Lect 33 Bioterror Handout

7/28/2019 Lect 33 Bioterror Handout

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Lecture 33 Bioterrorism BSCI 437

Reading: these notes (nothing relevant in your text)

"Advantages" of biological weapons: relatively inexpensive, easier to conceal than

conventional weapons, potentially easier to spread, have the potential to causewidespread panic, have been developed by military in a few countries (former U.S.S.R,

U.S.A, Iraq) to high level of sophistication.

Disadvantages of biological weapons: not easy to obtain, easier to "backfire" on those

using them, unproven weaponry that may not work, potentially traceable to original

source by DNA typing.

Possible viruses that bioterrorists might use: Variola (Smallpox), hemorrhagic feverviruses (Ebola, Marburg, etc), Influenza A.

Select Agents: Criteria for inclusion:

Centers for Disease Control and Prevention where charged with devising list of

"Select Agents" that might be used. Critera:1. highly infectious or extremely toxic

2. have the potential for high mortality with ensuing infection or poisoning

3. have consequences following exposure that are difficult to manage

medically4. vaccines, antivirals, or chemoprophylactic drugs are not readily available

for most of these agents.

Terrorists might acquire such agents in several ways:

1. Produce agents themselves -- this requires microbiological expertise,laboratories and equipment

2. Obtain from "rogue states" like Iraq, which has developed biological and

chemical weapons, probably still has stockpiles. Fomer Soviet Union hadmajor activity in this area, not clear whether stockpiles exist.

3. Steal existing agents from laboratories, hospitals, etc. "Select agent"

regulations try to control access to the select agents, terrorists may beprevented from obtaining and using these agents in an attack.

Viruses

Smallpox (Variola) Virus

Infectious agent is Variola majorvirus. Highly infectious -- only 10-100 particles can

cause infection.

Variola is highly infectious as aerosol.

Incubation period is 7-17 days, during which virus multiplies in respiratory tract, then

spreads to blood and lymph.


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Causes characteristic inflammations over surface of skin (pox).

The infectiousness of the virus was seen in 1970, when a German electrician returned

from Pakistan, having contracted the virus. He was hospitalised, and though he never lefthis room, he infected 4 patients on the floor he was staying, 8 on the floor above, and 9

two floors above. One person infected was simply a visitor to the hospital, and was nevercloser than 30 feet to the patients room

Virus has been officially eradicated as a result of successful worldwide vaccination andquarantine measures -- last known case occurred in 1970's, except for an infected lab

worker since.

However, known stocks survive in Center for Disease Control and Prevention (CDC) in

Atlanta, US, and in the Research Institute for Viral Preparation in Moscow, Russia.

It is possible that other stockpiles exist.

As the post-smallpox eradication era began, a special WHO committee oversaw

publication of a book documenting the program; field studies of monkeypox infections to

assure there was no threatening animal reservoir; and preserving vaccine and seed virusin case the vaccine should ever again be required.

As confidence grew that smallpox had really been eradicated, countries around the world

grew increasingly more insistent that steps be taken to destroy the remaining stocks of

smallpox virus in order to be that much more certain that they would not have to dealwith this feared disease once again. The WHO committee proposed that destruction be

delayed until a number of studies could be completed to more completely characterize the

smallpox virus genome and to preserve it in the form of cloned virus fragments. Later,sequence maps of the virus were prepared for a number of stains. Finally, in 1993, fivemajor national and international scientific bodies were formally approached by WHO and

asked to consider whether they would support destruction of the virus. All provided

written agreement assenting to this action. Few saw any reason to retain the virus.Essentially no research had been performed with the virus for more than ten years and

none was planned, at least in Western countries. At the World Health Assembly in May,

1996, member nations voted to destroy the virus at the end of June, 1999. That decisionwas debated finally at the World Health Assembly in May 1999. However, both the U.S.

and Russia decided to retain their smallpox stocks for research.

In 1993, Dr. Ken Alibek, the deputy director of the Soviet Union bioweapons programdefected to the United States. Meanwhile, in 1972, the Biological Weapons Conventionwas finalized and subsequently signed by most countries of the world, including the

United States, the Soviet Union, and Iraq. All signatories pledged to abandon research on

offensive bioweapons and to destroy such stocks as they had. However, reports obtainedduring the late 1980s suggested that, contrary to the Convention, the Soviet Union may

have been conducting research on such weapons and perhaps producing them. Dr. Alibek

brought the ultimate in grim news.


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As he explained, Soviet authorities in the 1970s had viewed the acceptance of the

Convention by virtually all countries as presenting an unusual opportunity for the Soviet

Union to gain an important advantage in the Cold War. Accordingly, an extensiveexpansion of its bioweapons research and production capacity began. In 1980, at the time

that many Russians were celebrating the demise of smallpox and Russias important

contributions to that effort, Soviet leadership saw yet another opportunity and embarkedon an aggressive program to weaponize smallpox and to produce it on a very large scale.

As Dr. Alibek described in convincing detail, the task proved more difficult than had

been anticipated, but finally, in the late 1980s, production of high titer smallpox virus inmulti-ton quantities was achieved. It had been weaponized so as to be able to be

transported in intercontinental ballistic missiles and to be dispersed effectively as an

aerosol after reaching its target.

The massive bioweapons facility that undertook the research and development program,is called VECTOR. It is located in Koltsovo in Central Siberia. It continues to function

today as a research enterprise, conducting studies of many exotic viruses, including

Ebola, Marburg, and Venezuelan Equine Encephalitis, and smallpox. The WHOlaboratory in Moscow that had collaborated with the smallpox eradication effort was

closed, and its virus stocks transferred to Koltsovo. The major production facility for the

smallpox virus is said to be at another location near Moscow, operated by the Ministry of

Defense. It has never been opened to inspection.

Smallpox virus thus exists in Russia, probably at two sites, at least. How secure the

stocks may be is uncertain, especially given the economic conditions in Russia today, and

the fact that salaries for scientists are paid very late or not at all. Many have left their

former institutions for other countries. Reasonable evidence exists that at least ten nationsare now engaged in the development of bioweapons and some are actively recruiting

scientists in Russia.

Why smallpox? The factors which until 1980 made smallpox the most feared of allinfections are, in fact, heightened today. Recall that until the 1970s, all countries

conducted routine vaccination programs, even those that had not experienced the disease

for decades. They feared the possible importation of the disease and its subsequent

spread. Smallpox kills 30% of the unvaccinated; there is no treatment. Moreover, asmany will remember, all travelers had to carry a yellow vaccination card attesting to the

fact that one had been successfully vaccinated within the preceding three years.

Smallpox is a virus disease that normally spreads from person to person by airborne

droplets. Twelve to 14 days after exposure, the patient develops very high fever, severeaching pains, and usually takes to bed. After two or three days, a pimple-like rash erupts

over the body; the pimples gradually fill with pus. Some have described the disease as

being similar to having thousands of boils all over the body. By the second week, if thepatient survives, scabs form. They fall off, leaving deeply pitted scars. Some people are

left blind. There are reasons to fear this disease above others.


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Today, very few persons have immunity, either acquired because of past infection or

because of vaccination. Vaccination ceased in this country in 1972. Thus, effectively no

one under the age of 25 has been vaccinated, and among those older, few now havesufficient immunity to protect against infection.

Smallpox in an aerosol form is very stable, and in a cool, dry environment would beexpected to survive for at least 24 hours. Borne by wind currents, it would be wholly

undetectable. If one were to suppose that as few as 50 to 100 persons were exposed, theywould begin experiencing acute, severe illness some two weeks later. Brought primarily

to physicians who have never before seen a smallpox case, the diagnosis would not be

made for several days to perhaps a week. Meanwhile, each patient would have been incontact with many others. A second wave of cases would occur two weeks later with 10

or more new infections for every case in the first wave or, in other words, 500 to 1000

cases in all. Complicating the problem would be the fact that perhaps as many patientsagain would be experiencing unknown illnesses with rash and fever, such as chickenpox

or a drug reaction, and would have to be treated as if they had smallpox until the

diagnosis was certain.

Because of the risk of virus transmission in hospital, patients would need to be housed inrooms under negative pressure and the exhaust air filtered. In Maryland, there are only 80

such beds.

Meanwhile, vaccination would be needed for health care workers, patients exposed in

hospitals and all the contacts of those with smallpox or suspect smallpox. The numberspossibly exposed and those clamoring for vaccine would quickly number in the tens of

thousands, and at least with the second wave of cases, mass vaccination would become a

necessity. Thus far, few cities have given serious thought as to how such a program could

be carried out, although I would note parenthetically, that you in New York are probablyfurther ahead than any city. Moreover, we now have only six to seven million doses of

vaccine in reserve in the United States. There are presently no vaccine producersanywhere in the world and substantial new production would require 36 months or more.

In brief, the vaccine supply would rapidly be exhausted; there are few reserves in other

countries.

Nationally, billions of dollars are being expended on counter-terrorist activities, virtuallyall of this money being directed to dealing with a chemical or nuclear event despite the

fact that experts rate the bioterrorist threat as potentially the more serious. A plan to train

and equip so-called first responders (police, fire, and emergency rescue personnel) in

120 major cities is being implemented by personnel from the Department of Defense;emergency teams of National Guardsmen are being trained for the same purpose; the

Federal Bureau of Investigation has been greatly strengthened.


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However, for a bioterrorist attack, the key personnel are not the first responders who

are now being trained, but infectious disease physicians, family physicians, emergency

room doctors and nurses, health department epidemiologists, laboratory directors, andadministrators. To date, none has received training. Moreover, the public health

infrastructure that is essential to countering an attack has been allowed to deteriorate over

recent years. Many state and local laboratories are but shadows of what once they were;epidemiologists are few and far between; significantly lacking is a network for reporting

and information which connects the infectious disease specialist, family practitioners,

emergency rooms, and hospital infections staff with state and federal resources. We aretoday ill-prepared to deal with a bioterrorist threat, but then we are no better prepared to

deal with the threat of new and emerging infections, the increasing tide of antibiotic

resistant organisms, and the special challenge of food-borne disease as we

internationalize and industrialize our food supply. We, as a nation, have quite forgottenthat our present salubrious state of health did not happen by indirection. It had a great

deal to do with public health measures.

Ebola and other hemorrhagic fever viruses

Viral Hemorrhagic Fevers (VHF) are caused by 4 viral families

o Arenaviruses

Argentine hemorrhagic fever

Bolivian hemorrhagic fever Sabia-associated hemorrhagic fever

Lassa fever

Lymphocyctic choriomeningitis Venezuelan hemorrhagic fever

o Filoviruses

Ebola hemorrhagic fever Marburg hemorrhagic fever

o Bunyaviruses

Crimean-Congo hemorrhagic fever

Rift Valley fever (Hantaan fever)

Hantavirus Pulmonary Syndrome

Hemorrhagic Fever with Renal Syndrome (HFRS)

o Flaviviruses

Tick-borne encephalitis

Kyasanur Forest disease

Omsk hemorrhagic fever

Viral hemorrhagic fevers share the following characteristics:o They are all RNA viruses

o They are all zoonotic (natural reservoir is an arthropod or other animal

host)o Disease is restricted to habitat of the host

o Humans become infected by contact with host

o Some viruses can be transmitted from human to human

Transmission to humans (depends upon specific virus)


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o By contact with rodent urine, feces, saliva, blood

o From mosquito or tick bites

o Contact with vector-infected livestock

Pathophysiology

o The target organ is the vascular bed. Dominant clinical features are due to

microvascular damage and changes in vascular permeabilityo In most cases of viral hemorrhagic fever, the coagulopathy is

multifactorial, including: hepatic damage, disseminated intravascularcoagulation, primary marrow injury to megakaryocytes

Symptoms

o Fever, fatigue, dizziness, myalgias, and prostration

o Signs of bleeding range from only conjunctival hemorrhage, mild

hypotension, flushing, and petechiae to shock and generalized mucous

membrane hemorrhage and evidence of pulmonary, hematopoietic, and

neurologic dysfunction

o Renal insufficiency is proportional to cardiovascular compromise except

in Hemorrhagic Fever and Renal Syndrome in which it is an integral partof the disease

Clinical syndromes

o Epidemiologic information is usually the most helpful clue to the

diagnosis, although some viral hemorrhagic fevers do present withsuggestive clinical syndromes

Jaundice and hepatitis dominate the clinical presentation in some

cases of Rift Valley, Congo-Crimean, Marburg, and Ebola

hemorrhagic fevers, and yellow fever Biphasic illnesses with pulmonary symptoms followed by central

nervous system manifestations are characteristics of Kyasanur

Forest disease and Omsk hemorrhagic fever Severe peripheral edema without significant hemorrhage suggests

Lassa fever

Severe hemorrhage and nosocomial transmission suggests Congo-Crimean hemorrhagic fever

Adult Respiratory Distress Syndrome is a sequela of Hantavirus

Diagnosis

o Key is a detailed travel history and a high index of suspicion

Suspect viral hemorrhagic fever in any patient who has traveled to

an endemic area and has a severe febrile illness with evidence of

vascular involvement

o Consider the possibility of a bioterrorist attack if one of the diseasesoccurs in persons not known to have traveled to an endemic area

o Laboratory findings

Thrombocytopenia is common to most viral hemorrhagic fever

infections with the exception of Lassa fever

Leukopenia is common to most viral hemorrhagic fever infectionswith the exceptions of Lassa, Hantaan, and some cases of Congo-

Crimean hemorrhagic fevers


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Proteinuria with or without hematuria is common and is always

found in Argentine hemorrhagic fever, Bolivian hemorrhagic

fever, and Hemorrhagic Fever and Renal Syndrome Virologic diagnosis

Rapid enzyme immunoassays

Viral culture (requires 3 to 10 days) Differential Diagnosis

o The major entity in the differential diagnosis is malaria

o Other entities that mimic viral hemorrhagic fevers include typhoid fever,

leptospirosis, rickettsial infections, shigellosis, relapsing fever, fulminant

hepatitis, and meningococcemia

o Noninfectious mimics include acute leukemia, systemic lupus

erythematosus, immune thrombocytopenic purpura, thrombotic

thrombocytopenic purpura, and hemolytic uremic syndrome

Treatment

o For most viral hemorrhagic fevers, there is no effective treatment other

than supportive care.o Ribavirin, which is available via compassionate use protocols, reduces

morbidity in Hemorrhagic Fever and Renal Syndrome, and reducesmorbidity and mortality in Lassa fever

o Convalescent plasma is being used experimentally to treat Argentine

hemorrhagic fever

Prevention

o Vaccination

The only licensed vaccine available is for yellow fever Experimental vaccine for Argentine hemorrhagic fever is under

investigation

o Control of rodent populationso Control of insect and other arthropod populations

Isolation and containment

o Viral hemorrhagic fever patients, with the exception of hantavirus and

dengue fever infections, have significant infectious virus in the blood andbody secretions

o Strict adherence to standard precautions

Keep patients in isolation Use of gowns, gloves, masks, eye protection

Among the most newsworthy viruses are those that cause rupture of capillaries,

internal bleeding = "Hemorrhagic Fever" viruses: Ebola, Lassa fever virus,Marburg virus, South American Haemorrhagic fever viruses, etc.

Ebola virus named for river in Democratic Republic of the Congo (formerly

Zaire) where outbreak was first recognized.


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Symptoms of infection begin with fever, headache, diarrhea, stomach pains --

symptoms that could be due to many infections. Within a week, most victims also

develop chest pain. Some some go blind, bleed from the nose, eyes, and otherorifices. Bleeding results from the virus blocking blood clotting as well as

stimulating leakage of blood vessels. Disease is very lethal: 70-90% of infected

people die

Even though this is a scary disease, it seems highly unlikely it would be a

potential terrorist weapon. The virus is so lethal that it is classified as a type IV

agent, and requires maximum protective features (sealed body suits, totally

contained laboratory environments) to protect those studying it. Other agents are

much easier to grow and safer for those interacting with them.

AGENT SYMPTOMS INFECTION VACCINE

Smallpox

About 12 days after

exposure, high fever,fatigue, back aches begin,followed in 2-3 days by a

rash and lesions on face,

arms and legs.

As many as 30% of

those infected maydie, usually during

the first two weeks of

illness.

Routine vaccinations

ceased in 1972, but about15 million does are still

available and more are in

production.

Viral

HemorrhagicFever

Depending on the virus,

(Ebola, Marburg, etc.)symptoms such as high

fever, muscle aches,

chills and diarrhea beginwithin a few days,

followed by severe chest

pain, shock and bleeding.

These diseases do

not always result indeath, but Ebola has

been up to 90% fatal

in some outbreaks,with death occurring

a week after

infection.

No vaccines exist for

hemorrhagic fevers,

except for yellow feverand Argentine

hemorrhagic fever.
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Lect 33 Bioterror Handout