• 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.

September 11

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.

Public Safety

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.

Physicians Urged to Learn ABCs Of Highly Infectious Q Fever

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
  Phone:(202) 628-5328
  Web Site: www.nafahq.org/default.htm

View American Lung Association Nationwide Research Awardees for 2001-2002

Web sites for additional info:

www.cdc.gov/anthrax

www.fda.gov

http://www.hhs.gov/news/press/2001pres/20011010a.html

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.

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. 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). 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 1999; 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.

Consensus Methods

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.

SECTION A: HISTORY OF CURRENT THREAT

SECTION B: 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. A published report states that anthrax killed 1 million sheep in Iran in 1945; this number is supported by an unpublished Iranian governmental document. Animal vaccination programs have reduced drastically the animal mortality from the disease. However, B anthracis spores remain prevalent in soil samples throughout the world and cause anthrax cases among herbivores annually.

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.

Cutaneous anthrax is the most common naturally occurring form, with an estimated 2000 cases reported annually worldwide. The disease typically follows exposure to anthrax-infected animals. In the United States, 224 cases of cutaneous anthrax were reported between 1944 and 1994. One case was reported in 2000. 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.

Although gastrointestinal anthrax is uncommon, outbreaks are continually reported in Africa and Asia following ingestion of insufficiently cooked contaminated meat. Two distinct syndromes are oral-pharyngeal and abdominal. Little 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. 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.

SECTION C: MICROBIOLOGY

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. B 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. 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. This contrasts with the environmentally hardy properties of the B anthracis spore, which can survive for decades in ambient conditions.

SECTION D: PATHOGENESIS AND CLINICAL MANIFESTATIONS

Inhalational Anthrax

Inhalational anthrax follows deposition into alveolar spaces of spore-bearing particles in the 1- to 5-µm range. 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. The trigger(s) responsible for the transformation of B anthracis spores to vegetative cells is not fully understood. In Sverdlovsk, cases occurred from 2 to 43 days after exposure. In experimental infection of monkeys, fatal disease occurred up to 58 days40 and 98 days 43 after exposure. Viable spores were demonstrated in the mediastinal lymph nodes of 1 monkey 100 days after exposure.

Once germination occurs, clinical symptoms follow rapidly. Replicating B anthracis bacilli release toxins that lead to hemorrhage, edema, and necrosis. In experimental animals, once toxin production has reached a critical threshold, death occurs even if sterility of the bloodstream is achieved with antibiotics. Extrapolations from animal data suggest that the human LD50 (i.e., dose sufficient to kill 50% of persons exposed to it) is 2500 to 55000 inhaled B anthracis spores. The LD10 was as low as 100 spores in 1 series of monkeys. Recently published extrapolations from primate data suggest that as few as 1 to 3 spores may be sufficient to cause infection. 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 factor that 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. The molecular target of lethal and edema factors within the affected cell is not yet elucidated. 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. An additional factor contributing to B anthracis pathogenesis is the high concentration of bacteria occurring in affected hosts.

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. These findings are consistent with other human case series and experimentally induced inhalational anthrax in animals. 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.

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, 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. 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.

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. A chest radiograph most often showed a widened mediastinum consistent with lymphadenopathy. 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.

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. At Sverdlovsk, it had been reported that 68 of the 79 patients with inhalational anthrax died. However a separate report from a hospital physician recorded 358 ill with 45 dead; another recorded 48 deaths among 110 patients. A recent analysis of available Sverdlovsk data suggests there may have been as many as 250 cases with 100 deaths. 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. 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.

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. 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.

The Anthrax threat as posed to the United States in 2001-2 was focused on the use of the mail to deliver these dangerous weapons. According to an article in September of 2002 entitled: Can These Boxes Be Locked Against Terror? By Andrew C. Revkin:

U.S. postal authorities scramble to strengthen security of the mail, they face a daunting realization: the process will take years, it will cost at least a billion dollars and until it is finished the nation is probably even more vulnerable than it was last fall, when anthrax-tainted letters killed five people, sickened at least 17 more and caused widespread disruption and fear.

Engineers are rushing to devise steps to deter bioterrorist mailings, or to speed detection of any such attacks. They are reconsidering almost every step in the chain that moves 200 billion pieces of mail a year - from the design of the 350,000 street-corner mailboxes to the way postage stamps are printed and sold. Meanwhile, though, the postal system stands revealed as a potent tool for terrorism.

"We cannot believe that whoever did this is the only one capable or willing to do this," said Thomas G. Day, the Postal Service's vice president for engineering. The attacks last year served as a blueprint, he said. "Clearly anyone who hadn't thought of it now fully understands it."

In fact, despite their toll, some postal authorities view last year's attacks as a close call, not a true disaster. For one thing, the tainted letters were apparently designed to affect only the mail recipients. Their seams were carefully taped and they were precisely addressed. But as they passed through high-speed machinery, they spewed a trail of spores that infected postal workers and, apparently, people who received other mail moving through the system at the same time.

"If such an incident was repeated on a larger scale, the consequence to the economic health of the entire nation could be truly incalculable," said Patrick R. Donahoe, the Postal Service's senior vice president for operations, in an August letter to the General Accounting Office.

The Postal Service, consulting with several federal agencies, contractors, scientists, and the Royal Mail and other postal agencies overseas, is proceeding with the first stages of a long-term plan to secure its sprawling system, in which almost every collection box is an unguarded portal.

Private corporations and government agencies that are potential targets or that handle floods of mail, among them Pitney Bowes and the Internal Revenue Service, are also conducting their own searches for ways to defuse biological threats without impeding their work. The only mail being routinely irradiated with bacteria-killing electron beams or X-rays is that bound for government agencies in Washington, leaving other offices, like the many addresses for paying tax bills, unsecured.

The mail network - linking every address in America in a chain of boxes, trucks, letter sorters, 750,000 letter carriers and other postal workers - will never be immune to terror, postal officials and experts say. But a number of steps could reduce the threat.

Some efforts focus on reducing the volume of anonymous mail, which now constitutes about 17 percent of the daily flow of some 680 million items.

For example, the Postal Service plans eventually to change most stamps from uniform bits of sticky paper to personalized, encrypted records that would provide the postal equivalent of caller ID. This would make it harder for someone to send a malicious letter anonymously.

Letters, either the postage itself or a return address label, would be imprinted with a box containing a dense checkered pattern that encodes far more information than a conventional bar code, according to the postal security plan.

Such postage is already being sold over the Internet by companies like Stamps.com to consumers seeking convenience. But the Postal Service and private mail companies are considering a vast expansion of this technology, even offering it door to door.

Letter carriers may eventually wield hand-held printers - somewhat like those used by workers checking in rental cars - that can spit out personalized postage for each outgoing letter.

Any concerns about reduced privacy would most likely be outweighed, officials and experts said, by the knowledge that such mail would be in the fast lane - in the same way that proposed special identification cards for frequent travelers might someday allow them to pass airport checkpoints.

Besides serving as a deterrent, the data-containing postage - read by sorting machinery all along a letter's path - would allow investigators of an attack to more easily trace an envelope back to its point of origin or sender.

The investigation of last fall's attacks remains hampered by a lack of any data trail pointing to a perpetrator.

In fact, the only recent lead in the 11-month-old investigation is a chance trace of anthrax found on a single mailbox in Princeton, N.J., after swabs were done of more than 600 collection boxes in the central part of the state, where all the tainted letters are thought by investigators to have originated.

The tainted box was removed from a street corner and now sits in a sealed enclosure at the Army's Edgewood center, undergoing more analysis to see if its anthrax strain matches the deadly Ames variant used in the attacks, investigators said. In another effort to reduce the amount of potentially suspicious mail, the Postal Service is also working on certifying as secure the operations of the dominant users of its system: commercial mailing houses sending electric bills, fashion catalogs and the like.

With adequate security and screening of employees, such mail could be deemed "safe," postal officials say, cutting the volume of mail bound for biohazard detection systems or subject to irradiation.

The number of blue mailboxes is likely to be reduced, and those that remain may eventually be monitored by video cameras and have replaceable plastic liners that will prevent any contamination from spreading.

Other efforts focus on detecting the presence of pathogens in the mail.

At two mail-sorting hubs in Virginia, postal engineers and the National Institute for Occupational Safety and Health say they successfully tested new systems that check the dust that arises from sorting machinery as the mail moves through it. The checks, performed hourly using a process called polymerase chain reaction, would bathe dust samples in enzymes that cause DNA to explosively replicate, allowing quick comparisons to a library of known DNA sequences from anthrax, bubonic plague or other pathogens.

In theory, if DNA from one of the threats were present in the dust, the system would detect it and contaminated mail could be stopped before the first trucks rolled.

Detection systems are important, postal experts say, because even a single contaminated envelope can spread pathogens widely. This potential was vividly demonstrated in recent tests run on postal machinery assembled at the Edgewood Chemical Biological Center, the Army's main research center for testing chemical and biological defenses, in Aberdeen, Md.

Video cameras recorded close-up images as test envelopes containing spores of a harmless anthrax cousin moved through the machinery. "It's amazing how much comes out even when the corners on the envelope are taped shut," Mr. Day said.

The Postal Service is planning to award $200 million in contracts this fall to install the detection systems.

Meanwhile, companies like Lockheed Martin are developing more sophisticated detection systems for vulnerable agencies and businesses. These would set off extra biochemical tests if they detected particularly minute particles with the signature of bacterial spores.

In a separate effort to prevent spores from dispersing, the service also plans to spend an estimated $245 million on large networks of exhaust vents and vacuums that will draw dust out of the sorting machines and trap any particles in filters.

Until last fall's attacks, workers cleaned the machines by blowing compressed air through them, a process that is believed to have spread any anthrax that escaped from tainted letters.

It will take months to install the new equipment at all of the postal system's 282 hangarlike sorting centers.

Two sorting centers that handled the tainted mail, the Brentwood facility that serves Washington and one in Hamilton Township, N.J., where all the tainted letters apparently originated, remain sealed, awaiting cleansing with the same chlorine dioxide gas used to kill any lingering anthrax in the Hart Senate Office Building. That is where the anthrax mailings first came to light after the letter to Senator Tom Daschle, the Democratic majority leader from South Dakota, was opened in a cloud of powder on Oct. 15.

Other post offices and transfer points where trace contamination was seen, from Florida to Connecticut, were cleaned last fall and remain open.

It remains to be seen, however, whether the new security and safety measures will work the way engineers hope they will. Yesterday, for example, the General Accounting Office, the investigating arm of Congress, strongly recommended more testing and analysis before the Postal Service begins installing the vacuum exhaust systems. One concern, the G.A.O. analysts said, is that the vacuums could disrupt the separate effort to sample air and test for biological hazards. Another is the cost of running them and providing enormous amounts of electricity.

On Friday, a new federal task force under the White House Office of Homeland Security and drawn from eight agencies will hold the first of several meetings to assess the DNA detection method that postal officials prefer.

Dr. Lawrence D. Kerr, the director of bioterrorism research and development in the Office of Homeland Security, said it would be a mistake to invest heavily in a new system, only to find out that it was still porous.

"The Postal Service has been in an almost yearlong 24-hour, 7-days-a-week process of searching for the ideal system to implement nationwide," he said. "But as we look to this technology, we still need to make sure it passes rigorous scientific review."

The prospect of further delays is frustrating to postal officials and workers alike. Employees from Brentwood and Hamilton, still traumatized by the deaths and illnesses of co-workers, say they are worried that the pace of adopting new protections will be too slow to save them from the side effects of another assault.

Mr. Day, the Postal Service official, said he was confident that the bioterrorism plan would pass muster and that the American public would be willing to invest in improvements that would make the postal system safer for employees and mail recipients.

"We're convinced that the technical fix we have coming forward will reduce the threat," he said. "If you're going to send a biohazard through the mail, we're going to detect it very quickly, get it isolated and contained and, if necessary, get people medicated."

In the end, however, the last line of defense will simply be mail handlers and recipients on the alert for suspicious envelopes or contents, and health workers alert to symptoms of exposure to biological or chemical weapons.

Dr. Clifton R. Lacy, the New Jersey health and senior services commissioner, whose state remains a focal point in the anthrax investigation, said he was confident that from this perspective at least the response to any new assault would be far more effective.

"It's like what happens to the human body when it's exposed to a foreign substance a virus, the flu, whatever," he said. "With the second exposure, the response is quicker, more coordinated and more decisive."

"Health care providers and the public have undergone quite an education," he said. "We're ready."

Cutaneous Anthrax

Historically, cutaneous anthrax has been known to occur following the deposition of the organism into skin; previous cuts or abrasions made one especially susceptible to infection.30, 67 Areas of exposed skin, such as arms, hands, face, and neck, were the most frequently affected. In Sverdlovsk, cutaneous cases occurred only as late as 12 days after the original aerosol release; no reports of cutaneous cases appeared after prolonged latency.

After the spore germinates in skin tissues, toxin production results in local edema. An initially pruritic macule or papule enlarges into a round ulcer by the second day. Subsequently, 1- to 3-mm vesicles may appear that discharge clear or serosanguinous fluid containing numerous organisms on Gram stain. Development of a painless, depressed, black eschar follows, often associated with extensive local edema. The anthrax eschar dries, loosens, and falls off in the next 1 to 2 weeks. Lymphangitis and painful lymphadenopathy can occur with associated systemic symptoms. Differential diagnosis of eschars includes tularemia, scrub typhus, rickettsial spotted fevers, rat bite fever, and ecthyma gangrenosum. Noninfectious causes of eschars include arachnid bites and vasculitides. Although antibiotic therapy does not appear to change the course of eschar formation and healing, it does decrease the likelihood of systemic disease. Without antibiotic therapy, the mortality rate has been reported to be as high as 20%; with appropriate antibiotic treatment, death due to cutaneous anthrax has been reported to be rare.

Following the anthrax attacks of 2001, there have been 11 confirmed or probable cases of cutaneous anthrax. One case report of cutaneous anthrax resulting from these attacks has been published. This child had no reported evidence of prior visible cuts, abrasions, or lesions at the site of the cutaneous lesion that developed. The mean incubation period for cutaneous anthrax cases diagnosed in 2001 was 5 days, with a range of 1 to 10 days, based on estimated dates of exposure to B anthracis–contaminated letters. Cutaneous lesions occurred on the forearm, neck, chest, and fingers.

The only published case report of cutaneous anthrax from the attacks of 2001 is notable for the difficulty in recognition of the disease in a previously healthy 7-month-old, the rapid progression to severe systemic illness despite hospitalization, and clinical manifestations that included microangiopathic hemolytic anemia with renal involvement, coagulopathy, and hyponatremia. Fortunately, this child recovered, and none of the cutaneous cases of anthrax diagnosed after the 2001 attacks were fatal.

Gastrointestinal Anthrax

Some think gastrointestinal anthrax occurs after deposition and germination of spores in the upper or lower gastrointestinal tract. However, considering the rapid transit time in the gastrointestinal tract, it seems more likely that many such cases must result from the ingestion of large numbers of vegetative bacilli from poorly cooked infected meat rather than from spores. In any event, the oral-pharyngeal form of disease results in an oral or esophageal ulcer and leads to the development of regional lymphadenopathy, edema, and sepsis. Disease in the lower gastrointestinal tract manifests as primary intestinal lesions occurring predominantly in the terminal ileum or cecum, presenting initially with nausea, vomiting, and malaise and progressing rapidly to bloody diarrhea, acute abdomen, or sepsis. Massive ascites has occurred in some cases of gastrointestinal anthrax. Advanced infection may appear similar to the sepsis syndrome occurring in either inhalational or cutaneous anthrax. Some authors suggest that aggressive medical intervention as would be recommended for inhalational anthrax may reduce mortality. Given the difficulty of early diagnosis of gastrointestinal anthrax, however, mortality may be high. Postmortem examinations in Sverdlovsk showed gastrointestinal submucosal lesions in 39 of 42 patients, but all of these patients were also found to have definitive pathologic evidence of an inhalational source of infection. There were no gastrointestinal cases of anthrax diagnosed in either the Sverdlovsk series or following the anthrax attacks of 2001.

SECTION E: DIAGNOSIS

Given the rarity of anthrax infection, the first clinical or laboratory suspicion of an anthrax illness must lead to early initiation of antibiotic treatment pending confirmed diagnosis and should provoke immediate notification of the local or state public health department, local hospital epidemiologist, and local or state public health laboratory. In the United States, a Laboratory Response Network (LRN) has been established through a collaboration of the Association of Public Health Laboratories and the CDC (details are available at: www.bt.cdc.gov/LabIssues/index.asp. Currently 81 clinical laboratories in the LRN can diagnose bioweapons pathogens. Several preliminary diagnostic tests for B anthracis can be performed in hospital laboratories using routine procedures. B anthracis is a gram-positive, nonhemolytic, encapsulated, penicillin-sensitive, spore-forming bacillus. Confirmatory tests such as immuno-histochemical staining, gamma phage, and polymerase chain reaction assays must still be performed by special reference laboratories in the LRN.

The determination of individual patient exposure to B anthracis on the basis of environmental testing is complex due to the uncertain specificity and sensitivity of rapid field tests and the difficulty of assessing individual risks of exposure. A patient (or patients) seeking medical treatment for symptoms of inhalational anthrax will likely be the first evidence of a clandestine release of B anthracis as a biological weapon. The appearance of even a single previously healthy patient who becomes acutely ill with nonspecific febrile illness and symptoms and signs consistent with those described here and whose condition rapidly deteriorates should receive prompt consideration for a diagnosis of anthrax infection. The recognition of cutaneous cases of anthrax may also be the first evidence of an anthrax attack.

The likely presence of abnormal findings on either chest x-ray film or chest CT scan is diagnostically important. Although anthrax does not cause a classic bronchopneumonia pathologically, it can cause widened mediastinum, massive pleural effusions, air bronchograms, necrotizing pneumonic lesions, and/or consolidation, as has been noted above. The result can be hypoxemia and chest imaging abnormalities that may or may not be clinically distinguishable from pneumonia. In the anthrax attacks of 2001, each of the first 10 patients had abnormal chest x-ray film results and each of 8 patients for whom CT scans were obtained had abnormal results. These included widened mediastinum on chest radiograph and effusions on chest CT scan. Such findings in a previously healthy patient with evidence of overwhelming febrile illness or sepsis would be highly suggestive of advanced inhalational anthrax.

The bacterial burden may be so great in advanced inhalational anthrax infection that bacilli are visible on Gram stain of peripheral blood, as was seen following the 2001 attacks. The most useful microbiologic test is the standard blood culture, which should show growth in 6 to 24 hours. Each of the 8 patients who had blood cultures obtained prior to initiation of antibiotics had positive blood cultures. However, blood cultures appear to be sterilized after even 1 or 2 doses of antibiotics, underscoring the importance of obtaining cultures prior to initiation of antibiotic therapy (J. Gerberding, oral communication, March 7, 2002). If the laboratory has been alerted to the possibility of anthrax, biochemical testing and review of colonial morphology could provide a preliminary diagnosis 12 to 24 hours after inoculation of the cultures. Definitive diagnosis could be promptly confirmed by an LRN laboratory. However, if the clinical laboratory has not been alerted to the possibility of anthrax, B anthracis may not be correctly identified. Routine procedures customarily identify a Bacillus species in a blood culture approximately 24 hours after growth, but some laboratories do not further identify Bacillus species unless specifically requested. This is because the isolation of Bacillus species most often represents growth of the common contaminant Bacillus cereus. Given the possibility of future anthrax attacks, it is recommended that routine clinical laboratory procedures be modified, so B anthracis is specifically excluded after identification of a Bacillus species bacteremia unless there are compelling reasons not to do so. If it cannot be excluded then the isolate should be transferred to an LRN laboratory.

Sputum culture and Gram stain are unlikely to be diagnostic of inhalational anthrax, given the frequent lack of a pneumonic process. Gram stain of sputum was reported positive in only 1 case of inhalational anthrax in the 2001 series. If cutaneous anthrax is suspected, a Gram stain and culture of vesicular fluid should be obtained. If the Gram stain is negative or the patient is taking antibiotics already, punch biopsy should be performed, and specimens sent to a laboratory with the ability to perform immunohistochemical staining or polymerase chain reaction assays. Blood cultures should be obtained and antibiotics should be initiated pending confirmation of the diagnosis of inhalational or cutaneous anthrax.

Nasal swabs were obtained in some persons believed to be at risk of inhalational anthrax following the anthrax attacks of 2001. Although a study has shown the presence of B anthracis spores in nares of some monkeys following experimental exposure to B anthracis spores for some time after exposure, the predictive value of the nasal swab test for diagnosing inhalational anthrax in humans is unknown and untested. It is not known how quickly antibiotics make spore recovery on nasal swab tests impossible. One patient who died from inhalational anthrax had a negative nasal swab. Thus, the CDC advised in the fall of 2001 that the nasal swab should not be used as a clinical diagnostic test. If obtained for an epidemiological purpose, nasal swab results should not be used to rule out infection in a patient. Persons who have positive nasal swab results for B anthracis should receive a course of postexposure antibiotic prophylaxis since a positive swab would indicate that the individual had been exposed to aerosolized B anthracis.

Antibodies to the protective antigen (PA) of B anthracis, termed anti-PA IgG, have been shown to confer immunity in animal models following anthrax vaccination. Anti-PA IgG serologies have been obtained from several of those involved in the 2001 anthrax attacks, but the results of these assays are not yet published. Given the lack of data in humans and the expected period required to develop an anti-PA IgG response, this test should not be used as a diagnostic test for anthrax infection in the acutely ill patient but may be useful for epidemiologic purposes.

Postmortem findings are especially important following an unexplained death. Thoracic hemorrhagic necrotizing lymphadenitis and hemorrhagic necrotizing mediastinitis in a previously healthy adult are essentially pathognomonic of inhalational anthrax. Hemorrhagic meningitis should also raise strong suspicion of anthrax infection. However, given the rarity of anthrax, a pathologist might not identify these findings as caused by anthrax unless previously alerted to this possibility.

If only a few patients present contemporaneously, the clinical similarity of early inhalational anthrax infection to other acute febrile respiratory infections may delay initial diagnosis although probably not for long. The severity of the illness and its rapid progression, coupled with unusual radiological findings, possible identification of B anthracis in blood or cerebrospinal fluid, and the unique pathologic findings should serve as an early alarm. The index case of inhalational anthrax in the 2001 attacks was identified because of an alert clinician who suspected the disease on the basis of large gram-positive bacilli in cerebrospinal fluid in a patient with a compatible clinical illness, and as a result of the subsequent analysis by laboratory staff who had recently undergone bioterrorism preparedness training.

SECTION F: VACCINATION

The US anthrax vaccine, named anthrax vaccine adsorbed (AVA), is an inactivated cell-free product, licensed in 1970, and produced by Bioport Corp, Lansing, Mich. The vaccine is licensed to be given in a 6-dose series. In 1997, it was mandated that all US military active- and reserve-duty personnel receive it. The vaccine is made from the cell-free filtrate of a nonencapsulated attenuated strain of B anthracis. The principal antigen responsible for inducing immunity is the PA. In the rabbit model, the quantity of antibody to PA has been correlated with the level of protection against experimental anthrax infection.

Preexposure vaccination with AVA has been shown to be efficacious against experimental challenge in a number of animal studies. A similar vaccine was shown in a placebo-controlled human trial to be efficacious against cutaneous anthrax. The efficacy of postexposure vaccination with AVA has been studied in monkeys. Among 60 monkeys exposed to 8 LD50 of B anthracis spores at baseline, 9 of 10 control animals died, and 8 of 10 animals treated with vaccine alone died. None of 29 animals died while receiving doxycycline, ciprofloxacin, or penicillin for 30 days; 5 developed anthrax once treatment ceased. The remaining 24 all died when rechallenged. The 9 receiving doxycycline for 30 days plus vaccine at baseline and day 14 after exposure did not die from anthrax infection even after being rechallenged.

The safety of the anthrax vaccine has been the subject of much study. A recent report reviewed the results of surveillance for adverse events in the Department of Defense program of 1998-2000. At the time of that report, 425 976 service members had received 1 620 793 doses of AVA. There were higher rates of local reactions to the vaccine in women than men, but "no patterns of unexpected local or systemic adverse events" were identified. A recent review of safety of AVA anthrax vaccination in employees of the United States Army Medical Research Institute of Infectious Diseases (USAMRIID) over the past 25 years reported that 1583 persons had received 10 722 doses of AVA. One percent of these inoculations (101/10 722) were associated with 1 or more systemic events (defined as headache, malaise, myalgia, fever, nausea, vomiting, dizziness, chills, diarrhea, hives, anorexia, arthralgias, diaphoresis, blurred vision, generalized itching, or sore throat). The most frequently reported systemic adverse event was headache (0.4% of doses). Local or injection site reactions were reported in 3.6%. No long-term sequelae were reported in this series.

The Institute of Medicine (IOM) recently published a report on the safety and efficacy of AVA,84 which concluded that AVA is effective against inhalational anthrax and concluded that if given with appropriate antibiotic therapy, it may help prevent the development of disease after exposure. The IOM committee also concluded that AVA was acceptably safe. Committee recommendations for new research include studies to describe the relationship between immunity and quantitative antibody levels; further studies to test the efficacy of AVA in combination with antibiotics in preventing inhalational anthrax infection; studies of alternative routes and schedules of administration of AVA; and continued monitoring of reported adverse events following vaccination. The committee did not evaluate the production process used by the manufacturer.

A recently published report85 analyzed a cohort of 4092 women at 2 military bases from January 1999 to March 2000. The study compared pregnancy rates and adverse birth outcomes between groups of women who had been vaccinated with women who had not been vaccinated and the study found that anthrax vaccination with AVA had no effect on pregnancy or adverse birth outcomes.

A human live attenuated vaccine has been produced and used in countries of the former Soviet Union. In the Western world, live attenuated vaccines have been considered unsuitable for use in humans because of safety concerns.

Current vaccine supplies are limited, and the US production capacity remains modest. Bioport is the single US manufacturing facility for the licensed anthrax vaccine. Production has only recently resumed after a halt required the company to alter production methods so that it conformed to the US Food and Drug Administration (FDA) Good Manufacturing Practice standard. Bioport has a contract to produce 4.6 million doses of vaccine for the US Department of Defense that cannot be met until at least 2003 (D. A. Henderson, oral communication, February 2002).

The use of AVA was not initiated immediately in persons believed to have been exposed to B anthracis during the 2001 anthrax attacks for a variety of reasons, including the unavailability of vaccine supplies. Subsequently, near the end of the 60-day period of antibiotic prophylaxis, persons deemed by investigating public health authorities to have been at high risk for exposure were offered postexposure AVA series (3 inoculations at 2-week intervals, given on days 1, 14, and 28) as an adjunct to prolonged postexposure antibiotic prophylaxis. This group of affected persons was also offered the alternatives of continuing a prolonged course of antibiotics or of receiving close medical follow-up without vaccination or additional antibiotics. This vaccine is licensed for use in the preexposure setting, but because it had not been licensed for use in the postexposure context, it was given under investigational new drug procedures.

The working group continues to conclude that vaccination of exposed persons following a biological attack in conjunction with antibiotic administration for 60 days following exposure provide optimal protection to those exposed. However, until ample reserve stockpiles of vaccine are available, reliance must be placed on antibiotic administration. To date, there have been no reported cases of anthrax infection among those exposed in the 2001 anthrax attacks who took prophylactic antibiotics, even in those persons not complying with the complete 60-day course of therapy.

Preexposure vaccination of some persons deemed to be in high-risk groups should be considered when substantial supplies of vaccine become available. A fast-track program to develop recombinant anthrax vaccine is now under way. This may lead to more plentiful vaccine stocks as well as a product that requires fewer inoculations. Studies to evaluate intramuscular vs. subcutaneous routes of administration and less frequent dosing of AVA are also under way. (J. Hughes, oral communication, February 2002.)

SECTION G: THERAPY

Recommendations for antibiotic and vaccine use in the setting of an aerosolized B anthracis attack are conditioned by a very small series of cases in humans, a limited number of studies in experimental animals, and the possible necessity of treating large numbers of casualties. A number of possible therapeutic strategies have yet to be explored experimentally or to be submitted for approval to the FDA. For these reasons, the working group offers consensus recommendations based on the best available evidence. The recommendations do not necessarily represent uses currently approved by the FDA or an official position on the part of any of the federal agencies whose scientists participated in these discussions and will need to be revised as further relevant information becomes available.

Given the rapid course of symptomatic inhalational anthrax, early antibiotic administration is essential. A delay of antibiotic treatment for patients with anthrax infection may substantially lessen chances fo