Biological Warfare Attack, Diagnosis, Treatment

Biological Warfare Attack Diagnosis and Treatment Dan Gervich, MD Gregory C. Gray, MD, MPH

“The one that scares me to death, perhaps even more so than tactical nuclear weapons, and the one we have the least capability against is biological weapons.”

General Colin Powell, 1993

NY Times 10/14/01

http://abcnews.go.com/sections/us/terrorism_groups/

Ideal Biological Warfare Agents • • • • • • •

Inexpensive Easy to produce Aerosolized (1 to 10um diameter) Survives sunlight, drying, and heat Causes lethal or disabling disease Results in person-to-person transmission Has no effective therapy or prophylaxis.

Osterholm, MT. Bioterrorism: A real modern threat. In Emerging Infections 5. Scheld WM, Craig, WA, and Hughes JM eds. ASM Press, Washington, DC. 2001. Pps 213-222

Russian Bioweapons Program • 25,000 and 32,000 people were employed in a network of 20 to 30 military and civilian laboratories and research institutions • 40,000 metric tons of bioagents were produced; much was weaponized • The program was supposedly dismantled in 1992 •Preston R. Annals of Warfare New Yorker 1998 March; Alibek K Biohazard Random House, NY, NY 2000; Emerg Infect Dis 1999;5:523-27.

Russian Bioweapons Program • • • •

Smallpox Anthrax Plague Equine encephalitis viruses • Tularemia • Marburg virus • Q fever

• • • •

Typhus Melioidosis Foot and mouth virus African swine fever virus • Trichothecenes mycotoxins • Glanders

•Alibek K Biohazard Random House, NY, NY 2000 •Kortepeter MG, Parker GW. Potential Biological Weapon Threats Emerg Infect Dis 1999;5:523-27. •Preston R. Annals of Warfare New Yorker 1998 March

Destroying the Evidence “In 1988, Soviet scientists were scrambling to destroy their secret stockpile of anthrax, which they had manufactured in violation of the Biological and Toxin Weapons Convention (BWC). Alarmed at the possibility that the West was catching on and could call for inspections, the Soviets moved quickly to cover their tracks. Scientists placed hundreds of tons of the deadly pink powder in huge stainless steel canisters, doused it with bleach to kill the spores, then sent the drums on a 1,000-mile train ride to a remote island in the Aral Sea, a secret biological weapons testing site. There soldiers dumped the sludge into 11 shallow pits, poured in more bleach, and buried the anthrax mixture under Vozrozhdeniye Island’s sandy soil.” Choffnes E. Germs on the Loose. Bulletin of Atomic Scientists 2001 March/April

From NASA’s Terra satellite….. Rebirth island joins the mainland http://earthobservatory.nasa.gov

http://www.lonelyplanet.com/mapshells/central_asia/uzbekistan/uzbekistan.htm

Iraq’s Bioweapons Program • Anthrax • Congo-Crimean hemorrhagic fever virus • Yellow fever virus • Enterovirus 17 • Human rotavirus • Trichothecenes mycotoxins

• Botulism toxin • Clostridium perfringens • Aflatoxin • Ricin • Camelpox • Wheat cover smut JAMA 1997;278:418-424

Epidemiologic Clues of a Biowarfare Attack • Large epidemic with similar disease in a discrete population • Many cases of unexplained disease • More severe disease than expected • Disease unusual for the population • Disease normally transmitted by a vector uncommon in your area • Uncommon disease • Unusual strains of pathogens

From USAMRIID’s Medical Management of Biological Casualties Handbook, 2001

Public Health Assessment • Many diseases caused by bioterrorism actions will initially present with nonspecific clinical symptoms • Your responsibility is to be informed regarding biowarfare threats and to weigh this information along with clinical and epidemiological data in assessing your patients

• Dan Gervich begins presentation here

Viruses Causing Encephalitis as Biowarfare Agents • Venezuelan equine encephalitis • Western equine encephalitis • Nipah viruses • Others less likely - Eastern equine encephalitis, Japanese encephalitis, St. Louis encephalitis, Murray Valley encephalitis, Lacrosse encephalitis, etc.

Venezuelan Equine Encephalitis • Endemic - The Americas • 8 mosquito-born viruses cause disease in horses, mules, donkeys, and humans • Zoonotic reservoirs - bats, birds, rodents, and certain tropical jungle mammals. • Weaponized by the United States under a program that was discontinued in 1969 • Transmission – aerosolized threat; human to human and equine to equine risk is low • Infective dose (aerosol) -10-100 organisms

Venezuelan Equine Encephalitis • Incubation – 1-5 days • Duration of illness – days to weeks • Lethality – Low (17,000 human cases in Mexico 1969-71 with no deaths) • Vaccines – Two IND human unlicensed VEE vaccines under study; do not protect against all serotypes • Immunoprophylaxis – none • Chemoprophylaxis – alpha-interferon and interferon-inducer poly-ICLC effective in animal models

Venezuelan Equine Encephalitis • Clinical presentation (similar to influenza) – nearly 100% of infected develop symptoms – Sudden onset general malaise, chills, spiking fevers (380C to 40.50C), rigors, severe headache, photophobia, leg and back myalgias, nausea, vomiting, cough, sore throat, injected conjunctiva – leukopenia – <4% children & <1% adults develop encephalitis • Diagnosis – virus isolation (blood, CSF) – Serologic studies include IgM ELISA indirect FA, hemagglutination inhibition, CF, and IgG ELISA – PCR • Management – Supportive, no quarantine needed

Hemorrhagic Fever Viruses as Biowarfare Agents • Arenaviridae – Junin (Argentinian), Machupo (Bolivian), Guanarito (Venezuelan), and Sabia (Brazilian) fever, and Lassa Fever viruses • Bunyaviridae – Nairovirus - Congo-Crimean hemorrhagic fever virus – Flebovirus – Rift Valley Fever virus – Hantaviruses

• Filoviridae – Ebola, and Marburg viruses • Flaviviridae – dengue, yellow fever, West Nile viruses

Crimean-Congo Hemorrhagic Fever • Endemic – Kazakhstan, Uzbekistan, Pakistan, Afghanistan, Dubai, Iraq, South Africa, Greece, Turkey, Albania, and India. • Weaponized - by Russia • Transmission – Aerosolized threat; transmission by tick bites (genus Hyalomma), also direct or aerosolized exposure to the blood of viremic sheep, cattle, or humans. Nosocomial transmission is common. • Reservoir - include hares, hedgehogs, birds, and large animals. • Infective dose (aerosol) –1-10 organisms

SAMJ, Vol. 62, p576-580, October,1982

Crimean-Congo Hemorrhagic Fever • • • •

Incubation – 1-3 days, range 1-12 days Duration of illness – days to weeks Lethality – can be high Vaccines – inactivated mouse brain vaccine has been used in Russia; no vaccine available in the United States • Prophylaxis – tick repellants • Chemoprophylaxis – none

Crimean-Congo Hemorrhagic Fever •

•

•

Clinical presentation – abrupt high fever, myalgias, headache, abdominal pain, back pain, diarrhea, dry cough. 75% of patients show hemorrhagic features after 3-5 days: petechial rash often appears in the throat, nosebleeds, hematemesis, ecchymoses. DIC may follow symptoms as well as shock and ARDS. Diagnosis – virus isolation (blood) in VERO cells – Serologic studies include IgM ELISA Management – Isolation and containment with full precautions (glove, gowns, masks, eye protection), and extreme care in handling lab specimens, and body fluids – Supportive care – There is evidence that CCHF responds to treatment with ribavirin

CCHF Virus. Ecchymoses encompassing left upper extremity one week after onset of CCHF. (Photo courtesy of Robert Swaneopoel, PhD, DTVM, MRCVS, National Institute of Virology, Sandringham, South Africa.) eMedicine Journal, October 15 2001, Volume 2, Number 10

Cholera • Endemic – Endemic in many parts of Africa, India and the developing world. Transmission – oral / fecal transmission. Thought to be a possible bioterrorism agent through contamination of drinking water. • Reservoir – man; copepods and other zooplankton in brackish waters • Infective dose –10-500 organisms

Cholera • • • •

Incubation – 2-3 days, range 4 hrs – 5 days Duration of illness – >=week Lethality – low with treatment; high without treatment Vaccines – current killed whole cell vaccine offers only 50% protection for 3-6 months in endemic areas • Chemoprophylaxis – close contacts only: tetracycline, doxycycline, erythromycin,TMP-SMX, ciprofloxacin, etc.

Cholera Clinical presentation - sudden onset of profuse painless watery stools (rice water stools), nausea, and vomiting; if untreated rapid dehydration, acidosis, shock, hypoglycemia in children, renal failure Diagnosis - Bacterial isolation; toxin production should be confirmed by the laboratory Management - Isolation is not necessary; hospitalization with enteric precautions; aggressive rehydration therapy, administration of antibiotics, and treatment of complications

Toxins as Biowarfare Agents • • • •

Botulinum Staplococcal enterotoxin B Trichothecene mycotoxins Ricin

Comparative Lethality and Dose for Toxins in Mouse Models

Agent

LD50 / Molecular wt (ug/kg)/ (daltons)

Quantity of toxin Open-air exposure to 100 km2

Botulinum

0.001 / 150,000

85kg

Ricin

3.0 / 64,000

400 metric tons

USAMRIID. Medical Management of Biological Casualties Handbook February 2001. http://usamriid.detrick.army.mil/

Botulinum Toxin • Source – One of several toxins (termed A-G) from Clostridium bacteria; most potent neurotoxins known; 100,000 times more toxic than the nerve agent Sarin • Iraq had 10,000 liters of botulism toxin • Endemic – Worldwide distribution; 3 forms: foodborne, infantile, and wound botulism • Transmission – aerosolized or food borne threat; no human-to-human; inhalation syndrome is similar to food borne disease • Infective dose –0.001 ug/kg is LD50 • Method of Action – blocks neuromuscular transmission

Botulinum Toxin • Detoxified – air (12 hours); sunlight (1-3 hours) • Incubation – symptoms after inhalation can occur in 12 to 36 hours; low dose exposure delays sxs • Duration of illness – death can occur in 24-72 hours • Lethality – high without respirator support • Vaccines – pentavalent toxoid vaccine is effective in primates and is under IND status (3 dose series with annual booster); available only for high risk groups • Chemoprophylaxis – none

Botulinum Toxin • Clinical presentation – Dry mouth, blurred or double vision, cranial nerve palsies, photophobia, difficulty swallowing

• Diagnosis – Clinical - Patient is afrebrile, alert, oriented; reduced gag reflect; pupils may be dilated or fixed; reduced deep tendon reflexes; respiratory distress may lead to cyanosis; progressive symmetrical descending flaccid muscle paralysis

• Management – Supportive care; ventilatory support; antixons (CDC) – Draw sera sample for future neutralization assay – Aerosols from patients are not a hazard

Staphlococcal Enterotoxin B • Source – One of several toxins from Staphlococcal aureus; associated with food poisoning • Transmission – aerosolized threat; no human-to-human transmission • Infective dose –30 ug/person incapacitates

Staphlococcal Enterotoxin B • • • • • • •

Incubation – 3-12 hours after inhalation Duration of illness – hours Lethality – <1% Vaccines – vaccine under development Prophylaxis – use of a protective mask Chemoprophylaxis – none Mechanism of action – pyrogenic toxins produce toxic-shock like response

Staphlococcal Enterotoxin B • Clinical presentation – abrupt onset fever, chills, headache, myalgias, nonproductive cough. In more severe cases dyspnea and retrosternal chest pain. Nausea, vomiting and diarrhea are likely to occur. Fever may last several days. Cough may persist for several weeks. High doses are expected to be fatal. • Diagnosis – Clinical (febrile respiratory syndrome without CXR findings); large number of patients would suggest an a large scale attack • Management – Supportive care; ventilation may be necessary – Standard precautions for healthcare workers; aerosols from patients are not a hazard

Trichothecene Mycotoxins • Source – A Group of over 40 compounds produced by the grain mold (genus Fusarium); easy to produce; allegedly released as “yellow rain” in Laos (1975-81), Kampuchea (1979-81), Afghanistan (1979-81), and Sudan (1999) • Transmission – aerosolized threat; mycotoxins can adhere to and penetrate the skin; can be inhaled and ingested; no human-to-human transmission but contaminated clothing can serve as a reservoir • Infective dose – uncertain • Method of Action – cytotoxic; inhibits protein and nucleic acid synthesis

Trichothecene Mycotoxins • • • • •

Incubation – 2-4 hours Duration of illness – days to months Lethality – moderate Vaccines – under development Chemoprophylaxis – topical products under development

Trichothecene Mycotoxins • Clinical presentation • Early symptoms are rapid and include: burning skin pain, redness, tenderness, blistering, leading to skin necrosis and sloughing of skin. • If inhaled respiratory symptoms include cough, dyspnea, and wheezing. • Gatrointestinal symptoms may include nausea, vomiting, and diarrhea.

Vesicles and erosions on the back of hairless guinea pigs at 1 day after application of (bottom to top) 25 ng, 50 ng, 100 ng, or 200 ng of T-2 mycotoxin in 2mcL of methanol. (from Wannamacher RW Jr, Wiener SL. Trichothecene mycotoxins. In: Zajtchuk R, Bellamy RF, eds. Medical Aspects of Chemical and Biological Warfare- Textbook of Military Medicine. Washington, DC: US Department of the Army, Office of the Surgeon General, and Borden Institute; 1997: 666.)

Trichothecene Mycotoxins • Diagnosis – Clinical (high attach rates, dead animals, and physical evidence (yellow, red, green or other pigmented oily liquids) febrile respiratory syndrome without CXR findings); other than mustard one of the few agents to affect the skin (mustard agents have an odor and symptoms are delayed) • Management – Supportive care; remove clothing; bathing; burn care – Collect serum and urine for future study

References Alibek K, Haldelman S. Biohazard : The Chilling True Story of the Largest Covert Biological Weapons Program in the World-Told from Inside by the Man Who Ran It. Random House, Inc. New York, NY 1999. USAMRIID. Medical Management of Biological Casualties Handbook February 2001. http://usamriid.detrick.army.mil/ CDC - http://www.bt.cdc.gov/ American Society Microbiology - http://www.asmusa.org/pcsrc/bioprep.htm Iowa DPH - http://www.idph.state.ia.us/Terrorism/default.htm JHU - http://www.hopkins-biodefense.org/ California DHS - http://www.dhs.ca.gov/ps/dcdc/bt/index.htm