow, other tissues
Serum agglutination test
Fourfold or greater rise in titer
Samples 2 weeks apart
Immunofluorescence of organism in clinical specimen
PCR
23
Treatment of Choice
Combination therapy has the best efficacy
Doxycycline for six weeks in combination with streptomycin for 2-3 weeks or rifampin for 6 weeks
CNS cases treat 6-9 months
Same for endocarditis cases plus surgical replacement of valves
24
Brucella as a Bioweapon
Aerosolized B. melitensis
City of 100,000 people
Inhale 1,000 cells (2% decay per min)
Case-fatality rate of 0.5%
50% hospitalized for 7 days
Outpatients required 14 visits
5% relapsed
Results
82,500 cases requiring extended therapy
413 deaths
$477.7 million in economic impact
25
Glanders & Melioidosis
Image courtesy of USDA ARS
26
Burkholderia
Burkholderia mallei
Gram negative bacillus
Exists primarily in infected host
Withstands drying for 2-3 weeks
Killed by sunlight and high temp
Related to Burkholderia pseudomallei
Cause of meliodiosis
Image courtesy of CDC PHIL
27
History
3rd Century BC
Described by Aristotle
1664: Contagious nature recognized
1830: Zoonotic nature suspected
1891: Mallein test developed
1900: Control programs implemented
28
History
World War I
Suspected use as biological
agent to infect Russian horses
and mules
Affected troops and supply convoys
Large number of human cases
in Russia during and after WWI
29
History
World War II
Japanese infected horses, civilians
and POW’s
U.S. and Russia investigated
use as biological weapon
30
History
1934
Eliminated from animals in U.S.
1945
Six laboratory-acquired cases at Camp Detrick
2000
Human case in laboratory worker at USAMRIID
31
Transmission: Humans
Direct contact with infected animals
Abraded skin
Mucous membranes
Inhalation
Person-to-person (rare)
Ingestion has never been recorded in humans
32
Glanders is transmitted to humans by direct contact with infected animals. The bacteria enter the body through abraded or lacerated skin and through mucosal surfaces of the eyes, nose and mouth. The bacteria can also be acquired through inhalation of infectious material. Cases of human-to-human transmission have also been reported. No known cases of human intestinal glanders are recorded.
Transmission: Animals
Ingestion: Major route
Inhalation: Less likely
Direct contact: Minor route
Enhanced by shared food and water facilities
33
Epidemiology
Endemic
Parts of Africa, the Middle East, and Asia
Sporadic cases
South and Central America
Possible occurrence
Balkan states and former Soviet republics
Once widespread, has been eradicated in many countries
No longer endemic to North America
34
Host Range
Affects solipeds
Donkeys and mules
Acute form
Horses
Chronic form
Carnivores, humans and goats susceptible
Swine and cattle resistant
35
Who Is At Risk Normally?
Veterinarians
Groomers
Horsemen
Butchers
Lab workers
36
Disease in Humans
Four forms of infection
Localized cutaneous
Pulmonary
Septicemia
Chronic form
Generalized symptoms
Fever, malaise, muscle aches, chest pain
Case-fatality rate: 95% (untreated)
37
Clinical Signs: Cutaneous
Incubation period: 1-5 days
Erythema and ulceration of skin
Lymphadenopathy
Nodules
Along lymph vessels
Highly infectious exudate
Case fatality rate: 20% treated
38
Clinical Signs: Pulmonary
Incubation period: 10-14 days
Inhalation of aerosolized bacteria
Hematogenous spread to lungs
Pneumonia, pulmonary abscesses, pleural effusion
39
Clinical Signs: Septicemia
Incubation period: 7-10 days
Any site of infection can lead to sepsis
Fever, chills, myalgia, chest pain, rash
Tachycardia, jaundice, photophobia, lacrimation
Case-fatality rate: 60% treated
Rapidly fatal
40
Clinical Signs: Chronic
Glanders - “Farcy”
Multiple abscesses
Muscles, joints, spleen, liver
Case-fatality rate: 60% (treated)
Relapses common
41
Glanders - Differential Diagnosis
Typhoid fever
Tuberculosis
Syphilis
Erysipelas
Lymphangitis
Pyemia
Yaws
Melioidosis
42
Diagnosis: Humans
Culture and gram stain
Sputum, urine, skin lesions, blood
Gram negative bacilli
Safety pin appearance
Agglutination tests
May be positive after 7-10 days
High background titer in normal sera makes interpretation difficult
43
Diagnosis: Humans
Complement fixation
More specific
Positive if titer is equal to or greater than 1:20
Chest radiograph
44
Treatment
Limited information on treatment
Long term antibiotic treatment necessary (1-12 months)
No proven pre- or post-exposure prophylaxis
No vaccine
45
Prevention: Humans
Elimination of disease in animals
Biosafety level 3 required in labs
Protective clothing during exams and necropsy
Gloves and mask
46
Prevention
Horses
Early detection and quarantine with disinfection
Reportable to state veterinarian
Vaccine not available for humans or animals
47
Glanders as a Biological Weapon
History
Very few organisms required to cause disease
Easily produced
Pulmonary form has high mortality
Limited experience with disease can slow diagnosis and treatment
48
Q Fever
Query Fever
Coxiellosis
Image courtesy of USDA ARS
49
Coxiella burnetii
Rickettsial agent
Obligate intracellular parasite
Stable and resistant
Killed by pasteurization
Two antigenic phases
Phase 1: virulent
Phase 2: less pathogenic
Spore forming
50
History
1935
1st described in Queensland, Australia
Found in ticks in Montana
Outbreaks
Among military troops
When present in areas with infected animals
Cities and towns
Downwind from farms
By roads traveled by animals
51
Transmission
Aerosol
Parturient fluids
109 bacteria per gram of placenta
Urine, feces, milk
Wind-borne
Direct contact
Fomites
Ingestion
Arthropods (ticks)
52
Transmission
Person-to-person (rare)
Transplacental (congenital)
Blood transfusions
Bone marrow transplants
Intradermal inoculation
Possibly sexually transmitted
53
Epidemiology
Worldwide
Except New Zealand
Reservoirs
Domestic animals
Sheep, cattle, goats
Dogs, cats
Birds
Reptiles
Wildlife
54
Epidemiology
Occupational and environmental hazards
Farmers, producers
Veterinarians and technicians
Meat processors, abattoir
Laboratory workers
55
Image courtesy of CDC
Human Disease
Incubation: 2-5 weeks
One organism may cause disease
Humans are dead-end hosts
Usually show clinical signs of illness
Disease
Asymptomatic (50%)
Acute
Chronic
57
Acute Infection
Flu-like, self limiting
Atypical pneumonia (30-50%)
Non-productive cough, chest pain
Acute respiratory distress possible
Hepatitis
Skin rash (10%)
Other signs (< 1%)
Myocarditis, pericarditis, meningoencephalitis
Death: 1-2%
58
Chronic Disease
1-5% of those infected
Prior heart disease, pregnant women, immunocompromised
Endocarditis
Other
Osteomyelitis
Granulomatous hepatitis
Cirrhosis
50% relapse rate after antibiotic therapy
59
Diagnosis
Serology (rise in titer)
IFA, CF, ELISA, microagglutination
DNA detection methods
PCR
Isolation of organism
Risk to laboratory personnel
Rarely done
60
Treatment
Treatment
Doxycycline
Chronic disease – long course
2-3 years of medication
Immunity
Long lasting (possibly lifelong)
61
Q Fever as a Biological Weapon
Accessibility
Low infectious dose
Stable in the environment
Aerosol transmission
WHO estimate
5 kg agent released on 5 million persons
125,000 ill - 150 deaths
Could travel downwind for over 20 km
62
Psittacosis
Avian Chlamydiosis
Parrot Fever
Ornithosis
63
Chlamydia psittaci
Obligate intracellular bacteria
Elementary body
Infectious
Survive for months in environment
Reticulate body
Non-infectious
Image courtesy of CDC PHIL
64
New Taxonomic Classification
Genus Chlamydia
C. trachomatis
C. muridarum
C. suis
Genus Chlamydophila
C. abortus
C. felis
C. pecorum
C. pneumoniae
C. caviae
C. psittaci
65
The Organism
Resistant to drying
Remains infectious for months
Remains viable on surfaces for 2-3 weeks
Survives in turkey carcass for >1 yr.
66
History
1879
First recognized human outbreak
7 people in contact with sick parrots
1929-1930
750 human cases
20% mortality
Large scale importation of infected birds from Argentina
1935
Wild psittacines in Australia
67
Epidemiology
Occurs worldwide
50-100 confirmed cases per year in U.S.
1-2 deaths
True incidence unknown
Nationally reportable in humans
Pet store employees, bird owners, poultry processing plant workers
68
Epidemiology
1988-2002
923 cases in U.S.
Many cases unreported or misdiagnosed
1980’s
70% of cases with known source due to exposure to caged birds
69
Psittacosis in U.S.: 1972-2002
Year
Reported Cases
250
225
200
175
150
125
100
75
50
25
0
1972 1977 1982 1987 1992 1997 2002
MMWR
Image courtesy of CDC
70
Populations at Risk
Lab workers
Veterinarians
Avian quarantine workers
Zoo workers
Farmers
Pregnant women
Bird fanciers (pigeon fanciers too)
Bird owners
Pet shop employees
Poultry slaughter and processing workers
Wildlife rehab workers
71
Transmission to Humans
Inhalation
Dried infective droppings
Secretions or dust from feathers
Mouth-to-beak
Direct contact
Handling plumage or tissues of infected birds
Person-to-person transmission
Not proven
Venereal transmission reported
72
Human Disease: Psittacosis
Incubation period: 1-4 weeks
Range
Inapparent infection
Systemic infection with pneumonia
Pneumonia 30-60 years of age
Common signs – abrupt onset
Fever, chills, headache, malaise, myalgia, sore throat, cough, dyspnea, splenomegaly, rash
73
Clinical Signs
May also see
Myocarditis, endocarditis
Arthritis, lethargy, hepatitis, epistaxis
Placentitis, fetal death
Encephalitis, jaundice, respiratory failure
Thrombocytopenia, coma, arthralgia
74
Diagnosis
Confirmed case
Clinical signs + laboratory results
Culture
4-fold rise in titer
IgM detected by MIF
Probable case
Linked epidemiologically to confirmed case of Psittacosis
Single titer 1:32
75
Differential Diagnosis
Coxiella burnetii (Q fever)
Legionella
Chlamydia pneumoniae
Mycoplasma pneumoniae
Influenza
Tularemia
76
Treatment and Prognosis
With treatment
1-5% case-fatality rate
Tetracyclines are drug of choice
Remission of symptoms
Usually in 48-72 hours
Relapse possible
Without treatment
May resolve in few weeks-months
10-40% case-fatality rate
77
Avian Species Affected
Isolated from over 100 avian species
Psittacines
Especially cockatiels and parakeets
Egrets, gulls, ratites
Pigeons, doves, mynah birds, sparrows
Turkeys, ducks
Rarely chickens
78
Diagnosis
Diagnosis difficult
Case definitions
Confirmed, probable, suspect
Single test may not be adequate
Combination testing recommended
Proper sample collection techniques critical for accurate results
Consult an experienced avian veterinarian
79
Psittacosis: The Bioweapon
Easily obtained
Aerosolized
Stable in the environment
80
Viral Encephalitis
Image courtesy of CDC PHIL
81
Human Clinical Signs
Most cases are asymptomatic
Flu-like illness in some
Sudden fever, headache, myalgia, malaise, prostration
Small proportion develop encephalitis
Permanent neurological damage
Death
82
Human Treatment
Manage symptoms
Reduce fever
Maintain hydration and electrolytes
Maintain blood oxygen levels
Anticonvulsants
Osmotic diuretics for intracranial pressure
Physical therapy
No effective anti-virals available
83
Human Risks and Outcomes
St. Louis Encephalitis (SLE)
Most common
Elderly most at risk
Case fatality rate: 5-15%
La Crosse Encephalitis (LAC)
Children <16 years most at risk
Human fatalities less than 1%
84
Human Risks and Outcomes
Eastern Equine Encephalitis (EEE)
Elderly most at risk
Case fatality rate: 33%
Western Equine Encephalitis (WEE)
Children younger than 1 year most at risk
Case fatality rate approximately 3%
Venezuelan Equine Encephalitis (VEE)
Children most often affected
Fatalities are rare
85
Animal Risks and Outcomes
Horse - Case-fatality rate
EEE ~ 90%
VEE ~ 40-80%
WEE ~ 20-50%
Vaccine available in the U.S.
Trivalent formalin-inactivated
SLE, LAC do not cause disease in horses or other non-human mammals
86
Venezuelan Equine Encephalitis
Peste loca
Image courtesy of CDC PHIL
87
VEE Viral Strains
Epizootic/Epidemic
I-A, I-B and I-C
Disease in humans and horses
Transmission by many mosquito species
Natural reservoir unknown
Horses and donkeys act as amplifiers
Enzootic/Endemic
Disease in humans
Transmission mainly by Culex (Melanoconion) species
Natural reservoir is rodents living in swamps and forests
88
VEE History
Western Hemisphere disease
Primarily Central and South America
1938: Isolated from a horse brain
1962-1964
Outbreak in Venezuela
23,000 human cases
1967
Outbreak in Colombia
220,000 human cases
Over 67,000 horse deaths
89
VEE History
1969-1971
Largest recorded outbreak in Guatemala
Area from Costa Rica to Rio Grande Valley in Texas
Thousands of human encephalitis cases
Over 100,000 horses died
Small outbreaks occur occasionally
1995
Venezuela and Colombia
Over 90,000 human cases
90
VEE Epidemiology
1971
Only U.S. outbreak - in Texas
Enzootic variant Everglades virus in south Florida
2-3 human cases, no horse disease
Infection in humans less severe than EEE or WEE
Fatalities rare, less than 1%
91
Human VEE
Initial signs
Last 24-48 hours
Fever, malaise, dizziness, chills, headaches, anorexia, severe myalgia, arthralgia, nausea, vomiting
Lethargy and anorexia can last 2-3 weeks
4-15% of cases become neurological
Mortality rates less than 1%
Most often in children with encephalitis
92
Human VEE
In utero death
Possible in pregnant women who contract the disease
Diagnosis
Paired sera with rising titer
ELISA IgG or IgM
Treatment: Supportive care
No vaccine available
Prognosis
Variable, often chronic fatigue and headaches
93
Animal VEE
Incubation period: 1-5 days
Horses most susceptible
Fever, anorexia, depression, flaccid lips, droopy eyelids and ears, incoordination and blindness
Death 5-14 days after clinical onset
Case-fatality rate: 38-83%
In utero transmission results in abortion, stillbirth
94
Animal VEE
Diagnosis
Paired sera with rising titer
ELISA IgG or IgM
Treatment: Supportive care
Vaccine available for horses
Trivalent, formalin inactivated
WEE, EEE, VEE combination
Days 0 and 30
Annual or biannual booster
95
VEE as a Biological Weapon
Aerosolized VEE
Human and equine disease occur simultaneously
Flu-like symptoms in humans
Possible neurological signs in horses
Large number of cases in a given geographic area
96
VEE as a Biological Weapon
50 kg virulent VEE particles
Aerosolized over city of 5 million people
150,000 people exposed
30,000 people ill
300 deaths
97
Ricin
Image courtesy of Lynne Railsback
98
Toxin
Castor plant - Ricinus communis
From processing waste
Castor beans for oil
Very stable
In several forms
Powder, mist, pellet, dissolved
in water or weak acid
Irreversibly blocks protein synthesis
Potential medical uses
99
History of Ricin
World War I
Considered for use as weapon by US
1978: London
Assassination of Bulgarian exile, Georgi Markov
1991: Minnesota
Patriot’s Council plot to kill US Marshal
100
History of Ricin (continued)
Iran-Iraq war
Reports of ricin use
Found in Al Qaeda caves in Afghanistan
2003
Ricin found in London apartment
2004
Toxin found in Senator’s office
Found in letter in South Carolina; source unknown
101
Transmission
Three routes
Inhalation
Ingestion
Injection
Person-to-person transmission does not occur
102
Signs and Symptoms
Inhalation
Incubation less than 8 hours
Ingestion
Incubation few hours to few days
Injection
Incubation immediate to hours
103
Clinical Symptoms
Inhalation
Cough, weakness, fever, nausea, muscle aches, chest pain and cyanosis
Pulmonary edema, 18-24 hours after inhalation
Severe respiratory distress
Death from hypoxemia, 36-72 hours
104
Clinical Symptoms
Ingestion
Least toxic form
Less toxic if castor beans swallowed whole
Severe GI symptoms, 1-2 hours
Rapid heartbeat
Internal bleeding
Vascular collapse
Death occurs in 3 days or more
105
Clinical Symptoms
Injection
Local pain and necrosis at site of injection
Systemic signs similar to those of ingestion
106
Diagnosis
Based on clinical symptoms
ELISA
Serum or respiratory secretions
Immunohistochemistry
Tissues
Serology for retrospective diagnosis
Ricin is very immunogenic
107
Treatment
No treatment, vaccine or antisera currently available
Supportive care
Dependent on route of exposure
Ventilator
Gastric lavage or cathartics
108
Ricin as a Biological Weapon
Extreme ease of production
Widely available
Relatively high toxicity
Currently no treatment
Supportive care only
109
Discussion Questions
Describe the life cycle of an arbovirus? Which of the viral Encephalitides has been exploited in former BW programs?
What is it about ricin that causes it to be used in so many recent biocrimes?
What are the attributes of Category B agents? Apply each of the criteria to the diseases discussed in Chapter 4.
In what ways are Brucella normally transmitted to humans?
In what ways would an intentional outbreak of Q fever overwhelm the medical and public health communities?
Chapter 4 Summary
Category B contains the agents of great concern
Be certain you know the criteria!
Know why each agent has been placed within the category – apply the criteria
Realize the potential that each agent has to confuse healthcare providers and create chaos
Content
Critical Thinking
Content
Discussion Questions