2. HISTORY
• Microbial pathogens were used as potential
weapons of war or terrorism from ancient times:
– the poisoning of water supplies in the sixth century
B.C. with the fungus Calviceps purpurea (rye ergot)
by the Assyrians
– the hurling of the dead bodies of plague victims over
the walls of the city of Kaffa by the Tartar army in
1346
– the spreading of smallpox via contaminated blankets
by the British to the native American population loyal
to the French in 1767.
3. Key Features of Biologic Agents
Used as Bioweapons
• High morbidity and mortality
• Potential for person-to-person spread
• Low infective dose and highly infectious by aerosol
• Lack of rapid diagnostic capability
• Lack of universally available effective vaccine
• Potential to cause anxiety
• Availability of pathogen and feasibility of production
• Environmental stability
• Database of prior research and development
• Potential to be “weaponized”
4. CLASSIFICATION
• Centers for Disease Control and Prevention (CDC) classifies potential
biologic threats into three categories: A, B, and C
• Category A agents are the highest-priority pathogens:
– can be easily disseminated or transmitted from person to person
– result in high mortality rates
– have the potential for major public health impact
– might cause public panic and social disruption
– require special action for public health preparedness.
• Category B agents include those that are moderately easy to
disseminate, result in moderate morbidity rates and low mortality rates,
and require specifically enhanced diagnostic capacity.
• Category C agents include emerging pathogens
– the general population lacks immunity
– could be engineered for mass dissemination in the future because of
availability, ease of production, ease of dissemination
– The recent emergence of novel viruses leading to outbreaks of severe
acute respiratory syndrome (SARS), Nipah, hantavirus are examples
7. Anthrax as a Bioweapon
• Anthrax may be the prototypic disease of bioterrorism
although rarely spread from person to person
• U.S. and British government scientists studied anthrax
as a biologic weapon beginning approximately at the
time of World War II (WWII).
• Soviet Union in the late 1980s stored hundreds of tons of
anthrax spores for potential use as a bioweapon
• At present there is suspicion that research on anthrax is
ongoing by several nations and extremist groups
• One example of this is the release of anthrax spores by
the Aum Shrinrikyo cult in Tokyo in 1993. Fortunately,
there were no casualties associated with this episode.
8. Anthrax as a Bioweapon II
• 1979: the accidental release of spores into the atmosphere from a Soviet
Union bioweapons facility in Sverdlosk:
– at least 77 cases of anthrax were diagnosed with certainty, of which 66 were fatal
– victims have been exposed in an area within 4 km downwind of the facility
– deaths due to anthrax were also noted in livestock up to 50 km away from the
facility
– interval between probable exposure and development of clinical illness ranged from
2 to 43 days (the majority of cases were within the first 2 weeks)
– death typically occurred within 1 to 4 days following the onset of symptoms
– the anthrax spores can lie dormant in the respiratory tract for at least 4 to 6 weeks
• September 2001: anthrax spores delivered through the U.S. Postal System.
– CDC identified 22 confirmed or suspected cases of anthrax (11 patients with
inhalational anthrax, of whom 5 died, and 11 patients with cutaneous anthrax - 7
confirmed - all of whom survived)
– cases occurred in individuals who opened contaminated letters as well as in postal
workers involved in the processing of mail
– one letter contained 2 g of material, equivalent to 100 billion to 1 trillion spores
(inoculum with a theoretical potential of infecting up to 50 million individuals)
– The strain used in this attack was the Ames strain - was susceptible to all
antibiotics
9. Bacillus anthracis
• Aerobic, sporing Gram-positive rod:
infection usually transmitted by spores
• Generally more sensitive to antibiotics
than other Bacillus species, but multi drug
resistant strains have been found in nature
• BUT not sensitive to 3rd generation
cephalosporins
• Easily dismissed as a contaminant when
identified in general hospital laboratories
11. B. anthracis toxins
• Lethal toxin (LeTx): intracellular
endopeptidase, probably directly damages
endothelial cells; also immunosuppressive.
• Oedema toxin (ETx): potent adenyl
cyclase; contributes to shock and
potentiates LeTx.
• Protective antigen: the portion of the
binary LeTx and ETx complexes which
mediates attachment to target cells
12. Bacillus anthracis: epidemiology
• Spores of B. anthracis are widely dispersed in
nature: in soil, animal carcases and skins, and items
made from skin, wool or hair (eg drums made with
animal skins, bags, fur robes, plaster reinforced with
horse-hair etc)
• It is relatively difficult to infect humans: usually skin
inoculation or a large inhalational exposure is
required
• The organism is therefore classified at biosafety
level 3 (CL 3)
13. Anthrax presentations
• Inhalational: ‘flu’
followed by
mediastinitis and
pneumonitis
• Cutaneous
• Gastrointestinal
• Meningitic
CUTANEOUS ANTHRAX
Most common presentation:
Look for black eschar; halo of
vesicles; extensive oedema
19. Intestinal Anthrax
(Armed Forces Institute of Pathology, USA)
• Ingestion of contaminated
meat
• Incubation: <1 - 7 days
• Fever, acute abdomen,
vomiting, bloody diarrhoea
• Intestinal eschar (similar to
cutaneous lesion)
• Progression to sepsis
syndrome
• Mortality 50 - 100% despite
treatment
20. Inhalational anthrax
• Flu’-like onset, respiratory
failure develops abruptly
after 3-4 days-fatal in 1 or
2 days
• CXR suggestive, but
features can be subtle
• Blood cultures pos.(CL3)
• PCR possible (ref.lab)
• responds to early
vigorous treatment
Jernigan et al. EID 2001; 7: 933
21. Confirmed anthrax cases associated with bioterrorism: U.S., 2001.
A. Geographic location and clinical manifestation of the 11 cases of
confirmed inhalational and 7 cases of confirmed cutaneous anthrax.
B. Epidemic curve for the 18 confirmed cases of inhalational and
cutaneous anthrax and 4 cases of suspected cutaneous anthrax.
22. Progression of chest x-ray findings in a patient with inhalational anthrax.
Findings evolved from subtle hilar prominence and right perihilar infiltrate
to a progressively widened mediastinum, marked perihilar infiltrates,
peribronchial cuffing, and air bronchograms.
23. Recognising inhalational
anthrax
• 10 cases of inhalational anthrax: USA
• WCC 7.5-13.3 x109/l (6 < 10.0)
• 6/6 had >70,000 RBCs in pleural fluid, with
high protein and low WBCs
• 6/6 had PaO2 80mmHg or less on air
• 5/7 treated within 5 days of onset survived
• 1/3 treated after 5 days survived
JA Jernigan et al. EID 2001; 7: 933
24. Treating inhalational anthrax
• Severe chest
infection of
unknown cause.
• DON’T use 3rd gen.
Cephalosporin alone.
• Use a penicillin eg.co-
amoxyclav plus a
macrolide/ciproflox.
• Or add gentamicin.
• Antibiotics effective
for anthrax.
• Ciprofloxacin.
• Benzyl penicillin.
• Macrolides.
• Gentamicin (plus
pen.).
• Doxycycline.
• Chloramphenicol.
25. Vaccination and Prevention
• The first successful vaccine for anthrax was developed
for animals by Louis Pasteur in 1881.
• At present, the single vaccine licensed for human use is
a product from the cell-free culture supernatant of an
attenuated, nonencapsulated strain of B. anthracis
(Stern strain) - anthrax vaccine adsorbed (AVA).
• Clinical trials for safety in humans and efficacy in
animals are currently under way to evaluate the role of
recombinant protective antigen (one of the major
components, along with lethal factor and edema factor,
of B. anthracis toxins) as an alternative to AVA.
• The efficacy of AVA in a postexposure setting in humans
has not been established.
• The current recommendation for postexposure
prophylaxis is 60 days of antibiotics (ciprofloxacin or
doxycycline).
26. Chemo-prophylaxis of
anthrax
Prophylaxis Adult doses Child doses
Ciprofloxacin 500mg orally bd
for 6 weeks
20-30mg/kg bd
Doxycycline (if
cipro x tolerated
/indicated)
100mg orally bd 5mg/kg orally in
two divided
doses
Although normally used with caution or contraindicated,
these drugs may be given in pregnancy, lactation and
childhood to protect against anthrax
27. PLAGUE
MICROBIOLOGICAL FEATURES:
gram-negative, rod-shaped, facultative anaerobic
bipolar staining, non-motile, non-sporulating
BIOLOGICAL SURVIVAL:
15 minutes in 55° C/ few hours in sunlight
weeks in water, grains, moist soil, dry sputum, flea feces
lives months/years at just above 0°C
HOST RANGE:
zoonotic disease of rodents: rats, mice, ground squirrels
intracellular organism: monocytes/macrophages
=> long-term survival requires host
=> Circumstances for natural human outbreaks:
disasters/ disruption of rat habitats/ rat dis- or relocation
28. SYNDROMIC PRESENTATION – SESSION 1
PLAGUE EPIDEMIOLOGY I
NATURALLY OCCURING PLAGUE
Since 1965: approximately 1500 cases/year
25 countries reported cases
50% Eastern and South Africa, esp. Madagascar
1980-1994: 18,739 cases reported from 20 countries to WHO
2000 – 2005: Zambia, Algeria, Malawi, DR Congo
December 2007: n=1, marmoth hunter, China
Endemic in U.S. 1947-96: 390 cases/y
1970-2003: 5-15 cases/y
83% Bubonic
15% Septicemic
2% Primary Pneumonic
29. SYNDROMIC PRESENTATION – SESSION 1
PLAGUE TRANSMISSION
4 ROUTES FOR HUMAN INFECTION
1. Flea-bite (most common)
=> Rat-borne urban epidemics in history
=> Human overcrowding, indoor contacts
2. Handling infected animals (skin contact, scratch, bite)
=> Endemic sylvatic plague with sporadic outbreaks
=> Occupational risks
3. Inhalation of contaminated aerosol (human/animal)
=> Only pneumonia capable of person to person spread
4. Ingestion of infected meat
30. 3 TYPES OF DISEASE
Bubonic
Septicaemic
Pneumonic
SYNDROMIC PRESENTATION – SESSION 1
PLAGUE CLINICAL COURSE I
31. Plague: Clinical Forms
Bubonic
(CDC image library)
• Common form of naturally
occurring plague, following bite
of infected flea
• Inguinal, axillary, or cervical
lymph nodes are the most
commonly affected
• 80% can become
bacteraemic
• 60% mortality if untreated
32. SYNDROMIC PRESENTATION – SESSION 1
PLAGUE CLINICAL COURSE II
1. “CLASSIC” Bubonic Plague
ENTRY: Bite of infectious flea
Contact/ ingestion of infected animals
Contact/ ingestion of infectious material
BUBOES: Enlarged tender lymphnodes (unilateral)
Usually inguinal/ femoral in adults
Cervical/ submaxillary common < 10y
CFR: 40-60% untreated, <5% treated
Overall 14% in U.S. (delayed diagnosis/ therapy)
COMPLICATION: BACTERAEMIA
secondary septicaemic plague
secondary pneumonic plague
secondary plague meningitis
www.cdc.gov
33. 3. Pneumonic Plague
US cases: 2% PRIMARY PNEUMONIC
12% SECONDARY PNEUMONIC
PRIMARY: Result of droplet inhalation
Only few cases in endemic areas
ENTRY: Aerosol => other patients/ infected animals/ BW
SECONDARY: Hematogenously spread to lungs
Initially: interstitial pattern/ later: abscess
CFR: ~ 100% if untreated/ therapy delayed > 18-24h after onset
Remains high despite treatment: Overall 57% (U.S.)
DEATH WITHIN 2-4 DAYS (max 6d): cyanosis, stridor, resp. failure
35. SYNDROMIC PRESENTATION – SESSION 1
PLAGUE TREATMENT
FIRST LINE:
STREPTOMYCIN =>bacteriocidal
CHILDREN: 30 mg/kg IM divided q8-12h (max 2g/day)
ADULTS: 1g IM bid
GENTAMYCIN => as effective, qd dosage
CHILDREN: 2.5mg/kg im/iv q8h
ADULTS: 5mg/kg iv qd (check levels) OR
load 2mg/kg, then 1.7mg/kg q8h
SECOND LINE:
DOXYCYCLIN => good in vitro + good human data
1. Single 200mg iv loading dose
2. 100mg iv bid or 200 mg iv qd adults/ kids >45kg
=> 1st choice po therapy for mass casualties/ PEP
37. The variola virus
• A member of the family of Orthopoxviridae
• The largest viral genome: double-stranded
DNA
• An enveloped virus, but the envelope is
not essential for infectiousness
38. The Yugoslavia outbreak 1972
• Single index case spent time in Iraq
– 11 contacts developed smallpox
• 100 secondary cases in contacts and
other hospital patients
• 14 tertiary cases
• Spread to other cities
• Total 175 cases, 35 deaths
40. Variola: 4th day of rash
•For the first time-on
the fourth day of the
rash and the fifth day
of infectiousness, a
typical vesicular
appearance is seen
41. Variola major: drying rash (7-9
days)
•The rash is
becoming less
infectious
•Conjunctival
lesions are usually
benign and heal
completely
44. Smallpox Clinical Course
• Prodrome (day 1-
3)
• Erythematous
rash (days 2-3)
• Maculopapular
rash (days 4-6)
• Vesicular
pustular rash (days
8-14+) (Fenner F et al. Smallpox and its eradication. WHO 1998.
http://whqlibdoc.who.int/smallpox/9241561106.pdf )
45. Boys aged 13 years, infected from the same source-admitted same day:
right-unvaccinated; left-vaccinated in infancy
Variola major: variation in
severity
46. Diagnosis of smallpox:
(must be in CL4 facility)
• Classical tests
EM of vesicle fluid for
poxvirus
Virus culture
(CFT and ELISA for plasma
antibodies-not reliable)
PCR: rapid,
specific, can
distinguish
between
poxviruses-
performed on
blood or vesicle
fluid
47. Smallpox vs. Chickenpox
• Smallpox
• Incubation 7-17d
• Severe illness
• Prodrome
• Headache and back pain
• Centrifugal
• Synchronous
• Rash not initially itchy
• Lesions round
• Scabs form 10-14d
• Scabs separate 14-28d
• Chicken pox
• Incubation 14-21 d
• Usually mild
• Prodrome
• Mild malaise
• Centripetal
• Asynchronous
• Rash initially itchy
• Lesions oval
• Scabs form 4-7d
• Scabs separate <14d
48. Management of smallpox
• General supportive measures
• Analgesia (the rash is very painful)
• Good hygiene (secondary infection is a
danger-the skin is a common portal of
entry)
• Antibiotics to treat secondary infection and
limit scarring
• ?antiviral drugs
49. Smallpox vaccine
• Live vaccinia vaccines
Lister-Elstree
NYCBH
2nd generation live
(Modified vaccinia and others)
• Given by scarification
50. Burkholderia pseudomallei
– Aerobic, gram-negative, motile bacillus
– Found in water and moist soil
– Opportunistic pathogen
– Produces exotoxins
– Can survive in phagocytic cells
• Latent infections common
MELIOIDOSIS
51. disease of rice farmers
endemic in tropics and subtropics:
Southeast Asia, Australia, the Middle East, India, China,
Caribbean
U.S. and EU cases linked with travel abroad
SYNDROMIC PRESENTATION – SESSION 1
MELIOIDOSIS V Epidemiology II
52. Clinical disease uncommon
in endemic areas
– antibodies in 5-20% of
agricultural workers
– no history of disease
Seasonal increase (wet season)
– heavy rainfall
– high humidity or temperature
SYNDROMIC PRESENTATION – SESSION 1
MELIOIDOSIS VI Epidemiology III
53. WOUND INFECTION
– Contact with contaminated soil
or water
INGESTION
– Contaminated water
INHALATION
– Dust/ contaminated soil
RARELY
– Person-to-person
– Animal-to-person
SYNDROMIC PRESENTATION – SESSION 1
MELIOIDOSIS VIII Transmission
54. INCUBATION PERIOD: 1-21 days (~ 9 days) up to 30 years
Always Fever, chills, malaise
Soft tissue: Abscess
Pulmonary: Productive cough, dyspnoea
Septicaemic/disseminated: Multiple abscesses, Septic shock
MOST INFECTIONS ASYMPTOMATIC/ LATENT
MODE OF TRANSMISSION INDUCES DIFFERENT CLINICAL FORMS:
INOCULATION => Focal (wound) infection
INHALATION => Acute pulmonary infection
Both can result in secondary SEPTICEMIA
CNS involvement is rare
SYNDROMIC PRESENTATION – SESSION 1
MELIOIDOSIS IX Clinical Course I
55. Abscess/ granuloma formation
– Skin
– Bone and/or muscle
– Joints
– Internal organs
– Genitourinary
– Nervous system (infrequent)
FOCAL INFECTIONS
SYNDROMIC PRESENTATION – SESSION 1
MELIOIDOSIS X Clinical Course II
56. Most common form:
High fever, headache
Dull aching chest pain
Cough, tachypnea, rales
Chest X-rays
– Upper lobe consolidation
– Nodular lesions
– Pleural effusion
ACUTE PULMONARY INFECTION
SYNDROMIC PRESENTATION – SESSION 1
MELIOIDOSIS XI Clinical Course III
57. PULMONARY INFECTION - RADIOLOGY FINDINGS
USE CT
IF AVAILIABLE !
SYNDROMIC PRESENTATION – SESSION 1
MELIOIDOSIS XII Clinical Course IV
58. DIAGNOSIS:
Clinical suspicion => travel to endemic areas
low budget, outdoor travel
=> occupational exposure
medical, military
Microbiology => Isolation of organism
=> Various serological tests
PREVENTION
Avoid contact with soil/water => Chlorination if needed
Handling infected animals with care
Thorough cleaning of wounds
SYNDROMIC PRESENTATION – SESSION 1
MELIOIDOSIS XIV Diagnosis and prevention
