Lecture Notes Bioterrorism

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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 cause
widespread 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 fever
viruses (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
               medically
          4. 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 had
               major 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 be
               prevented from obtaining and using these agents in an attack.

Viruses

Smallpox (Variola) Virus
Infectious agent is Variola major virus. 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.
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 left
his 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 never
closer than 30 feet to the patients room

Virus has been officially eradicated as a result of successful worldwide vaccination and
quarantine 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 virus
in 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 deal
with 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, five
major 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 decision
was 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 program
defected to the United States. Meanwhile, in 1972, the Biological Weapons Convention
was 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 obtained
during 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.

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 extensive
expansion of its bioweapons research and production capacity began. In 1980, at the time
that many Russians were celebrating the demise of smallpox and Russia’s important
contributions to that effort, Soviet leadership saw yet another opportunity and embarked
on 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 in
multi-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 WHO
laboratory 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 nations
are 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 all
infections 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, as
many 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, severe
aching 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 the
patient survives, scabs form. They fall off, leaving deeply pitted scars. Some people are
left blind. There are reasons to fear this disease above others.

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 have
sufficient immunity to protect against infection.

Smallpox in an aerosol form is very stable, and in a cool, dry environment would be
expected 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, they
would 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 in
contact 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 patients
again 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 in
rooms 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 numbers
possibly 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 probably
further 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 producers
anywhere 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, virtually
all 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.

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, and
administrators. 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 are
today 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 forgotten
that 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)
        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 permeability
        o In most cases of viral hemorrhagic fever, the coagulopathy is
           multifactorial, including: hepatic damage, disseminated intravascular
           coagulation, 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 part
           of the disease
   Clinical syndromes
        o Epidemiologic information is usually the most helpful clue to the
           diagnosis, although some viral hemorrhagic fevers do present with
           suggestive 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 diseases
            occurs 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 infections
                    with the exceptions of Lassa, Hantaan, and some cases of Congo-
                    Crimean hemorrhagic fevers
                 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 reduces
            morbidity 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 populations
        o 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 and
            body 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.

      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 other
       orifices. 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
              About 12 days after
              exposure, high fever,        As many as 30% of       Routine vaccinations
              fatigue, back aches          those infected may      ceased in 1972, but
Smallpox      begin, followed in 2-3       die, usually during     about 15 million does
              days by a rash and           the first two weeks     are still available and
              lesions on face, arms and    of illness.             more are in production.
              legs.
            Depending on the virus,
                                           These diseases do
            (Ebola, Marburg, etc.)
                                           not always result in
            symptoms such as high                                  No vaccines exist for
                                           death, but Ebola has
Viral       fever, muscle aches,                                   hemorrhagic fevers,
                                           been up to 90% fatal
Hemorrhagic chills and diarrhea begin                              except for yellow fever
                                           in some outbreaks,
Fever       within a few days,                                     and Argentine
                                           with death occurring
            followed by severe chest                               hemorrhagic fever.
                                           a week after
            pain, shock and
                                           infection.
            bleeding.

				
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