BioAgents of Concern – Anthrax, Botulism, Smallpox, Plague
TABLE OF CONTENTS
Learning Objectives 3
Anthrax as a Biological Weapon 11
History of Current Threat 13
Epidemiology of Anthrax 14
Pathogenesis and Clinical Manifestations 16
Infection Control 33
Smallpox as a Biological Weapon 47
History and Potential as a Bioweapon 47
Pathongenesis and Clinical Presentation 49
Preexposure Preventive Vaccination 52
Postexposure Therapy 53
Postexposure Infection Control 54
Hospital Epidemiology and Infection Control 55
Vaccine Administration and Complications 56
Smallpox Update 61
Botulism as a Bioterror Weapon 81
History of Current Threat 81
Microbiology and Virulence Factors 82
Pathogenesis and Clinical Manifestations 83
Diagnosis and Differential Diagnosis 87
Special Populations 90
Infection Control 92
Research Needs 92
Plague as a Biological Weapon 103
History and Potential as a Bioterrorist Agent 103
Microbiology and Virulence Factors 105
Pathogenesis and Clinical Manifestations 105
Postexposure Prophylaxis Recommendations 112
Infection Control 113
Environmental Decontamination 114
Upon successful completion of this continuing education module, you will be able to:
Identify and discuss the history, epidemiology, microbiology, pathogenesis, clinical manifestations, diagnosis, treatment and prevention of: Anthrax, Small Pox, Botulism and Plague
Bioterrorism has become a common household term ever since anthrax was spread across a wide reach of the nation last fall. Now, it almost appears everyone is involved in serious anti-terrorism campaigns which are not as readily seen as flags attached to cars, homes and clothing.
In the event of another bioterrorist attack, will you as a caregiver be prepared?
RTs and Nurses are in the first line of defense in combating biohazard substances because inhalation is the major pathways for toxic and biological agents to infect humans. The airway is one of the primary routes infectious agents follow to enter the body, and the harm caused by the agent would impact the respiratory system first, so RTs and Nurses need to be alert.
Tom Johnson, MS, RRT, program director of respiratory care and professor at Long Island University in New York, was an officer during the Vietnam era. He trained military personnel about chemical warfare. Thirty years later, he teaches RTs and Nurses about bioterrorism and how they need to be prepared in the event of a biological disaster.
Johnson urges all RTs and Nurses to recognize potential bioterrorist agents. "During the Gulf War, biowarfare became an issue, and I realized I was ignorant and did not know anthrax was already weaponized." Bioterrorism is not a new idea. "We have had the threat of bioterrorism for a long time in history," he said.
Today's need is different. Caregivers need to be prepared and knowledgeable in bioterrorism in order to treat patients in the best manner possible.
Knowledge Is Power In the event of a bioterrorist attack, every second counts, especially when caregivers are trying to determine whether, in fact, a patient has symptoms of a bioterrorist agent. If health care professionals are keen enough to know what symptoms to look for, the impact of a potentially deadly bioterrorist attack can be lessened.
"RTs and nurses are the front line in an attack," Johnson said. If they have a suspicion and knowledge of which tests to run, the treatment can begin. "RTs and Nurses can help in the epidemiological standpoint and help blunt the attack," Johnson said. The key is to be alert in the event a bioterrorist attack happens. "Therapists need to be aware of which drugs to administer by IV and when to begin intubation," he said.
Early detection of an agent allows health care professionals more time to treat the patient and yield a cured patient. "RTs and Nurses need to be very quick thinking and detect early. Also, RTs and Nurses should have strong airway control skills and be very familiar with oxygenation ventilation issues with biological warfare," he said.
The goal is not to make experts of everyone; it's to heighten awareness. "RTs and Nurses can be under-recognized and underutilized, and we have to not only improve our skills but get those skills recognized, maybe within our licensure laws so if we have another disaster, natural or man-made, we can adequately respond as part of the health care team," Johnson said.
As Americans watched the events surrounding 9/11 unfold on national television, their gasps and sobs could be heard around the country. Little did they know it was just the beginning, a foreshadowing to the anthrax scare.
"Never before has the U.S. become so acutely aware of biological, chemical and radiological threats," said Frank Rando, MS, Ph, CRT, CVT, EMT-P, a certified hazardous materials specialist. Rando is a special adviser on counter-terrorism and public health preparedness and respiratory causality management.
"Respiratory therapists have never received detailed instruction or reading materials on how to handle these types of casualties," said Rando, who became a part of counter-terrorism because he felt RTs and Nurses need to become more aware and oriented about how to medically manage biological, chemical and radiological casualties since they are first-line health care providers. There is a one in 10 chance, he explained, there would be casualties with some degree of respiratory impairment.
Crisis Plans One of the things that would help galvanize hospital staff is to have them prepare response plans and enforce them. Response plans are one key step in advancing a response system to alert staff members and operationalize a plan.
Patrick Libbey, director of Thurston County Public Health and Social Service Department, Olympia, Wash., and the president of the National Association of County and City Health Officials, recognizes the importance of crisis management plans in the event of natural or terrorism events.
"When you have an earthquake or a flood, you have a very set geographic and time-specific event to respond to. Bioterrorism may roll out very differently," he said.
As a result of national campaigns, numerous agencies are creating more concise and structured plans to augment earlier models. Other agencies are creating disaster plans for the first time. All emergency agencies need to be alerted in the event of a disaster. If a hospital activates as a result of an existing condition, it acts in conjunction with the emergency management agency of that jurisdiction, Libbey explained.
Emergency response systems must work cohesively with each other, he added. "If any of the systems are acting independently, that is where the troubles are. They need to work together to make the earliest and most complete intervention," he said.
Crisis drills help prepare individuals involved to have at least a vague idea of what to expect when something does happen. "The more you can think through a scenario, the needs for accessing resources, and who needs to be involved, the better prepared you will be when a situation does occur," Libbey said.
September 11 was a wake up call, not only to public safety and law enforcement officers but to the health care establishment as well because the country discovered how vulnerable it is to terrorist attacks and how devastating terrorist attacks can be.
We have become more acutely aware of bioterrorism because of the anthrax mailings, subsequent to the 9/11 attacks. The events of September and beyond have lead health care facilities to revamp and reevaluate their existing disaster response capabilities. Everyone has become leery of planes passing overhead and suspicious looking letters in the mailbox.
"The tricky piece is that many biologic agents can be used, and the initial presenting symptoms are very parallel to other on-going ailments," Johnson said. One of the keys is spotting unusual signs, "to notice if there is something specific in the presenting characteristics of the individual."
Secondly, health care personnel should notice if there is something unusual going on within the community. If there are some out of the ordinary occurring, that merits broader attention, Libbey said. When treating any patient today, clinicians need to be more aware of things they have not thought of before.
"I think it's prudent that RTs and Nurses have a knowledge of this," Johnson said. "We don't all have to be experts in neonatal or geriatrics; we just need to know something about bioterrorism."
Top Five Issues for RTs and Nurses In Bio-Terrorism Attacks
1. Have some familiarity with the top seven biological weapons: anthrax, smallpox, botulism, tularemia, bubonic/pneumonic plague, viral encephalitis, and Staphylococcus enterotoxin B. Therapists need to remembers terrorists get creative and may not use traditional agents.
2. Early warning: The therapist is a part of the early warning system of an attack.
3. Necessary Lab Tests: This will help determine which agent was used and what antibiotic will help treat it.
4. Personal protection: Health care professionals need to protect themselves and their facility. There are bioagents which require only standard precautions.
5. Therapeutic Interventions: This may include oxygen and ventilation as necessary, especially with a botulism attack.
Q fever, is not the most deadly agent to be used as a biological weapon, but it could be one of the most effective because of its ability to spread easily through the air and cause widespread debilitating illness, according to a report in the April 20 issue of Bioterror Medical Alert.
Q fever typically occurs when the bacteria is passed from farm animals to humans and can cause flu-like symptoms, in many cases followed by pneumonia and hepatitis. In some cases, infection leads to a particularly hard-to-treat form of endocarditis.
Public health officials worry about the use of Q fever by bioterrorists because it is already known to have been put into a weapon form by Russia and possibly by Iraq. No licensed vaccine exists, although the U.S. army is working rapidly to develop one.
FAQs regarding Anthrax
What is anthrax?
Anthrax is an infectious disease caused by a spore-forming bacterium called Bacillus anthracis. Anthrax is most often seen in hoofed mammals, but may also infect humans.
Are there different types of anthrax?
Three different types of anthrax infections that can occur in humans. These are: inhalation (breathing in spores), cutaneous (deposit of spores into skin that has cuts or abrasions) and intestinal (deposit of spores in intestinal tract due to the eating of contaminated meat)
How often is anthrax disease observed in the U.S?
Anthrax is primarily an occupational disease. It is occasionally identified in individuals exposed to dead animals and animal products or individuals who handle the hides of animals (e.g. farmers) and has been called “wool sorter’s disease.”
In the United States, the incidence of anthrax is extremely low. In the U.S. between 1944-1994, 224 cases of cutaneous anthrax were reported. Until this more recent exposure in Florida, no cases of inhalation anthrax were reported in the U.S. since 1978. Gastrointestinal anthrax is uncommonly reported, although outbreaks have occurred in Africa and Asia.
What are the symptoms of anthrax?
The symptoms of anthrax are different depending on how the disease was contracted Symptoms will generally occur within seven days after exposure, however it may take as long as sixty days.
Specific symptoms are as follows:
Inhalation anthrax: initial symptoms may resemble the flu and can include, cough, headache, vomiting, chills and general weakness. This can last from a few hours to a few days. The second stage of the illness may occur directly after the first, or following a short recovery period. The second stage develops with sudden fever, shortness of breath, perspiration and shock.
Cutaneous anthrax: areas of exposed skin, such as arms, hands and face are most frequently affected. Skin infection begins as a raised itchy bump that resembles an insect bite but within 1-2 days develops into a fluid filled bump and then a painless ulcer, usually 1-3 cm in diameter, with a characteristic black necrotic (dying) area in the center.
Gastrointestinal anthrax: Initial signs of the disease include nausea, loss of appetite, vomiting, fever are followed by abdominal pain, vomiting of blood, and severe diarrhea
How is anthrax diagnosed?
For people who have been exposed to anthrax, laboratory testing must be conducted to perform an accurate diagnosis.
These lab tests may include:
Examination of tissue under a microscope
Cultures of a person’s blood or spinal fluid (must be done before antibiotics are given)
Cultures of tissue or fluid from an affected area
The polymerase chain reaction (PCR) test can increase small amounts of anthrax DNA to show that the anthrax bacteria are present.
Nasal swabs can be used to detect anthrax spores that may be resting in the nose. Swabs may document exposure, but cannot rule it out, even if they are negative. Nasal swabs are useful to provide clues regarding exposure for investigative purposes, but are not a definitive measure.
How is anthrax spread?
The inhalation form of anthrax is contracted by breathing in spores. The cutaneous form is spread by contact of spores with a break in the skin, such as a scratch. The intestinal form is by eating contaminated meat.
Person to person transmission of anthrax is extremely rare and has only been reported with cutaneous anthrax. Spread of the disease is not a concern in managing or visiting patients with inhalation anthrax.
What is the treatment for anthrax?
The Food and Drug Administration has approved three antibiotics to treat or prevent the development of anthrax in exposed individuals: These are: penicillin, doxycycline, and cirprofloxacin.
Most naturally occurring strains of anthrax are sensitive to these antibiotics. Early antibiotic treatment of anthrax is essential as delay reduces the chances for survival.
Persons will exposure or contact with an environment known or suspected to be contaminated with anthrax should be considered for antibiotic treatment. Exposure or contact, not lab test results, should be the deciding factor for beginning treatment.
I don't have any reason to believe I've been exposed to anthrax but I'm still worried. Should I get tested?
No. People without symptoms are given antibiotics preventively only if they were in the area where anthrax was present. Nasal swabs can show that someone was exposed, but a negative swab does not mean someone was not exposed. These tests are given mostly to help authorities determine a pattern of exposure, not to diagnose individuals.
Should I get antibiotics from my doctor in case of an attack?
No, this is not a good idea. Taking antibiotics because you are afraid of an attack can cause more harm that good. It may lead to antibiotic resistance of other bacteria. People who take antibiotics when they are not needed may develop a resistance to the drugs, which may not be effective when they are needed to treat an actual disease in the future. And these drugs can have serious side effects, such as an irregular heartbeat or digestive problems.
Should I stock up on antibiotics just in case I need them later?
No. Federal officials say there are plenty available, and they plan to stockpile even more. They also are advising doctors against prescribing antibiotics to people who do not need them.
Should I buy a mask to protect myself from anthrax exposure?
It is strongly discouraged to purchase a gas mask for protection against a biological agent. Gas masks are intended for short term use and would only provide protection if worn at the time of a known release. Additionally, gas masks are useless unless properly fit tested. Unless a mask was worn all the time, it would not protect against the covert release of anthrax. Improper use of gas masks can cause serious injury or even death by accidental suffocation. Masks are not effective post exposure.
Can my heating and ventilation system prevent anthrax exposure?
Information on the effectiveness of air cleaning devices is dependent on many factors, including the air flow rate, the proximity of the source, capture efficiency, filtration efficiency, as well as other factors. For more information on HVAC systems please review to the summary of the “Achieving Healthy Indoor Air” Workshop.
The following agencies may be of some help in answering questions on heating, ventilation and air conditioning systems.
ASHRAE-American Society of Heating, Refrigerating and Air Conditioning Engineers
1791 Tullie Circle, N.E.
Atlanta, GA 30329
Phone: (800) 527-4723 (U.S. and Canada only)
Fax: (404) 321-5478
Web Site: www.ashrae.org
NAFA-National Air Filtration Association
1518 K Street, NW, Suite 503
Washington, DC 20005
Web Site: www.nafahq.org/default.htm
View American Lung Association Nationwide Research Awardees for 2001-2002
As you can see from the introduction above, RTs and Nurses play an important role in the defense against bio-terrorism. This continuing education unit will present to you a “consensus report” prepared by included 23 experts from academic medical centers, research organizations, and governmental, military, public health, and emergency management institutions and agencies.
ANTHRAX AS A BIOLOGICAL WEAPON, 2002
Updated Recommendations for Management
Authors/Contributors: Thomas V. Inglesby, MD; Tara O'Toole, MD, MPH; Donald A. Henderson, MD, MPH; John G. Bartlett, MD; Michael S. Ascher, MD; Edward Eitzen, MD, MPH; Arthur M. Friedlander, MD; Julie Gerberding, MD, MPH; Jerome Hauer, MPH; James Hughes, MD; Joseph McDade, PhD; Michael T. Osterholm, PhD, MPH; Gerald Parker, PhD, DVM; Trish M. Perl, MD, MSc; Philip K. Russell, MD; Kevin Tonat, DrPH, MPH; for the Working Group on Civilian Biodefense
Objective To review and update consensus-based recommendations for medical and public health professionals following a Bacillus anthracis attack against a civilian population.
Participants The working group included 23 experts from academic medical centers, research organizations, and governmental, military, public health, and emergency management institutions and agencies.
Evidence MEDLINE databases were searched from January 1966 to January 2002, using the Medical Subject Headings anthrax, Bacillus anthracis, biological weapon, biological terrorism, biological warfare, and biowarfare. Reference review identified work published before 1966. Participants identified unpublished sources.
Consensus Process The first draft synthesized the gathered information. Written comments were incorporated into subsequent drafts. The final statement incorporated all relevant evidence from the search along with consensus recommendations.
Conclusions Specific recommendations include diagnosis of anthrax infection, indications for vaccination, therapy, post-exposure prophylaxis, decontamination of the environment, and suggested research. This revised consensus statement presents new information based on the analysis of the anthrax attacks of 2001, including developments in the investigation of the anthrax attacks of 2001; important symptoms, signs, and laboratory studies; new diagnostic clues that may help future recognition of this disease; current anthrax vaccine information; updated antibiotic therapeutic considerations; and judgments about environmental surveillance and decontamination.
Of the biological agents that may be used as weapons, the Working Group on Civilian Biodefense identified a limited number of organisms that, in worst-case scenarios, could cause disease and deaths in sufficient numbers to gravely impact a city or region. Bacillus anthracis, the bacterium that causes anthrax, is one of the most serious of these.
Several countries are believed to have offensive biological weapons programs, and some independent terrorist groups have suggested their intent to use biological weapons. Because the possibility of a terrorist attack using bioweapons is especially difficult to predict, detect, or prevent, it is among the most feared terrorism scenarios.1 In September 2001, B anthracis spores were sent to several locations via the US Postal Service. Twenty-two confirmed or suspect cases of anthrax infection resulted. Eleven of these were inhalational cases, of whom 5 died; 11 were cutaneous cases (7 confirmed, 4 suspected).2 In this article, these attacks are termed the anthrax attacks of 2001. The consequences of these attacks substantiated many findings and recommendations in the Working Group on Civilian Biodefense's previous consensus statement published in 19993; however, the new information from these attacks warrant updating the previous statement.
Before the anthrax attacks in 2001, modern experience with inhalational anthrax was limited to an epidemic in Sverdlovsk, Russia, in 1979 following an unintentional release of B anthracis spores from a Soviet bioweapons factory and to 18 occupational exposure cases in the United States during the 20th century. Information about the potential impact of a large, covert attack using B anthracis or the possible efficacy of postattack vaccination or therapeutic measures remains limited. Policies and strategies continue to rely partially on interpretation and extrapolation from an incomplete and evolving knowledge base.
The working group comprised 23 representatives from academic medical centers; research organizations; and government, military, public health, and emergency management institutions and agencies. For the original consensus statement,3 we searched MEDLINE databases from January 1966 to April 1998 using Medical Subject Headings of anthrax, Bacillus anthracis, biological weapon, biological terrorism, biological warfare, and biowarfare. Reference review identified work published before 1966. Working group members identified unpublished sources.
The first consensus statement, published in 1999,3 followed a synthesis of the information and revision of 3 drafts. We reviewed anthrax literature again in January 2002, with special attention to articles following the anthrax attacks of 2001. Members commented on a revised document; proposed revisions were incorporated with the working group's support for the final consensus document.
The assessment and recommendations provided herein represent our best professional judgment based on current data and expertise. The conclusions and recommendations need to be regularly reassessed as new information develops.
HISTORY OF CURRENT THREAT
For centuries, B anthracis has caused disease in animals and serious illness in humans.4 Research on anthrax as a biological weapon began more than 80 years ago.5 Most national offensive bioweapons programs were terminated following widespread ratification or signing of the Biological Weapons Convention (BWC) in the early 1970s6; the US offensive bioweapons program was terminated after President Nixon's 1969 and 1970 executive orders. However, some nations continued offensive bioweapons development programs despite ratification of the BWC. In 1995, Iraq acknowledged producing and weaponizing B anthracis to the United Nations Special Commission.7 The former Soviet Union is also known to have had a large B anthracis production program as part of its offensive bioweapons program.8 A recent analysis reports that there is clear evidence of or widespread assertions from nongovernmental sources alleging the existence of offensive biological weapons programs in at least 13 countries.6
The anthrax attacks of 2001 have heightened concern about the feasibility of large-scale aerosol bioweapons attacks by terrorist groups. It has been feared that independent, well-funded groups could obtain a manufactured weapons product or acquire the expertise and resources to produce the materials for an attack. However, some analysts have questioned whether "weapons grade" material such as that used in the 2001 attacks (i.e., powders of B anthracis with characteristics such as high spore concentration, uniform particle size, low electrostatic charge, treated to reduce clumping) could be produced by those not supported by the resources of a nation-state. The US Department of Defense recently reported that 3 defense employees with some technical skills but without expert knowledge of bioweapons manufactured a simulant of B anthracis in less than a month for $1 million.9 It is reported that Aum Shinrikyo, the cult responsible for the 1995 release of sarin nerve gas in a Tokyo subway station,10 dispersed aerosols of anthrax and botulism throughout Tokyo at least 8 times.11 Forensic analysis of the B anthracis strain used in these attacks revealed that this isolate most closely matched the Sterne 34F2 strain, which is used for animal vaccination programs and is not a significant risk to humans.12 It is probable that the cult attacks produced no illnesses for this and other technical reasons. Al Quaeda also has sought to acquire bioweapons in its terrorist planning efforts although the extent to which they have been successful is not reported.13
In the anthrax attacks of 2001, B anthracis spores were sent in at least 5 letters to Florida, New York City, and Washington, DC. Twenty-two confirmed or suspected cases resulted. All of the identified letters were mailed from Trenton, NJ. The B anthracis spores in all the letters were identified as the Ames strain. The specific source (provenance) of B anthracis cultures used to create the spore-containing powder remains unknown at time of this publication.
It is now recognized that the original Ames strain of B anthracis did not come from a laboratory in Ames, Iowa, rather from a laboratory in College Station, Tex. Several distinct Ames strains have been recognized by investigating scientists, which are being compared with the Ames strain used in the attack. At least 1 of these comparison Ames strains was recovered from a goat that died in Texas in 1997.14
Sen. Daschle's letter reportedly had 2 g of B anthraciscontaining powder; the quantity in the other envelopes has not been disclosed. The powder has been reported to contain between 100 billion to 1 trillion spores per gram15 although no official analysis of the concentration of spores or the chemical composition of the powder has been published.
The anthrax attacks of 2001 used 1 of many possible methods of attack. The use of aerosol-delivery technologies inside buildings or over large outdoor areas is another method of attack that has been studied. In 1970, the World Health Organization16 and in 1993 the Office of Technology Assessment17 analyzed the potential scope of larger attacks. The 1979 Sverdlovsk accident provides data on the only known aerosol release of B anthracis spores resulting in an epidemic.18
An aerosol release of B anthracis would be odorless and invisible and would have the potential to travel many kilometers before dissipating.16, 19 Aerosol technologies for large-scale dissemination have been developed and tested by Iraq7 and the former Soviet Union8 Few details of those tests are available. The US military also conducted such trials over the Pacific Ocean in the 1960s. A US study near Johnston Atoll in the South Pacific reported a plane "sprayed a 32-mile long line of agent that traveled for more then 60 miles before it lost its infectiousness."20
In 1970, the World Health Organization estimated that 50 kg of B anthracis released over an urban population of 5 million would sicken 250 000 and kill 100 000.16 A US Congressional Office of Technology assessment analysis from 1993 estimated that between 130 000 and 3 million deaths would follow the release of 100 kg of B anthracis, a lethality matching that of a hydrogen bomb.17
EPIDEMIOLOGY OF ANTHRAX
Naturally occurring anthrax in humans is a disease acquired from contact with anthrax-infected animals or anthrax-contaminated animal products. The disease most commonly occurs in herbivores, which are infected after ingesting spores from the soil. Large anthrax epizootics in herbivores have been reported.21 A published report states that anthrax killed 1 million sheep in Iran in 194522; this number is supported by an unpublished Iranian governmental document.23 Animal vaccination programs have reduced drastically the animal mortality from the disease.24However, B anthracis spores remain prevalent in soil samples throughout the world and cause anthrax cases among herbivores annually.22, 25, 26
Anthrax infection occurs in humans by 3 major routes: inhalational, cutaneous, and gastrointestinal. Naturally occurring inhalational anthrax is now rare. Eighteen cases of inhalational anthrax were reported in the United States from 1900 to 1976; none were identified or reported thereafter. Most of these cases occurred in special-risk groups, including goat hair mill or wool or tannery workers; 2 of them were laboratory associated.27
Cutaneous anthrax is the most common naturally occurring form, with an estimated 2000 cases reported annually worldwide.26 The disease typically follows exposure to anthrax-infected animals. In the United States, 224 cases of cutaneous anthrax were reported between 1944 and 1994.28 One case was reported in 2000.29 The largest reported epidemic occurred in Zimbabwe between 1979 and 1985, when more than 10 000 human cases of anthrax were reported, nearly all of them cutaneous.30
Although gastrointestinal anthrax is uncommon, outbreaks are continually reported in Africa and Asia26, 31, 32 following ingestion of insufficiently cooked contaminated meat. Two distinct syndromes are oral-pharyngeal and abdominal.31, 33, 34Little information is available about the risks of direct contamination of food or water with B anthracis spores. Experimental efforts to infect primates by direct gastrointestinal instillation of B anthracis spores have not been successful.35 Gastrointestinal infection could occur only after consumption of large numbers of vegetative cells, such as what might be found in raw or undercooked meat from an infected herbivore, but experimental data is lacking.
Inhalational anthrax is expected to account for most serious morbidity and most mortality following the use of B anthracis as an aerosolized biological weapon. Given the absence of naturally occurring cases of inhalational anthrax in the United States since 1976, the occurrence of a single case is now cause for alarm.
B anthracis derives from the Greek word for coal, anthrakis, because of the black skin lesions it causes. B anthracis is an aerobic, gram-positive, spore-forming, nonmotile Bacillus species. The nonflagellated vegetative cell is large (1-8 µm long, 1-1.5 µm wide). Spore size is approximately 1 µm. Spores grow readily on all ordinary laboratory media at 37°C, with a "jointed bamboo-rod" cellular appearance and a unique "curled-hair" colonial appearance. Experienced microbiologists should be able to identify this cellular and colonial morphology; however, few practicing microbiologists outside the veterinary community have seen B anthracis colonies beyond what they may have seen in published material.37B anthracis spores germinate when they enter an environment rich in amino acids, nucleosides, and glucose, such as that found in the blood or tissues of an animal or human host. The rapidly multiplying vegetative B anthracis bacilli, on the contrary, will only form spores after local nutrients are exhausted, such as when anthrax-infected body fluids are exposed to ambient air.22 Vegetative bacteria have poor survival outside of an animal or human host; colony counts decline to being undetectable within 24 hours following inoculation into water.22 This contrasts with the environmentally hardy properties of the B anthracis spore, which can survive for decades in ambient conditions.37
PATHOGENESIS AND CLINICAL MANIFESTATIONS
Inhalational anthrax follows deposition into alveolar spaces of spore-bearing particles in the 1- to 5-µm range.38, 39 Macrophages then ingest the spores, some of which are lysed and destroyed. Surviving spores are transported via lymphatics to mediastinal lymph nodes, where germination occurs after a period of spore dormancy of variable and possibly extended duration.35, 40, 41 The trigger(s) responsible for the transformation of B anthracis spores to vegetative cells is not fully understood.42 In Sverdlovsk, cases occurred from 2 to 43 days after exposure.18 In experimental infection of monkeys, fatal disease occurred up to 58 days40 and 98 days43 after exposure. Viable spores were demonstrated in the mediastinal lymph nodes of 1 monkey 100 days after exposure.44
Once germination occurs, clinical symptoms follow rapidly. Replicating B anthracis bacilli release toxins that lead to hemorrhage, edema, and necrosis.32, 45 In experimental animals, once toxin production has reached a critical threshold, death occurs even if sterility of the bloodstream is achieved with antibiotics.27 Extrapolations from animal data suggest that the human LD50 (i.e., dose sufficient to kill 50% of persons exposed to it) is 2500 to 55 000 inhaled B anthracis spores.46 The LD10 was as low as 100 spores in 1 series of monkeys.43 Recently published extrapolations from primate data suggest that as few as 1 to 3 spores may be sufficient to cause infection.47 The dose of spores that caused infection in any of the 11 patients with inhalational anthrax in 2001 could not be estimated although the 2 cases of fatal inhalational anthrax in New York City and Connecticut provoked speculation that the fatal dose, at least in some individuals, may be quite low.
A number of factors contribute to the pathogenesis of B anthracis, which makes 3 toxins protective antigen, lethal factor, and edema factorthat combine to form 2 toxins: lethal toxin and edema toxin. The protective antigen allows the binding of lethal and edema factors to the affected cell membrane and facilitates their subsequent transport across the cell membrane. Edema toxin impairs neutrophil function in vivo and affects water homeostasis leading to edema, and lethal toxin causes release of tumor necrosis factor and interleukin 1 , factors that are believed to be linked to the sudden death in severe anthrax infection.48 The molecular target of lethal and edema factors within the affected cell is not yet elucidated.49 In addition to these virulence factors, B anthracis has a capsule that prevents phagocytosis. Full virulence requires the presence of both an antiphagocytic capsule and the 3 toxin components.37 An additional factor contributing to B anthracis pathogenesis is the high concentration of bacteria occurring in affected hosts.49
Inhalational anthrax reflects the nature of acquisition of the disease. The term anthrax pneumonia is misleading because typical bronchopneumonia does not occur. Postmortem pathological studies of patients from Sverdlovsk showed that all patients had hemorrhagic thoracic lymphadenitis, hemorrhagic mediastinitis, and pleural effusions. About half had hemorrhagic meningitis. None of these autopsies showed evidence of a bronchoalveolar pneumonic process although 11 of 42 patient autopsies had evidence of a focal, hemorrhagic, necrotizing pneumonic lesion analogous to the Ghon complex associated with tuberculosis.50 These findings are consistent with other human case series and experimentally induced inhalational anthrax in animals.40, 51, 52 A recent reanalysis of pathology specimens from 41 of the Sverdlovsk patients was notable primarily for the presence of necrotizing hemorrhagic mediastinitis; pleural effusions averaging 1700 mL in quantity; meningitis in 50%; arteritis and arterial rupture in many; and the lack of prominent pneumonitis. B anthracis was recovered in concentrations of up to 100 million colony-forming units per milliliter in blood and spinal fluid.53
In animal models, physiological sequelae of severe anthrax infection have included hypocalcemia, profound hypoglycemia, hyperkalemia, depression and paralysis of respiratory center, hypotension, anoxia, respiratory alkalosis, and terminal acidosis,54, 55 suggesting that besides the rapid administration of antibiotics, survival might improve with vigilant correction of electrolyte disturbances and acid-based imbalance, glucose infusion, and early mechanical ventilation and vasopressor administration.
Historical Data Early diagnosis of inhalational anthrax is difficult and requires a high index of suspicion. Prior to the 2001 attacks, clinical information was limited to a series of 18 cases reported in the 20th century and the limited data from Sverdlovsk. The clinical presentation of inhalational anthrax had been described as a 2-stage illness. Patients reportedly first developed a spectrum of nonspecific symptoms, including fever, dyspnea, cough, headache, vomiting, chills, weakness, abdominal pain, and chest pain.18, 27 Signs of illness and laboratory studies were nonspecific. This stage of illness lasted from hours to a few days. In some patients, a brief period of apparent recovery followed. Other patients progressed directly to the second, fulminant stage of illness.4, 27, 56
This second stage was reported to have developed abruptly, with sudden fever, dyspnea, diaphoresis, and shock. Massive lymphadenopathy and expansion of the mediastinum led to stridor in some cases.57, 58 A chest radiograph most often showed a widened mediastinum consistent with lymphadenopathy.57 Up to half of patients developed hemorrhagic meningitis with concomitant meningismus, delirium, and obtundation. In this second stage, cyanosis and hypotension progressed rapidly; death sometimes occurred within hours.4, 27, 56
In the 20th-century series of US cases, the mortality rate of occupationally acquired inhalational anthrax was 89%, but the majority of these cases occurred before the development of critical care units and, in most cases, before the advent of antibiotics.27 At Sverdlovsk, it had been reported that 68 of the 79 patients with inhalational anthrax died.18 However a separate report from a hospital physician recorded 358 ill with 45 dead; another recorded 48 deaths among 110 patients.59 A recent analysis of available Sverdlovsk data suggests there may have been as many as 250 cases with 100 deaths.60 Sverdlovsk patients who had onset of disease 30 or more days after release of organisms had a higher reported survival rate than those with earlier disease onset. Antibiotics, antianthrax globulin, corticosteroids, mechanical ventilation, and vaccine were used to treat some residents in the affected area after the accident, but how many were given vaccine and antibiotics is unknown, nor is it known which patients received these interventions or when. It is also uncertain if the B anthracis strain (or strains) to which patients was exposed were susceptible to the antibiotics used during the outbreak. However, a community-wide intervention about the 15th day after exposure did appear to diminish the projected attack rate.60 In fatal cases, the interval between onset of symptoms and death averaged 3 days. This is similar to the disease course and case fatality rate in untreated experimental monkeys, which have developed rapidly fatal disease even after a latency as long as 58 days.40
2001 Attacks Data The anthrax attacks of 2001 resulted in 11 cases of inhalational anthrax, 5 of whom died. Several clinical findings from the first 10 patients with inhalational anthrax deserve emphasis.36, 61-66 Malaise and fever were presenting symptoms in all 10 cases. Cough, nausea, and vomiting were also prominent. Drenching sweats, dyspnea, chest pain, and headache were also seen in a majority of patients. Fever and tachycardia were seen in the majority of patients at presentation, as were hypoxemia and elevations in transaminases.
Importantly, all 10 patients had abnormal chest x-ray film results: 7 had mediastinal widening; 7 had infiltrates; and 8 had pleural effusions. Chest computed tomographic (CT) scans showed abnormal results in all 8 patients who had this test: 7 had mediastinal widening; 6, infiltrates; 8, pleural effusions.
Data are insufficient to identify factors associated with survival although early recognition and initiation of treatment and use of more than 1 antibiotic have been suggested as possible factors.61 For the 6 patients for whom such information is known, the median period from presumed time of exposure to the onset of symptoms was 4 days (range, 4-6 days). Patients sought care a median of 3.5 days after symptom onset. All 4 patients exhibiting signs of fulminant illness prior to antibiotic administration died.61 Of note, the incubation period of the 2 fatal cases from New York City and Connecticut is not known.