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Bio Warfare Handbook -
Types, Risks, Precautions

History of Biological Warfare and Current Threat
Medical Aspects of the Biological Threat
Q Fever
Venezuelan Equine Encephalitis
Viral Hemorrhagic Fevers
Biological Toxins
Staphylococcal Enterotoxin B
T-2 Mycotoxins
Personal Protection
Appendix A: Glossary of Medical Terms
Appendix B: Patient and Precaution Levels
Appendix C: Comparative Lethality: Toxins/Chemicals
Appendix D: Aerosol Toxicity: Toxins
Appendix E: Differential Diagnosis: Toxins/Nerve Agent
Appendix F: Specimens for Lab Diagnosis
Appendix G: BW Agents: Lab Identification
Appendix H: BW Agents: Characteristics
Appendix I: BW Agents: Vaccines, Therapeutics and Prophylactics
Third Edition
July 1998
COL Edward Eitzen
MAJ Julie Pavlin
LTC Ted Cieslak
LTC George Christopher
CDR Randall Culpepper
Comments and suggestions are solicited and should be addressed to:
Operational Medicine Division Attn: Mr. Paul Porreca U.S. Army Medical Research Institute of Infectious Diseases Fort Detrick, Maryland 21702-5011
The purpose of this Handbook is to provide concise supplemental reading material to assist in education of biological casualty management. Every effort has been made to make the information in this handbook consistent with official policy and doctrine. The information contained in this handbook is not official Department of the Army policy or doctrine, and it should not be construed as such.
This handbook would not be possible without the generous assistance and support of COL David Franz, COL Gerald Parker, LTC Gerald Jennings, SGM Raymond Alston, COL James Arthur, COL W. Russell Byrne, LTC Les Caudle, Dr. John Ezzell, COL Arthur Friedlander, Mr. Darren Gerlach, SGT Kevin Gianunzio, Dr. Robert Hawley, LTC Erik Henchal, COL(ret) Ted Hussey, Dr. Peter Jahrling, LTC Ross LeClaire, Dr. George Ludwig, Mr. William Patrick, Dr. Mark Poli, Mr. Paul Porreca, Dr. Fred Sidell, Dr. Jonathon Smith, Mr. Richard Stevens, COL Stanley Wiener, Mr. Benjamin Wilson and others too numerous to mention. The exclusion of anyone on this page is purely accidental and in no way lessens the gratitude we feel for contributions received.
Medical defense against biological warfare is an area of study for military health care providers which does not apply readily to the day to day mission of caring for patients in peacetime. However, during Operations Desert Shield/Desert Storm, it became obvious that the threat of biological attacks against our soldiers was real, and that we could do more to educate our medical professionals about how to prevent and treat biological warfare casualties. Many of our medical personnel who deployed for the Gulf War had less than an optimal understanding of the biological threat and of the medical means available to counter it. Since Desert Storm, there has been a renewed emphasis placed on making sure that our health care professionals gain the necessary background in this important area of military medicine.
In fact, our training efforts have significantly intensified over the past eighteen months following increased incidents and threats of domestic terrorism (e.g., New York City World Trade Center bombing, Tokyo subway sarin release, Oklahoma City federal building bombing, Atlanta Centennial Park bombing). Additionally, the recent escalation of tensions in Iraq and subsequent deployment of military troops to the Persian Gulf region underscored the importance of force protection from biological threats. The Secretary of Defense announced in November 1997 that all U.S. military troops will be immunized against anthrax. Finally, the disclosure of a sophisticated offensive biological warfare program in the Former Soviet Union (FSU) and subsequent media attention has reinforced the need for increased training and education.
The Medical Management of Chemical and Biological Casualties Course taught at both USAMRIID and USAMRICD was revised in March 1998 by doubling its class capacity providing education in both biological and chemical medical defense to over 560 military medical professionals per calendar year. Also, the highly successful 3-day USAMRIID satellite course on the Medical Management of Biological Casualties presented in September 1997 reached over 5600 military and other government health care professionals throughout the United States.
Through this handbook and the training courses noted above, military medical professionals will learn that effective medical countermeasures are available against many of the bacteria, viruses, and toxins which might be used as biological weapons against our military forces. The importance of this education cannot be overemphasized and it is hoped that our physicians, nurses, and allied medical professionals will develop a solid understanding of the biological threats we face and the medical armamentarium for defending against these threats.
The global biological warfare threat is taken seriously by our leaders. The United States was willing to return to war against Iraq in February 1998 to preserve the integrity and the independence of the UNSCOM inspectors such that they would have unconditional, unfettered and unrestricted access to all suspected sites in Iraq in their search for weapons of mass destruction. The threat is indeed serious, and the potential for devastating casualties is high for certain biological agents. However, with appropriate use of medical countermeasures either already developed or under development, many casualties can be prevented or minimized, and the fighting strength of our forces can be maintained.
The purpose for this handbook is to serve as a small and concise manual for medical personnel to carry in their BDU pocket as a guide to medical prophylaxis and management of biological casualties. It is designed as a quick reference and overview, and is not intended as a definitive text on the medical management of biological casualties.
The use of biological weapons and efforts to make them more useful as a means of waging war have been recorded numerous times in history. Two of the earliest reported uses occurred in the 6th century BC, with the Assyrians poisoning enemy wells with rye ergot, and Solon’s use of the purgative herb hellebore during the siege of Krissa. In 1346, plague broke out in the Tartar army during its siege of Kaffa (at present day Feodosia in Crimea). The attackers hurled the corpses of those who died over the city walls; the plague epidemic that followed forced the defenders to surrender, and some infected people who left Kaffa may have started the Black Death pandemic which spread throughout Europe. Russian troops may have used the same plague-infected corpse tactic against Sweden in 1710.
On several occasions, smallpox was used as a biological weapon. Pizarro is said to have presented South American natives with variola-contaminated clothing in the 15th century, and the English did the same when Sir Jeffery Amherst provided Indians loyal to the French with smallpox-laden blankets during the French and Indian War of 1754 to 1767. Native Americans defending Fort Carillon sustained epidemic casualties which directly contributed to the loss of the fort to the English.
In this century, there is evidence that during World War I, German agents inoculated horses and cattle with glanders in the U.S. before the animals were shipped to France. In 1937, Japan started an ambitious biological warfare program, located 40 miles south of Harbin, Manchuria, in a laboratory complex code named "Unit 731". Studies directed by Japanese General Ishii continued there until 1945, when the complex was leveled by burning it. A post World War II investigation revealed that numerous organisms had received Japanese research attention, and that experiments had been conducted on prisoners of war. Slightly less than 1,000 human autopsies apparently were carried out at Unit 731, most on victims exposed to aerosolized anthrax. Many more prisoners and Chinese nationals may have died in this facility - some have estimated up to 3,000 human deaths. In 1940, a plague epidemic in China and Manchuria followed reported overflights by Japanese planes dropping plague-infected fleas. By 1945, the Japanese program had stockpiled 400 kilograms of anthrax to be used in a specially designed fragmentation bomb.
In 1943, the United States began research into the offensive use of biological agents. This work was started, interestingly enough, in response to a perceived German biological warfare (BW) threat as opposed to a Japanese one. The United States conducted this research at Camp Detrick (now Fort Detrick), which was a small National Guard airfield prior to that time, and produced agents at other sites until 1969, when President Nixon stopped all offensive biological and toxin weapon research and production by executive order. Between May 1971 and May 1972, all stockpiles of biological agents and munitions from the now defunct U.S. program were destroyed in the presence of monitors representing the United States Department of Agriculture, the Department of Health, Education, and Welfare, and the states of Arkansas, Colorado, and Maryland. Included among the destroyed agents were Bacillus anthracis, botulinum toxin, Francisella tularensis, Coxiella burnetii, Venezuelan equine encephalitis virus, Brucella suis, and Staphylococcal enterotoxin B. The United States also had a medical defensive program, begun in 1953, that continues today at USAMRIID.
In 1972, the United States and many other countries signed the Convention on the Prohibition of the Development, Production and Stockpiling of Bacteriological (Biological) and Toxin Weapons and on Their Destruction, commonly called the Biological Weapons Convention. This treaty prohibits the stockpiling of biological agents for offensive military purposes, and also forbids research into such offensive employment of biological agents. The former Soviet Union and the government of Iraq were both signatories to this accord. However, despite this historic agreement among nations, biological warfare research continued to flourish in many countries hostile to the United States. There were also several cases of suspected or actual use of biological weapons. Among the most notorious of these were the "yellow rain" incidents in Southeast Asia, the accidental release of anthrax at Sverdlovsk, and the use of ricin as an assassination weapon in London in 1978.
Testimony from the late 1970’s indicated that the countries of Laos and Kampuchea were attacked by planes and helicopters delivering aerosols of several colors. After being exposed, people and animals became disoriented and ill, and a small percentage of those stricken died. Some of these clouds were thought to be comprised of trichothecene toxins (in particular, T2 mycotoxin). These attacks are lumped under the label "Yellow Rain". There has been a great deal of controversy about whether these clouds were truly biological warfare agents: some have argued that the clouds were nothing more than bee feces produced by swarms of bees.
In late April of 1979, an incident occurred in Sverdlovsk (now Yekaterinburg) in the former Soviet Union which appeared to be an accidental release of anthrax in aerosol form from the Soviet Military Compound 19, a microbiology facility. Residents living downwind from this compound developed high fever and difficulty breathing, and a large number died. The final death toll was estimated at the time to be between 200 and 1,000. The Soviet Ministry of Health blamed the deaths on the consumption of contaminated meat, and for years controversy raged in the press over the actual cause of the outbreak. All evidence available to the United States government indicated a massive release of aerosolized anthrax. In the summer of 1992, U.S. intelligence officials were proven correct when new Russian President Boris Yeltsin acknowledged that the Sverdlovsk incident was in fact a large scale accident involving the escape of an aerosol of anthrax spores from the military research facility. In 1994, Meselson and colleagues published an in-depth analysis of the Sverdlovsk incident (Science 266:1202-1208). They documented that all of the 1979 cases occurred within a narrow zone extending downwind in a southerly direction from Compound 19. A total of 77 patients were identified by Meselson’s team, including 66 fatalities and 11 survivors.
Before the Sverdlovsk incident, in 1978, a Bulgarian exile named Georgi Markov was attacked in London with a device disguised as an umbrella which injected a tiny pellet filled with ricin toxin into the subcutaneous tissue of his leg while he was waiting for a bus. He died several days later. On autopsy, the tiny pellet was found and determined to contain the toxin. This assassination, it was later revealed, was carried out by the communist Bulgarian government, and the technology to commit the crime was supplied to the Bulgarians by the former Soviet Union.
In August of 1991, the first United Nations inspection of Iraq’s biological warfare capabilities was carried out in the aftermath of the Gulf War. On August 2, 1991, representatives of the Iraqi government announced to leaders of United Nations Special Commission Team 7 that they had conducted research into the offensive use of Bacillus anthracis, botulinum toxins, and Clostridium perfringens (presumably one of its toxins). This was the first open admission of biological weapons research by any country in recent memory, and it verified many of the concerns of the U.S. intelligence community publicly. Iraq had extensive and redundant research facilities at Salman Pak and other sites, many of which were destroyed during the war.
In 1995, further information on Iraq’s offensive program was made available to United Nations inspectors. Iraq conducted research and development work on anthrax, botulinum toxins, Clostridium perfringens, aflatoxins, wheat cover smut, and ricin. Field trials were conducted with Bacillus subtilis (a simulant for anthrax), botulinum toxin, and aflatoxin. Biological agents were tested in various delivery systems, including rockets, aerial bombs, and spray tanks. In December 1990, the Iraqis filled 100 R400 bombs with botulinum toxin, 50 with anthrax, and 16 with aflatoxin. In addition, 13 Al Hussein (SCUD) warheads were filled with botulinum toxin, 10 with anthrax, and 2 with aflatoxin. These weapons were deployed in January 1991 to four locations. All in all, Iraq produced 19,000 liters of concentrated botulinum toxin (nearly 10,000 liters filled into munitions), 8,500 liters of concentrated anthrax (6,500 liters filled into munitions) and 2,200 liters of aflatoxin (1,580 liters filled into munitions).
The threat of biological warfare has increased in the last two decades, with a number of countries working on offensive use of these agents. The extensive program of the former Soviet Union is now controlled largely by Russia. Russian president Boris Yeltsin has stated that he will put an end to further offensive biological research; however, the degree to which the program has been scaled back, if any, is not known. Recent revelations from a senior BW program manager who defected from the FSU in 1992 outlined a remarkably robust biological warfare program including active research into genetic engineering, binary biologicals and chimeras. There is also growing concern that the smallpox virus, eliminated from the face of the earth in the late 1970’s and now stored in only two laboratories at the CDC in Atlanta and the Institute for Viral Precautions in Moscow, Russia, may have been "bargained" away by desperate Russian scientists seeking money.
There is intense concern in the West about the possibility of proliferation or enhancement of offensive programs in countries hostile to the western democracies, due to the potential hiring of expatriate Russian scientists. It was reported in January 1998 that Iraq had sent about a dozen scientists involved in BW research to Libya to help that country develop a biological warfare complex disguised as a medical facility in the Tripoli area. In a report issued in November 1997, Secretary of Defense William Cohen singled out Libya, Iraq, Iran, and Syria as countries "aggressively seeking" nuclear, biological, and chemical weapons.
There is also an increasing amount of concern over the possibility of terrorist use of biological agents to threaten either military or civilian populations. There have been cases of persons loyal to extremist groups trying to obtain microorganisms which could be used as biological weapons. The Department of Defense is leading a federal effort to train the first responders in 120 American cities to be prepared to act in case of a domestic terrorist incident involving WMD.
Certainly the threat of biological weapons being used against U.S. military forces is broader and more likely in various geographic scenarios than at any point in our history. Therefore, awareness of this potential threat and education of our leaders and medical care providers on how to combat it are crucial.
Many bacteria, fungi, viruses, rickettsial agents, and toxins have been mentioned in various literature sources as possible biological warfare agents. Those mentioned most often include Bacillus anthracis (anthrax), botulinum toxin, Yersinia pestis (plague), ricin, Staphylococcal enterotoxin B (SEB), and Venezuelan equine encephalitis virus (VEE). Despite the very different characteristics of these organisms, viruses, and toxins, biological agents used as weapons share some common characteristics. They can be dispersed in aerosols of particle size one to five micrometers (microns), which may remain suspended (in certain weather conditions) for hours and if inhaled will penetrate into distal bronchioles and terminal alveoli of victims. Particles larger than five microns would tend to be filtered out in the upper airway. The aerosols may be delivered by simple technology, including industrial sprayers with nozzles modified to generate the smaller particle size. The aerosol could be delivered from a line source such as an airplane or boat traveling upwind of the intended target, or from a point source such as a stationary sprayer or missile dispensing agent-containing bomblets in an area upwind of the target. The weather in the target area is very important in the employment of biological agents as aerosols, as higher wind speeds tend to break up the aerosol cloud, and stable wind direction is obviously important. Inversion conditions and lower wind speeds, 5 to 10 miles per hour, conditions which occur more often during nighttime and early morning hours, would be ideal for dispensing such aerosols. Other possible routes of exposure for biological agents include oral, by intentional contamination of food and water, and percutaneous. In general, these other routes of exposure are considered less important than the respiratory route.
Diseases produced by the offensive use of biological agents against U.S. forces could be lethal and/or disabling. From a military standpoint, incapacitation of a high percentage of friendly forces may be as operationally significant as effects caused by more lethal agents. Examples of lethal agents include Bacillus anthracis, botulinum toxin, and Francisella tularensis, while incapacitating agents include SEB and Coxiella burnetii. Some agents, such as Yersinia pestis and C. burnetii, would produce pulmonary syndromes characteristic of the endemic disease they produce in nature. Others, such as botulinum toxin, although delivered by a different route of exposure (respiratory) than usual with endemic disease, would produce a similar clinical picture to that commonly seen with oral exposure. Person-to-person spread could be important for some agents, such as smallpox and pneumonic plague, and local disease cycles might occur if a competent vector for a bacterium or virus is present in the environment (e.g., fleas for Y. pestis and certain mosquitoes for Venezuelan equine encephalitis).
The potential impact of biological weapons is well illustrated by a World Health Organization publication from 1970 (Health Aspects of Chemical and Biological Weapons, WHO, 1970). It was estimated that fifty kilograms of aerosolized B. anthracis spores, for example, dispensed by a line source 2 kilometers upwind of a population center of 500,000 unprotected people in ideal meteorological conditions, would travel greater than 20 kilometers downwind, and kill/incapacitate up to 125,000 people in the path of the biological cloud. If F. tularensis was dispensed, the number of dead/incapacitated was estimated to be about 125,000. Thus, if properly employed as offensive weapons under ideal meteorological conditions, certain biological organisms could truly be weapons of mass destruction.
In addition to their detrimental health effects on the targeted population, biological warfare agents would likely cause significant impacts on the medical care system. Overwhelming numbers of patients, and demands for intensive care would overwhelm medical resources. Special medications or vaccines not generally available in standard pharmaceutical stocks would be required. Medical care providers and laboratory personnel might need added protection, and autopsy and interment of remains could present hazards not commonly dealt with.
The medical response to the threat or use of biological weapons may be different depending on whether medical measures are employed prior to exposure, or whether exposure has already occurred and/or symptoms are present. If provided before exposure, active immunization or prophylaxis with antibiotics may prevent illness in those exposed. Active immunization may be effective against several potential biological warfare agents, and is probably the best modality for future protection of U.S. military forces against a wide variety of biological threats. After exposure, active or passive immunization as well as pre-treatment with therapeutic antibiotics or antiviral drugs may ameliorate disease symptoms. After onset of illness, only diagnosis of the disease and general or specific treatment are left to medical care providers. The good news is that excellent vaccines and antitoxins exist for several of the most likely biological warfare agents, and more are under development.
Bacteria are unicellular organisms. They vary in shape and size from spherical cells - cocci - with a diameter of 0.5-1.0 m m (micrometer), to long rod-shaped organisms - bacilli - which may be from 1-5 m m in size. Chains of bacilli may exceed 50 m m. The shape of the bacterial cell is determined by the rigid cell wall. The interior of the cell contains the nuclear material (DNA), cytoplasm, and cell membrane, that are necessary for the life of the bacterium. Many bacteria also have glycoproteins on their outer surfaces which aid in bacterial attachment to surface receptors on cells and are of special importance in their ability to cause disease. Under special circumstances some types of bacteria can transform into spores. The spore of the bacterial cell is more resistant to cold, heat, drying, chemicals and radiation than the bacterium itself. Spores are a dormant form of the bacterium and, like the seeds of plants, they can germinate when conditions are favorable.
Bacteria can cause diseases in human beings and animals by means of two mechanisms which differ in principle: in one case by invading the tissues, in the other by producing poisons (toxins). In many cases pathogenic bacteria possess both properties. The diseases they produce often respond to specific therapy with antibiotics. This manual will cover several of the bacteria or rickettsia considered to be potential BW threat agents: Bacillus anthracis (Anthrax), Brucella spp. (Brucellosis), Vibrio cholerae (Cholera), Burkholderia mallei (Glanders), Yersinia pestis (Plague), Francisella tularensis (Tularemia), and Coxiella burnetii (Q Fever).
Signs and Symptoms: Incubation period is 1-6 days. Fever, malaise, fatigue, cough and mild chest discomfort is followed by severe respiratory distress with dyspnea, diaphoresis, stridor, and cyanosis. Shock and death occurs within 24-36 hours after onset of severe symptoms.
Diagnosis: Physical findings are non-specific. A widened mediastinum may be seen on CXR. Detectable by Gram stain of the blood and by blood culture late in the course of illness.
Treatment: Although effectiveness may be limited after symptoms are present, high dose antibiotic treatment with penicillin, ciprofloxacin, or doxycycline should be undertaken. Supportive therapy may be necessary.
Prophylaxis: An FDA licensed vaccine is available. Vaccine schedule is 0.5 ml SC at 0, 2, 4 weeks, then 6, 12, and 18 months for the primary series, followed by annual boosters. Oral ciprofloxacin or doxycycline for known or imminent exposure.
Isolation and Decontamination: Standard precautions for healthcare workers. After an invasive procedure or autopsy is performed, the instruments and area used should be thoroughly disinfected with a sporicidal agent (chlorine).
Bacillus anthracis, the causative agent of Anthrax, is a rod-shaped, gram-positive, sporulating organism with the spores constituting the usual infective form. Anthrax is primarily a zoonotic disease of herbivores, with cattle, sheep and horses being the usual domesticated animal hosts, but other animals may be infected. Human disease may be contracted by handling contaminated hair, wool, hides, flesh, blood and excreta of infected animals and from manufactured products such as bone meal, as well as by purposeful dissemination of spores. Infection is introduced through scratches or abrasions of the skin, wounds, inhalation of spores, eating insufficiently cooked infected meat, or by flies. All human populations are susceptible. Recovery from an attack of the disease may be followed by immunity. The spores are very stable and may remain viable for many years in soil and water. They will resist sunlight for varying periods.
Anthrax spores were weaponized by the United States in the 1950's and 1960's before the old U.S. offensive program was terminated. Other countries have weaponized this agent or are suspected of doing so. The anthrax bacterium is easy to cultivate and spore production is readily induced. Spores are highly resistant to sunlight, heat and disinfectants - properties which could be advantageous when choosing a bacterial weapon. Iraq admitted to a United Nations inspection team in August of 1991 that it had performed research on the offensive use of B. anthracis prior to the Persian Gulf War of 1991, and in 1995 Iraq admitted to weaponizing anthrax. This agent could be produced in either a wet or dried form, stabilized for weaponization by an adversary and delivered as an aerosol cloud either from a line source such as an aircraft flying upwind of friendly positions, or as a point source from a spray device. Coverage of a large ground area could also be theoretically facilitated by multiple spray bomblets disseminated from a missile warhead at a predetermined height above the ground.

Anthrax presents as three distinct clinical syndromes in man: cutaneous, inhalational, and gastrointestinal disease. The cutaneous form (also referred to as malignant pustule) occurs most frequently on the hands and forearms of persons working with infected livestock. It begins with a papule followed by formation of a blister-like fluid-filled vesicle. The vesicle typically dries and forms a coal-black scab, hence the term anthrax (Greek for coal). Sometimes this local infection will develop into a systemic infection which is often fatal. Endemic inhalational anthrax, known as Woolsorters’ disease, is a rare infection contracted by inhalation of the spores. It occurs mainly among workers handling infected hides, wool, and furs. The intestinal form, which is also very rare in man, is contracted by the ingestion of insufficiently cooked meat from infected animals. In man, the mortality of untreated cutaneous anthrax ranges up to 25 per cent; in inhalational and intestinal cases, the case fatality rate is almost 100 percent.
After an incubation period of 1-6 days, presumably dependent upon the dose and strain of inhaled organisms, the onset of inhalation anthrax is gradual and nonspecific. Fever, malaise, and fatigue may be present, sometimes in association with a nonproductive cough and mild chest discomfort. These initial symptoms are often followed by a short period of improvement (hours to 2-3 days), followed by the abrupt development of severe respiratory distress with dyspnea, diaphoresis, stridor, and cyanosis. Shock and death usually follow within 24-36 hours after the onset of respiratory distress. Physical findings are typically non-specific. The chest X-ray may reveal a widened mediastinum ± pleural effusions late in the disease in about 55% of the cases, but typically is without infiltrates. Bacillus anthracis will be detectable by Gram stain of the blood and by blood culture with routine media, but often not until late in the course of the illness. Only vegetative encapsulated bacilli are present during infection. Spores are not found within the body unless it is open to ambient air. Studies of inhalation anthrax in non-human primates (rhesus monkey) showed that bacilli and toxin appear in the blood late on day 2 or early on day 3 post-exposure. Toxin production parallels the appearance of bacilli in the blood and tests are available to rapidly detect the toxin. Concurrently with the appearance of anthrax, the WBC count becomes elevated and remains so until death.
Almost all inhalational anthrax cases in which treatment was begun after patients were significantly symptomatic have been fatal, regardless of treatment. Penicillin has been regarded as the treatment of choice, with 2 million units given intravenously every 2 hours. Tetracyclines and erythromycin have been recommended in penicillin allergic patients. The vast majority of naturally-occurring anthrax strains are sensitive in vitro to penicillin. However, penicillin-resistant strains exist naturally, and one has been recovered from a fatal human case. Moreover, it might not be difficult for an adversary to induce resistance to penicillin, tetracyclines, erythromycin, and many other antibiotics through laboratory manipulation of organisms. All naturally occurring strains tested to date have been sensitive to erythromycin, chloramphenicol, gentamicin, and ciprofloxacin. In the absence of information concerning antibiotic sensitivity, treatment should be instituted at the earliest signs of disease with intravenous ciprofloxacin (400 mg q 8-12 hrs) or intravenous doxycycline (200 mg initially, followed by 100 mg q 12 hrs). Supportive therapy for shock, fluid volume deficit, and adequacy of airway may all be needed.
Standard Precautions should be practiced. After an invasive procedure or autopsy, the instruments and area used should be thoroughly disinfected with a sporicidal agent. Iodine can be used, but must be used at disinfectant strengths, as antiseptic-strength iodophors are not usually sporicidal. Chlorine, in the form of sodium or calcium hypochlorite, can also be used, but with the caution that the activity of hypochlorites is greatly reduced in the presence of organic material.
Vaccine: A licensed vaccine is derived from sterile culture fluid supernatant taken from an attenuated strain. The vaccination series consists of six 0.5 ml doses SC at 0, 2, and 4 weeks, then 6, 12 and 18 months, followed by yearly boosters. Limited human data suggest that the vaccine protects against cutaneous anthrax. There is insufficient data to know its efficacy against inhalational anthrax in humans, although studies in rhesus monkeys indicate that good protection can be afforded after only two doses (15 days apart) for up to 2 years. However, it should be emphasized that the vaccine series should be completed according to the routine 6 dose primary series. As with all vaccines, the degree of protection depends upon the magnitude of the challenge dose; vaccine-induced protection could presumably be overwhelmed by extremely high spore challenge.
Contraindications for use of this vaccine include hypersensitivity reaction to a previous dose of vaccine and age < 18 or 65. Reasons for temporary deferment of the vaccine include pregnancy; active infection with fever; or a course of immune suppressing drugs such as steroids. Reactogenicity is mild to moderate. Up to 6 percent of recipients will experience mild discomfort at the inoculation site for up to 72 hours (e.g., tenderness, erythema, edema, pruritus), while less than 1 percent will experience more severe local reactions, potentially limiting use of the arm for 1-2 days. Modest systemic reactions (e.g., myalgia, malaise, low-grade fever) are uncommon, and severe systemic reactions such as anaphylaxis, which precludes additional vaccination, are rare. The vaccine should be stored between 2-6 oC (refrigerator temperature, not frozen).
Antibiotics: The choice of antibiotics for prophylaxis is difficult to make; for example, it seems relatively easy to induce penicillin and tetracycline resistance in the laboratory. Therefore, prophylaxis with ciprofloxacin (500 mg po bid) or doxycycline (100 mg po bid) is recommended. If personnel are unvaccinated, a single 0.5 ml dose of vaccine should also be given subcutaneously. Should the attack be confirmed as anthrax, antibiotics should be continued for at least 4 weeks in all those exposed, and until all those exposed have received three doses of the vaccine. Two additional 0.5 ml doses of vaccine should be given 2 weeks apart in the unvaccinated; those previously vaccinated with fewer than three doses should receive a single 0.5 ml booster, while vaccination probably is not necessary for those who have received the initial three-doses of the primary series, within the previous six months. Upon discontinuation of antibiotics, patients should be closely observed; if clinical signs of anthrax occur, patients should be treated as indicated above. If vaccine is not available, antibiotics should be continued beyond 4 weeks and withdrawn under medical observation. Optimally, patients should have medical care available upon discontinuation of antibiotics, from a fixed medical care facility with intensive care capabilities and infectious disease consultants.
Signs and Symptoms: Incubation period from 5-60 days; average of 1-2 months. Highly variable. Acute and subacute brucellosis are non-specific. Irregular fever, headache, profound weakness and fatigue, chills, sweating, arthralgias, mylagias. Depression and mental status changes. Osteoarticular findings (i.e., sacroiliitis, vertebral osteomyleitis). Fatalities are uncommon.
Diagnosis: Blood cultures require a prolonged period of incubation in the acute phase. Bone marrow cultures produce a higher yield. Confirmation requires phage-typing, oxidative metabolism, or genotyping procedures. ELISA&rsquo;s followed by Western blotting are used.
Treatment: Doxycycline and rifampin for a minimum of six weeks. Ofloxacin + rifampin is also effective. Therapy with rifampin, a tetracycline, and an aminoglycoside is indicated for infections with complications such as endocarditis or meningoencephalitis.
Prophylaxis: No approved human vaccine is available. Avoid consumption of unpasteurized milk and cheese.
Isolation and Decontamination: Standard precautions for healthcare workers. Person-to-person transmission via tissue transplantation and sexual contact have been reported but are insignificant. Environmental decontamination can be accomplished with a 0.5% hypochlorite solution.
The Brucellae are a group of gram-negative cocco-baccillary organisms, of which four species are pathogenic in humans. Abattoir and laboratory worker infections suggest that Brucella spp. are highly infectious via the aerosol route. It is estimated that inhalation of only 10 to 100 bacteria is sufficient to cause disease in man. The relatively long and variable incubation period (5-60 days) and the fact that many infections are asymptomatic under natural conditions has made it a less desirable agent for weaponization, although large aerosol doses may shorten the incubation period and increase the clinical attack rate. Brucellosis infection has a low mortality rate (5% of untreated cases) with most deaths caused by endocarditis or meningitis. It is an incapacitating and disabling disease in its natural form.
History and Significance
Marston described disease caused by B. melitensis among British soldiers on Malta during the Crimean War as "Mediterranean gastric remittent fever". Work by the Mediterranean Fever Commission identified goats as the source of human brucella infection on Malta, and restriction of the ingestion of unpasteurized goats milk and cheese soon decreased the number of cases of brucellosis among military personnel.
In 1997, most cases were associated with ingestion of unpasteurized dairy products and abattoir and veterinary work. In the United States most cases are reported from Florida, California, Virginia, and Texas. It is a rare disease in the United States with an incidence of 0.5 per 100,000 population.
In 1954, Brucella suis became the first agent weaponized by the U.S. in the days of its offensive BW program at the newly constructed Pine Bluff Arsenal. Despite this, B. melitensis actually produces more severe human disease.
Clinical Features
Brucellosis may present as a nonspecific febrile illness which resembles influenza. Fever, headache, myalgia, arthralgia, back pain, sweats, chills, and generalized weakness and malaise are common complaints. Cough and pleuritic chest pain may occur in up to twenty percent of cases, but these are usually not associated with acute pneumonitis. Pulmonary symptoms may not correlate with radiographic findings. The chest x-ray may be normal, or show lung abscesses, single or miliary nodules, bronchopneumonia, enlarged hilar lymph nodes, and pleural effusions. Gastrointestinal symptoms occur in up to 70 percent of adult cases, and less frequently in children. These include anorexia, nausea, vomiting, diarrhea and constipation. Ileitis, colitis and granulomatous or a mononuclear infiltrative hepatitis may occur. Lumbar pain and tenderness can occur in up to 60% of cases and is due to various osteoarticular infections of the axial skeletal system. Paravertebral abscesses may occur and can be imaged by CT scan or MRI. CT scans often show vertebral sclerosis. Vertebral and disc space destruction may occur in chronic cases. One or, less frequently, both sacroiliac joints may be infected causing low back and buttock pain that is intensified by stressing the sacroiliac joints on physical exam. Hepatomegaly and splenomegaly can occur in up to 45-63 percent of cases. Peripheral joint involvement may vary from pain on range of motion testing to joint immobility and effusion. Peripheral joint effusions usually show a mononuclear cell predominance and organisms can be isolated in up to 50% of cases. The hip joints are the most commonly involved peripheral joints, but ankle, knee, and sternoclavicular joint infection may occur. Plain radiographs of involved sacroiliac joints usually show blurring of articular margins and widening of the joint space. Technetium or Gallium-67 bone scans are 90% sensitive for detecting sacroileitis and will also detect other sites of bone and joint involvement; they are also useful for differentiating sacroiliac from hip joint involvement.
Meningitis occurs in less than 5% of cases and may be an acute presenting illness of a chronic syndrome occurring late in the course of a persistent infection. The cerebrospinal fluid contains an increased number of lymphocytes and a low to normal glucose. Culture of the CSF has sensitivity of 50%, and specific brucella antibodies can be detected in the fluid in a higher percentage of cases. Encephalitis, peripheral neuropathy, radiculoneuropathy and meningovascular syndromes have also been observed in rare cases. Behavioral disturbances in children and psychoses may occur in the meningoencephalitic form of the disease. Epididymo-orchitis may occur in men as the most frequent genitourinary form of brucellosis. Rashes occur in less than 5% if cases and include macules, papules, ulcers, purpura, petechiae, and erythema nodosum.
The leukocyte count is usually normal but may be low. Anemia and thrombocytopenia may occur. Blood and bone marrow culture during the acute febrile phase of the illness will yield a positivity rate of 15-70% and 92% respectively. A biphasic culture method for blood (Castaneda bottle) may increase the number of isolates. The serum agglutination test (SAT) will detect both IgM and IgG antibodies. A titer of 1:160 or greater is indicative of active disease. The IgM titer can be measured by adding a reduced agent such as 2-mercaptoethanol to the serum. This will destroy the agglutinability of IgM allowing the IgM titer to be measured by subtracting the now lower titer from the total serum agglutinin titer. A dot-ELISA using an autoclaved extract of B. abortus has been found to be a sensitive and specific screening test for detection of Brucella antibodies under field conditions. ELISA tests for antibody detection require standardization using a specific antigen before they will be widely available. Antigen detection on DNA extracted from blood mononuclear cells has been accomplished using PCR analysis of a target sequence on the 31-kilodalton B. abortus protein BCSP 31. This test has been proven to be rapid and specific and may replace blood culture in the future, since the latter may require incubation for up to 6 weeks. PCR for Brucella species is not available at this time except in research laboratories, but shows promise for future use.
Medical Management
Isolation is not required other than contact isolation for draining lesions. Person to person transmission is possible via contact with such lesions. Biosafety level 3 practices should be used for suspected brucella cultures in the laboratory because of the danger of inhalation infection. Antibiotic therapy is recommended as the sole therapy unless there are surgical indications for the treatment of localized diseases (e.g., valve replacement for endocarditis).
The treatment recommended by the World Health Organization for acute brucellosis in adults is doxycycline 200 mg/day p.o. plus rifampin 600-900 mg/day for a minimum of six weeks. The previously established regimen of intramuscular streptomycin along with an oral tetracycline may give fewer relapses but is no longer the primary recommendation. Ofloxacin 400 mg/day and rifampin 600 mg/day p.o. is also an effective combination. Combination therapy with rifampin, a tetracycline, and an aminoglycoside is indicated for infections with complications such as meningoencephalitis or endocarditis. Doxycycline clearance is increased in the presence of rifampin and plasma levels are lower than when streptomycin is used instead of rifampin.
Live animal vaccines are used widely. Consumption of unpasteurized milk and cheese should be avoided. No approved human brucella vaccine is available. An experimental human brucellosis vaccine has been tested on 271 subjects with a 25% rate of unpleasant acute side effects, but no long term adverse side effects.
Signs and Symptoms: Incubation period 4 hours to 5 days; average 2-3 days. Asymptomatic to severe with sudden onset. Vomiting, headache, intestinal cramping with little or no fever followed rapidly by painless, voluminous diarrhea. Fluid losses may exceed 5 to 10 liters per day. Without treatment, death may result from severe dehydration, hypovolemia and shock.
Diagnosis: Clinical diagnosis. &lsquo;Rice water&rsquo; diarrhea and dehydration. Microscopic exam of stool samples reveals few or no red or white cells. Can be identified by darkfield or phase contrast microscopy, and by direct visualization of darting motile vibrio.
Treatment: Fluid and electrolyte replacement. Antibiotics (tetracycline, ciprofloxacin or erythromycin) may shorten the duration of diarrhea and, more importantly, reduce shedding of the organism.
Prophylaxis: A licensed, killed vaccine is available but provides only about 50 percent protection that lasts for no more than 6 months. Vaccination schedule is at 0 and 4 weeks, with booster doses every 6 months.
Isolation and Decontamination: Standard Precautions for healthcare workers. Personal contact rarely causes infection; however, enteric precautions and careful hand-washing should be employed. Bactericidal solutions (hypochlorite) would provide adequate decontamination.
Vibrio cholerae is a short, curved, motile, gram-negative, non-sporulating rod. There are two serogroups, O1 and O139, that have been associated with cholera in humans. The O1 serotype exists as 2 biotypes, classical and El Tor. The organisms are facultative anaerobes, growing best at a pH of 7.0, but able to tolerate an alkaline environment. They do not invade the intestinal mucosa, but rather "adhere" to it. Cholera is the prototype toxigenic diarrhea, which is secretory in nature. All strains elaborate the same enterotoxin, a protein molecule with a molecular weight of 84,000 daltons. The entire clinical syndrome is caused by the action of the toxin on the intestinal epithelial cell. Fluid loss in cholera originates in the small intestine with the colon being relatively insensitive to the toxin. The large volume of fluid produced in the upper intestine overwhelms the capacity of the lower intestine to absorb. Transmission is made through direct or indirect fecal contamination of water or foods, and by heavily soiled hands or utensils. All populations are susceptible, while natural resistance to infection is variable. Recovery from an attack is followed by a temporary immunity which may furnish some protection for years. The organism is easily killed by drying. It is not viable in pure water, but will survive up to 24 hours in sewage, and as long as 6 weeks in certain types of relatively impure water containing organic matter. It can withstand freezing for 3 to 4 days. It is readily killed by dry heat at 117 ° C, by steam and boiling, by short exposure to ordinary disinfectants, and by chlorination of water.
This agent has purportedly been investigated in the past as a biological weapon. Cholera does not easily spread from person-to-person. Therefore, to be an effective biological weapon, major drinking water supplies would need to be heavily contaminated. Recent naturally occurring cholera epidemics in South America have shown the devastating consequences of this disease. Cholera spread quickly in Peru and neighboring countries, despite all attempts to curb the epidemic at an early stage. Over 250,000 symptomatic cases have been reported in Peru alone, and the epidemic has spread to other countries. The rate of symptomatic to asymptomatic cases is 1:400, a factor mitigating against effective use of cholera as a BW agent.
Cholera is an acute infectious disease, characterized by sudden onset with nausea, vomiting, profuse watery diarrhea with 'rice water' appearance, the rapid loss of body fluids, toxemia, and frequent collapse. Mortality can range as high as 50 percent in untreated cases.
After an incubation period varying from 4 hours to 5 days (average 2-3 days), presumably dependent upon the dose of ingested organisms, onset is usually rather sudden, although the clinical manifestations range from an asymptomatic carrier state to severe illness. Initially the disease presents with intestinal cramping and painless diarrhea. Vomiting, malaise and headache often accompany the diarrhea, especially early in the illness. If fever is present, it is usually low grade. Diarrhea may be mild or profuse and watery, with fluid losses exceeding 5 to 10 liters or more per day. Electrolyte loss can explain almost all clinical signs and symptoms. Without treatment, death may result from severe dehydration, hypovolemia and shock.
On microscopic examination of stool samples there are few or no red cells or white cells and almost no protein. The absence of inflammatory cells and erythrocytes reflects the non-invasive character of V. cholerae infection of the intestinal lumen. The organism can be identified in liquid stool or enrichment broths by darkfield or phase contrast microscopy, and by identifying darting motile vibrio. The organism must be transported using Cary-Blair medium and then streaked for isolation onto TCBS (Thiosulfate Citrate Bile Salt Sucrose) medium. Bacteriologic identification is not necessary to treat cholera, as it can be diagnosed clinically.
Treatment of cholera depends primarily on replacement of fluid and electrolyte losses. This is best accomplished using oral rehydration therapy with the World Health Organization solution (3.5 g NaCl, 2.5 g NaHCO3, 1.5 g KCl and 20 g of glucose per liter). Intravenous fluid replacement is occasionally needed in patients with persistent vomiting or high rates of stool loss (10ml/kg/hr). Antibiotics will shorten the duration of diarrhea and thereby reduce fluid losses. Tetracycline (500 mg every 6 hours for 3 days) or doxycycline (300 mg once or 100 mg every 12 hours for 3 days) is generally adequate. However, due to widespread tetracycline resistance, ciprofloxacin (500 mg every 12 hours for 3 days) or erythromycin (500 mg every 6 hours for 3 days) should be considered. For pediatric treatment, tetracycline (50 mg/kg/d divided into 4 doses x 3 days) can be used, as dental staining has only occurred after 6 courses of treatment lasting 6 or more days. Alternates are erythromycin (40 mg/kg/d divided into 4 doses x 3 days), trimethoprim 8 mg and sulfamethoxazole 40 mg/kg day divided into 2 doses x 3 days, and furazolidone (5 mg/kg/d divided into 4 doses x 3 days or 7 mg/kg x one dose).
Vaccine: A licensed, killed vaccine is available for use in those considered to be at risk of exposure, however, it provides only about 50 percent protection that lasts for no more than 6 months. The vaccination schedule is an initial dose followed by a second dose 4 weeks later, with booster doses every 6 months. An inactivated oral vaccine (WC/rBS), which is licensed in Europe, is safe and provides rapid short-term protection. Licensure in the US is anticipated. WC/rBS requires 2 doses and has approximately 85% efficacy lasting 2-3 years for both El Tor and classical biotypes. Live attenuated oral vaccines show much promise, and one, CVD 103-HgR (classical biotype), will probably be available by 1999. There are no O139 serogroup vaccines close to licensure, and none of the above mentioned vaccines provide cross-protection against O139. Primary infection with V. cholerae O1 serogroup also provides no immunity against O139.
Prevention: Since the major biological threat from this organism appears to be sabotage of food and water supplies, it would seem justified to state that optimal prophylaxis in these circumstances would not be of a medical nature but would be proper safeguarding of these supplies to prevent the sabotage. The best way to prevent cholera in an endemic environment is to avoid contaminated water, ice, fruits, vegetables and also raw or undercooked seafood. Personal contact rarely causes infection because of the high inoculum required for infection; however, enteric precautions and careful hand-washing should be employed. Bactericidal solutions (hypochlorite) would provide adequate decontamination.
Signs and Symptoms: Incubation period ranges from 10-14 days after inhalation. Inhalational exposure produces fever, rigors, sweats, myalgia, headache, pleuritic chest pain, cervical adenopathy, splenomegaly, and generalized papular/pustular eruptions. Almost always fatal without treatment.
Diagnosis: Methylene blue stain of exudates may reveal scant small bacilli. CXR may show miliary lesions, small multiple lung abscesses, or bronchopneumonia. B. mallei can be cultured from infected secretions using meat nutrients.
Treatment: Few antibiotics have been evaluated in vivo. Sulfadiazine may be effective in some cases. Ciprofloxacin, doxycycline, and rifampin have in vitro efficacy. Extrapolating from melioidosis guidelines, a combination of TMP-SMX + ceftazidime ± gentamicin might be considered.
Prophylaxis: No human or veterinary vaccine. Post-exposure prophylaxis may be tried with TMP-SMX.
Isolation and Decontamination: Standard Precautions for healthcare workers. Person-to-person airborne transmission is unlikely, although secondary cases may occur through improper handling of infected secretions. Environmental decontamination using a 0.5% hypochlorite solution is effective.
The causative agent of Glanders is Burkholderia (formerly Pseudomonas) mallei, a gram-negative bacillus primarily noted for producing disease in horses, mules, and donkeys. In the past man has seldom been infected, despite frequent and often close contact with infected animals. This may be due to exposure to low concentrations of organisms from infected sites in sick animals and the fact that strains virulent for equids are often less virulent for man. There are four basic forms of disease in horses and man. The acute forms are more common in mules and donkeys and death typically follows in 3 to 4 weeks. The chronic form of the disease is more common in horses and causes generalized lymphadenopathy, multiple skin nodules that ulcerate and drain, and induration, enlargement and nodularity of regional lymphatics on the extremities and in other areas. The lymphatic thickening and induration has been called farcy. Human cases have occurred primarily in veterinarians, horse and donkey caretakers, and abattoir workers. The organism spreads to man by invading the nasal, oral, and conjunctival mucous membranes, by inhalation into the lungs, and by invading abraded or lacerated skin. Aerosols from cultures have been observed to be highly infectious to laboratory workers. Work with this organism in the laboratory requires biosafety level 3 containment practices. Despite the rarity of contagion to man from infected horses and donkeys, the attack rates caused by laboratory aerosols have been as high as 46% and cases have been severe. Since aerosol spread is efficient, and there is no available vaccine or really dependable therapy, B. mallei has been viewed as a potential BW agent. The disease in Equidae in its natural form poses a minimal threat to military personnel.
Despite the efficiency of spread in a laboratory setting, glanders has only been a sporadic disease in man, and no epidemics of human disease have been reported. There have been no naturally acquired cases of human glanders in the United States in over 59 years. Sporadic cases continue to occur in Asia, Africa, the Middle East and South America. During World War I glanders was believed to have been spread deliberately by agents of the Central Powers to infect large numbers of Russian horses and mules on the Eastern Front. This had an effect on troop and supply convoys as well as on artillery movement which were dependent on horses and mules. Human cases in Russia increased with the infections during and after WWI. The Japanese deliberately infected horses, civilians, and prisoners of war with B. mallei at the Pinfang (China) Institute during World War II. The United States studied this agent as a possible BW weapon in 1943-44 but did not weaponize it. The former Soviet Union is believed to have been interested in B. Mallei as a potential BW agent after World War II. The low transmission rates of B. mallei to man from infected horses is exemplified by the fact that in China, during World War II, thirty percent of tested horses were positive for glanders, but human cases were rare. In Mongolia, 5-25% of tested animals were reactive to B. mallei, but no human cases were seen. B. mallei exists in nature only in infected susceptible hosts and is not found in water, soil, or plants.
Glanders may occur in an acute localized form, as a septicemic rapidly fatal illness, or as an acute pulmonary infection. Combinations of these syndromes commonly occur in human cases. A chronic cutaneous form with lymphangitis and regional adenopathy is also frequent.
Aerosol infection produced by a BW weapon containing B. mallei could produce any of these syndromes. The incubation period ranges from 10- 14 days, depending on the inhaled dose and agent virulence. The septicemic form begins suddenly with fever, rigors, sweats, myalgia, pleuritic chest pain, photophobia, lacrimation, and diarrhea. Physical examination may reveal fever, tachycardia, cervical adenopathy and mild splenomegaly. Blood cultures are usually negative until the patient is moribund. Mild leukocytosis with a shift to the left or leukopenia may occur.
The pulmonary form may follow inhalation or arise by hematogenous spread. Systemic symptoms as described for the septicemic form occur. Chest radiographs may show miliary nodules (0.5-1.0 cm) and/or a bilateral bronchopneumonia, segmental, or lobar pneumonia and necrotizing nodular lesions.
Acute infection of the oral, nasal and/ or conjunctival mucosa can cause mucopurulent, blood streaked discharge from the nose, associated with septal and turbinate nodules and ulcerations. If systemic invasion occurs from mucosal or cutaneous lesions then a papular and/ or pustular rash may occur that can be mistaken for smallpox (another possible BW agent).
The chronic form is unlikely to be present within 14 days after a BW aerosol attack. It is characterized by cutaneous and intramuscular abscesses on the legs and arms. These lesions are associated with enlargement and induration of the regional lymph channels and nodes. Rare cases develop osteomyelitis, brain abscess, and meningitis. Recovery from chronic glanders may occur or the disease may erupt into an acute septicemic illness. Nasal discharge and ulceration are present in 50% of chronic cases.
Gram stain of lesion exudates reveals small gram negative bacteria. These stain irregularly with methylene blue. B. mallei grows slowly on ordinary nutrient agar, but growth is accelerated with addition of 1-5% glucose and or 5% glycerol. Primary isolation requires 48 hours at 37.5 ºC. Growth is also rapid on most meat infusion nutrient media. Agglutination tests are not positive for 7-10 days, and a high background titer in normal sera (1:320 to 1:640) makes interpretation difficult. Complement fixation tests are more specific and are considered positive if the titer is equal to, or exceeds 1:20. Cultures of autopsy nodules in septicemic cases will usually establish the presence of B. mallei. Occurrence in the absence of animal contact and/ or in a human epidemic form is presumptive evidence of a BW attack. Mortality will be high despite antibiotic use. In the hamster 1 to 10 organisms administered by aerosol is lethal. "Resistant species" such as albino mouse can be infected with higher inhalation doses.
Standard Precautions should be used to prevent person-to-person transmission in proven or suspected cases. Sulfadiazine 100 mg/kg per day in divided doses for 3 weeks has been found to be effective in experimental animals and in humans. Other antibiotics that have been effective in experimental infection in hamsters include doxycycline, rifampin, trimethoprim-sulfamethoxazole, and ciprofloxacin. The limited number of infections in humans has precluded therapeutic evaluation of most of the antibiotic agents, therefore, most antibiotic sensitivities are based on animal in vitro studies. Various isolates have markedly different antibiotic sensitivities, so that each isolate should be tested for its own individual resistance pattern.
Vaccine: There is no vaccine available for human use.
Antibiotics: Post-exposure chemoprophylaxis may be tried with TMP-SMX.

Signs and Symptoms: Pneumonic plague incubates 2-3 days. High fever, chills, headache, hemoptysis, and toxemia, progressing rapidly to dyspnea, stridor, and cyanosis. Death from respiratory failure, circulatory collapse, and a bleeding diathesis. Bubonic plague incubates 2-10 days. Malaise, high fever, and tender lymph nodes (buboes); may progress spontaneously to the septicemic form, with spread to the CNS, lungs, etc.
Diagnosis: Presumptive diagnosis can be made by Gram or Wayson stain of lymph node aspirates, sputum, or CSF. Plague bacilli may also be cultured on standard media.
Treatment: Early administration of antibiotics is very effective. Supportive therapy is required.
Prophylaxis: A licensed, killed vaccine is available. Primary series of an initial dose followed by a second smaller dose 1-3 months later, and a third dose 5-6 months after the second dose. Give 3 booster doses at 6 month intervals following dose 3 of the primary series then every 1-2 years. This vaccine is effective against bubonic plague, but probably not against aerosol exposure.
Isolation and Decontamination: Standard Precautions for healthcare workers exposed to bubonic plague. Droplet Precautions for healthcare workers exposed to pneumonic plague. Heat, disinfectants (2-5% hypochlorite) and exposure to sunlight renders bacteria harmless.
Yersinia pestis, a rod-shaped, non-motile, non-sporulating, gram-negative, bipolar staining, facultative anaerobic bacterium. It causes plague, normally a zoonotic disease of rodents (e.g., rats, mice, ground squirrels). Fleas which live on the rodents can sometimes pass the bacteria to human beings, who then suffer from the bubonic form of plague. The pneumonic form of the disease would be seen as the primary form after purposeful aerosol dissemination of the organisms. The bubonic form would be seen after purposeful dissemination through the release of infected fleas. All human populations are susceptible. Recovery from the disease may be followed by temporary immunity. The organism will probably remain viable in water and moist meals and grains for several weeks. At near freezing temperatures, it will remain alive from months to years but is killed by 15 minutes exposure to 72 ° C. It also remains viable for some time in dry sputum, flea feces, and buried bodies but is killed within several hours of exposure to sunlight.
The United States worked with Y. pestis as a potential biowarfare agent in the 1950's and 1960's before the old offensive biowarfare program was terminated, and other countries are suspected of weaponizing this organism. During World War II, there is reported evidence that Japan investigated the use of Y. pestis as a biological weapon. It was reported that they worked on a plan for attacking enemy troops with the organism by releasing plague-infected fleas. This bacterium could be delivered theoretically as an aerosol.
Plague normally appears in three forms in man; bubonic, primary septicemic, and pneumonic. The buboes in the bubonic form are normally seen in the inguinal lymph nodes as the legs are the most commonly "flea-bitten" part of the human body. Septicemia is common, as greater than 80 percent of blood cultures are positive for the organism in bubonic plague, although primary septicemia may occur without lymphadenopathy. The pneumonic form is an infection of the lungs due either to inhalation of the organisms (primary pneumonic plague), or spread to the lungs from septicemia (secondary pneumonic plague). In man, the mortality of untreated bubonic plague is approximately 50 percent, whereas in pneumonic plague the mortality rate is 100 percent.
After an incubation period varying from 2-3 days for primary pneumonic plague, onset is acute and often fulminant. The presentation is one of malaise, high fever, chills, headache, myalgia, cough with production of a bloody sputum, and toxemia. The chest X-ray reveals a patchy or consolidated bronchopneumonia. The pneumonia progresses rapidly, resulting in dyspnea, stridor, and cyanosis. The terminal event is one of respiratory failure, circulatory collapse, and a bleeding diathesis. In bubonic plague the incubation period ranges from 2 to 10 days with the onset also being acute and often fulminant. The presentation is one of malaise, high fever, and one or more tender lymph nodes. The liver and spleen are often tender and palpable. One quarter of patients will have various types of skin lesions. Occasionally a pustule, vesicle, eschar or papule containing leukocytes and bacteria will be apparent in the bubo distribution and presumably represents the site of the inoculating flea bite. Bubonic plague may progress spontaneously to the septicemic form with organisms spreading to the central nervous system, lungs, and elsewhere. Black necrotic and purpuric lesions caused by endotoxemia are also often present.
Laboratory findings include a leukocytosis, with a total WBC count up to 20,000 cells with increased bands, and greater than 80 percent polymorphonuclear cells. One also often finds increased fibrin split products in the blood indicative of a low-grade DIC, and the ALT, AST, and bilirubin are also elevated.
A presumptive diagnosis can be made microscopically by identification of the gram-negative coccobacillus with safety-pin bipolar staining in Gram or Wayson's stained smears from a lymph node needle aspirate, sputum, or cerebrospinal fluid sample. When available, immunofluorescent staining is very useful. A definitive diagnosis can be readily made by culturing the organism from blood, sputum, and bubo aspirates. The organism grows slowly at normal incubation temperatures, and may be misidentified by automated systems because of delayed biochemical reactions. It may be cultured on blood agar, MacConkey agar or infusion broth. Most naturally occurring strains of Y. pestis produce an F1-antigen in vivo, which can be detected in serum samples by immunoassay. A four-fold rise in antibody titer in patient serum is also diagnostic.
Use Standard Precautions for healthcare workers exposed to bubonic plague and Droplet Precautions for healthcare workers exposed to pneumonic plague until the patient has been on antibiotic therapy for at least 48 hours and there has been a favorable clinical response to treatment. Streptomycin, tetracycline, chloramphenicol, and gentamicin are highly effective, especially if begun early (within 24 hours of onset of symptoms). Plague pneumonia is almost always fatal if treatment is not initiated within 24 hours of the onset of symptoms. Streptomycin remains the drug of choice and is given 30 mg/kg/day (IM) in two divided doses for ten days. Gentamicin is acceptable if streptomycin is unavailable. While the patient is typically afebrile after 3 days, the extra week of therapy prevents relapses. Intravenous doxycycline 200 mg initially, followed by 100 mg every 12 hours for 10-14 days is also effective. Results obtained from laboratory animal, but not human, experience, indicate that quinolone antibiotics, such as ofloxacin and ciprofloxacin, may also be effective. The addition of chloramphenicol is required for the treatment of plague meningitis.
Usual supportive therapy required includes IV crystalloids and hemodynamic monitoring. Although low-grade DIC may occur, clinically significant hemorrhage is uncommon as is the need to treat with heparin. Finally, buboes rarely require incision and drainage or any form of local care, but instead recede with systemic antibiotic therapy. In fact, incision and drainage may pose a risk to others in contact with the patient.
Vaccine: A licensed, killed whole cell vaccine is available for use in those considered to be at risk of exposure. The primary series consists of three doses. The initial dose of 1.0 ml IM followed by 0.2 ml IM at 1 and 6 months. Three booster doses of 0.2 ml IM are given at 6 month intervals following the third dose of the primary series and then every 1-2 years thereafter. The current vaccine offers protection against bubonic plague, but is probably not effective against aerosolized Y. pestis. Presently, 8-10 percent of inoculations result in local reactions which include erythema, induration, tenderness and edema at the site of injection. These typically resolve within 48 hours. Approximately 7-10 percent of inoculations will result in systemic symptoms including malaise, lymphadenopathy, fever and very rarely anaphylaxis, tachycardia, urticaria, or hypotension.
Antibiotics: Because of oral administration and relative lack of toxicity, the choice of antibiotic for prophylaxis or for use in face-to-face contacts of patients with pneumonic plague or after a confirmed or suspected plague BW attack is doxycycline 100 mg orally twice daily, for seven days or the duration of risk of exposure, whichever is longer. Ciprofloxacin has also shown to be effective in preventing disease in exposed mice, and may be more available in a wartime setting as it is also distributed in blister-packs for anthrax post-exposure prophylaxis.
Signs and Symptoms: Ulceroglandular tularemia presents with a local ulcer and regional lymphadenopathy, fever, chills, headache and malaise. Typhoidal tularemia presents with fever, headache, malaise, substernal discomfort, prostration, weight loss and a non-productive cough.
Diagnosis: Clinical diagnosis. Physical findings are usually non-specific. Chest x-ray may reveal a pneumonic process, mediastinal lymphadenopathy or pleural effusion. Routine culture is possible but difficult. The diagnosis can be established retrospectively by serology.
Treatment: Administration of antibiotics (streptomycin or gentamicin) with early treatment is very effective.
Prophylaxis: A live, attenuated vaccine is available as an investigational new drug. It is administered once by scarification. A two week course of tetracycline is effective as prophylaxis when given after exposure.
Isolation and Decontamination: Standard Precautions for healthcare workers. Organisms are relatively easy to render harmless by mild heat (55 degrees Celsius for 10 minutes) and standard disinfectants.
Francisella tularensis, the causative agent of tularemia, is a small, aerobic non-motile, gram-negative cocco-bacillus. Tularemia (also known as rabbit fever and deer fly fever) is a zoonotic disease which humans typically acquire after contact of their skin or mucous membranes with tissues or body fluids of infected animals, or from bites of infected deerflies, mosquitoes, or ticks. Less commonly, inhalation of contaminated dusts or ingestion of contaminated foods or water may produce clinical disease. Respiratory exposure by aerosol would cause typhoidal or pneumonic tularemia. F. tularensis can remain viable for weeks in water, soil, carcasses, and hides, and for years in frozen rabbit meat. It is resistant for months to temperatures of freezing and below. It is rather easily killed by heat and disinfectants.
Tularemia was recognized in Japan in the early 1800&rsquo;s and in Russia in 1926. In the early 1900&rsquo;s, American workers investigating suspected plague epidemics in San Francisco isolated the organism and named it Bacterium tularense after Tulare County where the work was performed. Dr. Edward Francis, USPHS, established the cause of deer-fly fever as Bacterium tularense and subsequently devoted his life to researching the organism and disease, hence, the organism was later renamed Francisella tularensis
Francisella tularensis was weaponized by the United States in the 1950's and 1960's during the U.S. offensive biowarfare program, and other countries are suspected to have weaponized this agent. This organism could potentially be stabilized for weaponization by an adversary and theoretically produced in either a wet or dried form. It could then theoretically be delivered against U.S. forces in a similar fashion to the other bacteria discussed in this handbook.
After an incubation period varying from 1-21 days (average 3-5 days), presumably dependent upon the dose of organisms, onset is usually acute. Tularemia may appear in several forms in man depending upon the route of inoculation: ulceroglandular, glandular, typhoidal, oculoglandular, pharyngeal, and pneumonic tularemia. In humans, as few as 10 to 50 organisms will cause disease if inhaled or injected intradermally, whereas approximately 108 organisms are required with oral challenge.
Ulceroglandular tularemia (75-85 percent of cases) is most often acquired through inoculation of the skin or mucous membranes with blood or tissue fluids of infected animals. It is characterized by fever, chills, headache, and malaise, an ulcerated skin lesion and painful regional lymphadenopathy. The skin lesion is usually located on the fingers or hand.
Glandular tularemia (5-10 percent of cases) results in fever and tender lymphadenopathy but no skin ulcer.
Typhoidal tularemia accounts for 5-15 percent of naturally occurring cases and occurs mainly after inhalation of infectious aerosols, but can occur after intradermal or gastrointestinal challenge. It manifests as fever, prostration, and weight loss but without lymphadenopathy. Pneumonia may be associated with any form but is most common in typhoidal tularemia. Diagnosis of primary typhoidal tularemia is difficult, as signs and symptoms are non-specific and there frequently is no suggestive exposure history. Respiratory symptoms, substernal discomfort, and a non-productive cough may also be present. Radiologic evidence of pneumonia or mediastinal lymphadenopathy is most common with typhoidal disease but may or may not be present in all other forms of tularemia.
Oculoglandular tularemia (1-2 percent of cases) occurs after inoculation of the conjunctivae with infectious material. Patients have unilateral, painful, purulent conjunctivitis with preauricular or cervical lymphadenopathy. Chemosis, periorbital edema, and small nodular lesions or ulcerations of the palpebral conjunctiva are noted in some patients.
Oropharyngeal tularemia refers to primary ulceroglandular disease confined to the throat. It produces an acute exudative or membranous pharyngotonsillitis with cervical lymphadenopathy.
Pneumonic tularemia is an illness characterized primarily by pneumonia. Pneumonia is common in tularemia. It is seen in 30-80 percent of the typhoidal cases and in 10-15 percent of the ulceroglandular cases. The case fatality rate without treatment is approximately 5 percent for the ulceroglandular form and 35 percent for the typhoidal form. All ages are susceptible, and recovery is followed by permanent immunity.
Identification of organisms by staining ulcer fluids or sputum is generally not helpful. Routine culture is difficult, due to unusual growth requirements and/or overgrowth of commensal bacteria. Isolation represents a clear hazard to laboratory personnel and should only be attempted in BL-3 laboratory. The diagnosis can be established retrospectively serologically. A fourfold rise in the tularemia tube agglutination or microagglutination titer is diagnostic of infection. A single convalescent titer of 1:160 or greater is diagnostic of past or current infection. Titers are usually negative the first week of infection, positive the second week in 50-70 percent of cases and reach a maximum in 4-8 weeks.
Standard Precautions are recommended for healthcare workers. Streptomycin (1 gm every 12 hours IM for 10-14 days) is the treatment of choice. Gentamicin 3-5 mg/kg/day parenterally for 10-14 days is also effective. Tetracycline and chloramphenicol treatment are effective as well, but are associated with significant relapse rates. Although laboratory related infections with this organism are very common, person-to-person spread is unusual and respiratory isolation is not required.
Vaccine: A live, attenuated tularemia vaccine is available as an investigational new drug (IND). It is given by scarification. This vaccine has been administered to more than 5,000 persons without significant adverse reactions. It is of proven effectiveness in preventing laboratory acquired tularemia as well as in experimentally exposed human volunteers. As with all vaccines, the degree of protection depends upon the magnitude of the challenge dose; vaccine-induced protection could be overwhelmed by extremely high doses.
Antibiotics: Tetracycline 500 mg PO qid for two weeks is effective as prophylaxis when given after exposure.
Signs and Symptoms: Fever, cough, and pleuritic chest pain may occur as early as ten days after exposure. Patients are not generally critically ill, and the illness lasts from 2 days to 2 weeks.
Diagnosis: Q fever is not a clinically distinct illness and may resemble a viral illness or other types of atypical pneumonia. The diagnosis is confirmed serologically.
Treatment: Q fever is generally a self-limited illness even without treatment. Tetracycline or doxycycline are the treatments of choice and are given orally for 5 to 7 days. Q fever endocarditis (rare) is much more difficult to treat.
Prophylaxis: Treatment with tetracycline during the incubation period may delay but not prevent the onset of symptoms. An inactivated whole cell vaccine is effective in eliciting protection against exposure, but severe local reactions to this vaccine may be seen in those who already possess immunity.
Isolation and Decontamination: Standard Precautions are recommended for healthcare workers. Person-to-person transmission is rare. Patients exposed to Q fever by aerosol do not present a risk for secondary contamination or re-aerosolization of the organism. Decontamination is accomplished with soap and water or after a 30 minute contact time with 5% microchem plus (quaternary ammonium compound) or 70% ethyl alcohol.
The endemic form of Q fever is a zoonotic disease caused by a rickettsia, Coxiella burnetii. Its natural reservoirs are sheep, cattle and goats, and grows to especially high concentrations in placental tissues. Exposure to infected animals at parturition is an important risk factor for endemic disease. The organisms are also excreted in animal milk, urine, and feces. Humans acquire the disease by inhalation of aerosols contaminated with the organisms. Farmers and abattoir workers are at greatest risk occupationally. A biological warfare attack with Q fever would cause a disease similar to that occurring naturally. Q fever is also a significant hazard in laboratory personnel who are working with the organism.
Q fever was first described in Australia: it was called "Query fever" because the causative agent was initially unknown. Coxiella burnetii, the causative agent, was discovered in 1937. This organism is a rickettsial agent that is resistant to heat and desiccation and highly infectious by the aerosol route. A single inhaled organism may produce clinical illness. For all of these reasons, Q fever could be used as a biological warfare agent. This organism could be employed by an adversary as an incapacitating agent due to its highly infectious nature and likelihood of causing disease if delivered by the respiratory route.
Following the usual incubation period of 2-14 days (average 7 days), Q fever generally occurs as a self-limiting febrile illness lasting 2 days to 2 weeks. The incubation period varies according to the numbers of organisms inhaled, with longer periods between exposure and illness with lower numbers of inhaled organisms (up to forty days in some cases). The disease generally presents as an acute nondifferentiated febrile illness, with headaches, fatigue, and myalgias as prominent symptoms. Pneumonia manifested by an abnormal chest X-ray occurs in half of all patients, but only half of these, or 25 percent of patients, will have a cough (usually non-productive) or rales. Pleuritic chest pain occurs in about one-fourth of patients with Q fever pneumonia. Chest radiograph abnormalities, when present, are patchy infiltrates that may resemble viral or mycoplasma pneumonia. Rounded opacities and adenopathy have also been described.
Uncommon complications include chronic hepatitis, culture-negative endocarditis, aseptic meningitis, encephalitis and osteomyelitis. Most patients who develop endocarditis have pre-existing valvular heart disease.
Routine Laboratory Findings: The white blood cell count is elevated in one third of patients. Most patients with Q fever have a mild elevation of hepatic transaminase levels.
Differential Diagnosis: As Q fever usually presents as an undifferentiated febrile illness, or a primary atypical pneumonia, it may be difficult to distinguish from viral illnesses and must be differentiated from pneumonia caused by Mycoplasma pneumoniae, Legionella pneumophila, Chlamydia psittaci, and Chlamydia pneumoniae (TWAR). More rapidly progressive forms of Q fever pneumonia may look like bacterial pneumonias such as tularemia or plague. Significant numbers of soldiers (from the same geographic area) presenting over a one to two week period with a nonspecific febrile illness, with associated pneumonic symptoms in about half of cases, should trigger the possibility of an attack with aerosolized Q fever in the minds of the treating physicians. The diagnosis will often rest on the clinical and epidemiologic picture in the setting of a possible biowarfare attack.
Specific Laboratory Diagnosis: Identification of organisms by examination of the sputum is not helpful. Isolation of the organism is impractical, as the organism is difficult to culture and a significant hazard to laboratory workers. Serological tests for Q fever include identification of antibody to C. burnetii by indirect fluorescent antibody (IFA), enzyme-linked immunosorbent assay (ELISA), and complement fixation. Specific IgM antibodies may be detectable as early as the second week after onset of illness. ELISA testing is available at USAMRIID. A single serum specimen can be used to reliably diagnose acute Q fever with this test as early as 1 1/2 - 2 weeks into the illness. The most commonly available serologic test is the complement fixation test (CF) which is relatively insensitive and may not be useful if sera have intrinsic anti-complement activity.
Standard Precautions are recommended for healthcare workers. Most cases of acute Q fever will eventually resolve without antibiotic treatment. Tetracycline 500 mg every 6 hr or doxycycline 100 mg every 12 hr for 5-7 days will shorten the duration of illness, and fever usually disappears within one to two days after treatment is begun. Successful treatment of Q fever endocarditis is much more difficult. Tetracycline or doxycycline given in combination with trimethoprim-sulfamethoxazole (TMP-SMX) or rifampin for 12 months or longer has been successful in some cases. However, valve replacement is often required to achieve a cure.
Vaccine: A formalin-inactivated whole cell vaccine is available for immunization of at-risk personnel on an investigational basis, although a Q fever vaccine is licensed in Australia. Vaccination with a single dose of this killed suspension of C. burnetii provides complete protection against naturally occurring Q fever, and greater than 95 percent protection against aerosol exposure. Protection lasts for at least 5 years. The vaccine is generally safe in nonsensitized individuals. However, administration of this vaccine in immune individuals may cause severe local reactions including large areas of induration, sterile abscess formation, and even necrosis at the inoculation site. Newer vaccines are under development for use in sensitized persons.
Antibiotics: Tetracycline or doxycycline given prophylactically after exposure can delay the onset of disease, or even prevent symptoms if administered late in the incubation period. When prophylaxis is started one day after exposure and continued for 5 days, clinical disease has been shown to occur about three weeks after stopping therapy. If prophylaxis is begun 8 to 12 days post-exposure and continued for 5 days, clinical disease will not occur after treatment is discontinued.
Viruses are the simplest type of microorganism and consist of a nucleocapsid protein coat containing genetic material, either RNA or DNA. In some cases the virus particle is also surrounded by an outer layer of lipids. Viruses are much smaller than bacteria and vary in size from 0.02 m m to 0.2 m m (1 m m = 1/1000 mm). Viruses lack a system for their own metabolism and are therefore dependent on the synthetic machinery of their host cells: viruses are thus intracellular parasites. This also means that the virus, unlike the bacterium, cannot be cultivated in synthetic nutritive solutions but requires living cells in order to multiply. The host cells can be from human beings, animals, plants, or bacteria. Every virus needs its own special type of host cell because a complicated interaction is required between the cell and virus if the virus is to be able to multiply. Many virus-specific host cells can be cultivated in synthetic nutrient solutions and afterwards can be infected with the virus in question. Another usual way of cultivating viruses is to let them grow on chorioallantoic membranes (from fertilized eggs). The cultivation of viruses is costly, demanding, and time-consuming. A virus normally brings about changes in the host cell such that the cell dies. This handbook will cover a virus considered by some to be the most likely viral agent that would be used in a BW attack, the alpha virus that causes Venezuelan equine encephalitis, known as VEE. We also discuss smallpox and hemorrhagic fever viruses which could potentially be employed as BW agents.
Signs and Symptoms: Clinical manifestations begin acutely with malaise, fever, rigors, vomiting, headache, and backache. 2-3 days later lesions appear which quickly progress from macules to papules, and eventually to pustular vesicles. They are more abundant on the extremities and face, and develop synchronously.
Diagnosis: Electron and light microscopy are not capable of discriminating variola from vaccinia, monkeypox or cowpox. The new PCR diagnostic techniques may be more accurate in discriminating between variola and other Orthopoxviruses.
Treatment: At present there is no effective chemotherapy, and treatment of a clinical case remains supportive.
Prophylaxis: Immediate vaccination or revaccination should be undertaken for all personnel exposed. Vaccinia immune globulin (VIG) is of value in post-exposure prophylaxis of smallpox when given within the first week following exposure.
Isolation and Decontamination: Droplet and Airborne Precautions for a minimum of 16-17 days following exposure for all contacts. Patients should be considered infectious until all scabs separate.
Variola virus causes smallpox. It is an Orthopox virus and occurs in at least two strains, variola major and the milder disease, variola minor. Despite the global eradication of smallpox and continued availability of a vaccine, the potential weaponization of variola continues to pose a military threat. This threat can be attributed to the aerosol infectivity of the virus, the relative ease of large-scale production, and an increasingly Orthopoxvirus-naive populace. Although the fully-developed cutaneous eruption of smallpox is unique, earlier stages of the rash could be mistaken for varicella. Secondary spread of infection constitutes a nosocomial hazard from the time of onset of a smallpox patient's exanthem until scabs have separated. Quarantine with respiratory isolation should be applied to secondary contacts for 17 days post-exposure. Vaccinia vaccination and vaccinia immune globulin each possess some efficacy in post-exposure prophylaxis.
Endemic smallpox was declared eradicated in 1980 by the World Health Organization (WHO). Although two WHO-approved repositories of variola virus remain at the Centers for Disease Control and Prevention (CDC) in Atlanta and the Institute for Viral Preparations in Moscow, the extent of clandestine stockpiles in other parts of the world remains unknown. In January 1996, WHO&rsquo;s governing board recommended that all stocks of smallpox be destroyed by 30 June, 1999.
The United States stopped vaccinating its military population in 1989 and civilians in the early 1980s. These populations are now susceptible to variola major, although recruits immunized in 1989 may retain some degree of immunity. Variola may have been used by the British Army against native Americans by giving them contaminated blankets from the beds of smallpox victims during the eighteenth century. Japan considered the use of smallpox as a BW weapon in World War II and it has been considered as a possible threat agent against US forces for many years.
The incubation period of smallpox averaged 12 days, and contacts were quarantined for a minimum of 16-17 days following exposure. Clinical manifestations began acutely with malaise, fever, rigors, vomiting, headache, and backache; 15% of patients developed delirium. Approximately 10% of light-skinned patients exhibited an erythematous rash during this phase. Two to three days later, an enanthem appeared concomitantly with a discrete rash about the face, hands and forearms.
Following eruptions on the lower extremities, the rash spread centrally to the trunk over the next week. Lesions quickly progressed from macules to papules, and eventually to pustular vesicles. Lesions were more abundant on the extremities and face, and this centrifugal distribution is an important diagnostic feature. In distinct contrast to varicella, lesions on various segments of the body remained generally synchronous in their stage of development. From 8 to 14 days after onset, the pustules formed scabs which leave depressed depigmented scars upon healing. Although variola concentrations in the throat, conjunctiva, and urine diminished with time, virus could readily be recovered from scabs throughout convalescence. Therefore, patients should be isolated and considered infectious until all scabs separate.
For the past century, two distinct types of smallpox were recognized. Variola minor was distinguished by milder systemic toxicity and more diminutive pox lesions, and caused 1% mortality in unvaccinated victims. However, the prototypical disease variola major caused mortality of 3% and 30% in the vaccinated and unvaccinated, respectively. Other clinical forms associated with variola major, flat-type and hemorrhagic-type smallpox, were notable for severe mortality. A naturally occurring relative of variola, monkeypox, occurs in Africa, and is clinically indistinguishable from smallpox with the exception of notable enlargement of cervical and inguinal lymph nodes.