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.