- TABLE OF CONTENTS
- History of Biological Warfare and
- Medical Aspects of the Biological
- 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
- Appendix C: Comparative Lethality:
- Appendix D: Aerosol Toxicity: Toxins
- Appendix E: Differential Diagnosis:
- 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
- MEDICAL MANAGEMENT OF BIOLOGICAL
- U.S. ARMY MEDICAL RESEARCH
INSTITUTE OF INFECTIOUS DISEASES FORT DETRICK FREDERICK, MARYLAND
- 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
- 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.
- HISTORY OF CHEMICAL WARFARE
AND CURRENT THREAT
- 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
- 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
- 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.
- MEDICAL ASPECTS OF THE CHEMICAL
- 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
- 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
- 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.
- BACTERIAL AGENTS
- 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
- 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.
- HISTORY AND SIGNIFICANCE
- 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.
- MEDICAL MANAGEMENT
- 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
- 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’s followed by Western blotting
- 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
- 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.