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Inhalational Anthrax^*

Epidemiology, Diagnosis, and Management

^* From the Division of Pulmonary and Critical Care Medicine, Department of Medicine, Stanford University Medical Center, Stanford, CA.

Correspondence to: Thomas A. Raffin, MD, FCCP, Professor and Chief, Division of Pulmonary and Critical Care Medicine, Stanford University Medical Center, H-3151, Stanford, CA 94305-5236; tar@leland.stanford.edu

	Abstract

TOP Abstract Introduction Historical Background Epidemiology Microbiology Pathogenesis Clinical Manifestations Inhalational Anthrax Diagnosis and Treatment Prevention Conclusion References

 
Anthrax, a disease of great historical interest, is once again making headlines as an agent of biological warfare. Bacillus anthracis, a rod-shaped, spore-forming bacterium, primarily infects herbivores. Humans can acquire anthrax by agricultural or industrial exposure to infected animals or animal products. More recently, the potential for intentional release of anthrax spores in the environment has caused much concern. The common clinical manifestations of anthrax are cutaneous disease, pulmonary disease from inhalation of anthrax spores, and GI disease. The course of inhalational anthrax is dramatic, from the insidious onset of nonspecific influenza-like symptoms to severe dyspnea, hypotension, and hemorrhage within days of exposure. A rapid decline, culminating in septic shock, respiratory distress, and death within 24 h is not uncommon. The high mortality seen in inhalational anthrax is in part due to delays in diagnosis. Classic findings on the chest radiograph include widening of the mediastinum as well as pleural effusions. Pneumonia is less common; key pathologic manifestations include severe hemorrhagic mediastinitis, diffuse hemorrhagic lymphadenitis, and edema. Diagnosis requires a high index of suspicion. Treatment involves supportive care in an intensive care facility and high doses of penicillin. Resistance to third-generation cephalosporins has been noted. Vaccines are currently available and have been shown to be effective against aerosolized exposure in animal studies.

Key Words: anthrax • Bacillus species • inhalational anthrax • mediastinal hemorrhage • mediastinal widening

	Introduction

TOP Abstract Introduction Historical Background Epidemiology Microbiology Pathogenesis Clinical Manifestations Inhalational Anthrax Diagnosis and Treatment Prevention Conclusion References

 
Anthrax, a disease of extraordinary historical interest, has revisited the modern world, making headlines as a potential biological warfare agent. In 1941, the British conducted limited experiments by releasing spores of anthrax on Gruinard Island near Scotland. Viable anthrax spores persisted until the island was decontaminated with formaldehyde and seawater in 1986.^{1 2} The United States (US) experimented with biological weapons including anthrax spores in the 1950s and 1960s until President Nixon terminated the program in 1970. Other countries have been suspected of conducting research on anthrax use. Before the Persian Gulf War, US coalition forces trained extensively for biological warfare because they were suspicious of the Iraqi arsenal of biological weapons. A total of 150,000 US troops were vaccinated with anthrax toxoid. In 1991, Iraq admitted to the United Nations inspection team that it had conducted research on the offensive use of anthrax.³

Later, when matters had become grave, the horse’s eyes glittered and his breathing was labored and groaning, with occasional convulsive sobs drawn up from deep in his flanks. A dark bloody discharge appeared at the nostrils, and the tongue swelled as to obstruct the throat...

Virgil, Third Georgic

In North America, there have recently been several "anthrax scares" with anonymous phone calls or letters threatening to release anthrax in the local environment. All have turned out to be hoaxes. In the current state of world unrest, inhalational anthrax remains a potential agent of mass destruction and a viable terrorist threat. According to a World Health Organization report published in 1970, it is estimated that 50 kilograms of aerosolized Bacillus anthracis spores, if dispersed by an airplane two kilometers (km) upwind of a population center of 500,000 unprotected people in ideal meteorologic conditions, would travel > 20 km and kill 95,000 people.⁴ An analysis performed by the Centers for Disease Control and Prevention (CDC) estimated the economic impact of a bioterrorist attack to be $26 billion per 100,000 persons exposed to anthrax.⁵

This report focuses on inhalational anthrax, a rare disease with great potential for human suffering. Following a brief historical background review, we will discuss the epidemiology, microbiology, clinical presentation, and pathophysiology of anthrax in general, with special attention to the recognition and management of inhalational anthrax. We will conclude with a discussion on treatment and prevention of inhalational anthrax.

	Historical Background

TOP Abstract Introduction Historical Background Epidemiology Microbiology Pathogenesis Clinical Manifestations Inhalational Anthrax Diagnosis and Treatment Prevention Conclusion References

 
Early descriptions of anthrax date to 3,500 years ago; anthrax may have been responsible for two of the plagues that afflicted Egypt in 1491 BC. The Greek poet and scientist Virgil gave a richly detailed account of this disease, "the murrain of Noricum," in his third Georgic: "If anyone wore a garment made from the tainted wool, his limb was soon attacked by inflamed papules and a foul exudate, and if he delayed too long to remove the material a violent inflammation covered the parts it had touched."⁶ In 1877, Koch reported growing the anthrax bacillus in vitro and inducing the disease in healthy animals by inoculating them with pure cultures of the bacillus; thus, the model for Koch’s famous postulates was born.⁷ Around the same time, John Bell recognized woolsorter’s disease, or inhalational anthrax; and by setting standards for wool disinfection, he was able to reduce the incidence of this disease in England.⁸ William Greenfield and Louis Pasteur were pioneers in anthrax vaccination with their use of a live heat- cured anthrax vaccine in livestock.⁷

	Epidemiology

TOP Abstract Introduction Historical Background Epidemiology Microbiology Pathogenesis Clinical Manifestations Inhalational Anthrax Diagnosis and Treatment Prevention Conclusion References

 
The distribution of B anthracis is worldwide. All animals are susceptible to varying degrees, but the disease is most prevalent among herbivores (cattle, sheep, horses, and goats). Anthrax in herbivores tends to be severe, with a high mortality rate. Terminally ill animals tend to bleed from the nose, mouth, and bowel, thereby contaminating soil or water places with B anthracis that can subsequently sporulate and persist in the environment. The reasons for local proliferation of anthrax bacilli are still not very well understood.⁹ The results of studies of agricultural outbreaks have suggested that conditions for multiplication are favorable when the soil pH is > 6.0 and rich in organic matter. Major changes in the soil microenvironment, such as drought or rainfall, enhance the sporulation.¹⁰

Aggressive animal vaccination has lowered the incidence of anthrax among livestock. However, it remains problematic in parts of Asia and Africa where vaccination programs are sporadic in some developing countries. In the US, the microorganism remains endemic in the soil of Texas, Oklahoma, and the lower Mississippi valley.¹¹ Most cases in industrialized countries are associated with exposure to animal products, especially goat hair imported from Turkey, Sudan, and Pakistan where anthrax remains common among domestic livestock.⁷

The majority of human cases of anthrax are due to either agricultural or industrial exposure. There have been no reports in the literature of direct human-to- human transmission. Shepherds, farmers, and workers in manufacturing plants using infected animal products, particularly contaminated hide, goat hair, wool, or bone, are at highest risk. In the US in the past 20 years, less than one case of anthrax has been reported per year.^{7 12} Between 1984 and 1993, only three cases of cutaneous anthrax were reported to the CDC.¹² The last fatal case occurred in 1976; when a home craftsman died of inhalational anthrax after working with yarn imported from Pakistan.¹⁰

There are three predominant clinical forms of anthrax. Cutaneous anthrax, constituting > 95% of reported cases, results from entry of spores through skin abrasions. The remaining 5% of cases are due to inhalational or GI disease.^{12 13} GI disease is due to ingestion of contaminated meat; to date, there have been no reports of this form of anthrax in the US.

	Microbiology

TOP Abstract Introduction Historical Background Epidemiology Microbiology Pathogenesis Clinical Manifestations Inhalational Anthrax Diagnosis and Treatment Prevention Conclusion References

 
B anthracis, the etiologic agent responsible for anthrax, is a large (1 to 1.5 µm by 4 to 10 µm), square-ended, nonmotile, aerobic, Gram-positive rod, with a centrally located spore. On Gram’s stain preparations, the spore appears as unstained areas. In vitro, the cells frequently occur in long chains giving them a bamboo appearance. The chains of virulent forms of the bacteria are usually surrounded by a capsule.¹⁴

The microorganism grows well on blood agar plates within 18 to 24 h. The optimal growth temperature for the organism is 35°C (12 to 45°C) in a pH range of 7.0 to 7.4. When grown above 45°C, the bacteria becomes attenuated or avirulent due to loss of the capsule.¹⁵ On culture plates, the colonies of B anthracis are usually large (4 to 5 mm), opaque, and irregular, with characteristic comet tail protusions. Disturbed sections of the colony often stand up like "beaten egg whites."¹⁴ Several biochemical tests aid in differentiating B anthracis from other members of the species (chief among them is Bacillus cereus, which has been associated with outbreaks of human food poisoning). B anthracis is characterized by the absence of hemolysis on sheep blood agar, lack of motility, absence of salicin fermentation, gelatin hydrolysis, and lack of growth on phenylethyl alcohol medium.¹⁵

Oxygen is needed for sporulation but not germination of spores. Spores grow in culture plates, soil, and tissue of dead animals. They do not form in the blood or tissues of infected living animals. Spores are highly resistant to drying, boiling for 10 min, and most disinfectants. A temperature of 120°C for at least 15 min is normally used to inactivate the spores.¹⁶ In the spore form, B anthracis survives for many years in arid and semiarid environments.

	Pathogenesis

TOP Abstract Introduction Historical Background Epidemiology Microbiology Pathogenesis Clinical Manifestations Inhalational Anthrax Diagnosis and Treatment Prevention Conclusion References

 
The principal virulence factors of B anthracis are capsular polypeptide and anthrax toxin. The B anthracis capsule, which consists of poly-D-glutamic acid, is thought to confer resistance to phagocytosis. Anthrax toxin consists of three proteins called protective antigen (PA), edema factor (EF), and lethal factor (LF).¹⁷ The major virulence genes of B anthracis have been cloned.¹⁸ They are found on two large plasmids, pXO1 and pXO2. pXO1, which is 184 kilobases in size, contains the genes that produce anthrax toxin complex and their transcriptional regulators; pXO2 is 97 kilobases in size, featuring the genes responsible for capsule synthesis. The large nature of the plasmids suggests that there are perhaps other pathogenecity genes yet to be identified. The presence of both plasmids is required for virulence.¹⁸

PA, so named for its ability to provide experimental protective immunity against B anthracis, is considered the central component of anthrax toxin. PA is an 83-kd protein that binds to target cell receptors. A small 20-kd N-terminal fragment is proteolytically cleaved from it, thereby allowing the larger cell-bound PA fragment to act as a membrane channel. EF and LF bind to exposed sites on the PA fragment and form edema toxin and lethal toxin. PA then transfers these enzymatic proteins across cell membranes and releases them into the cell cytoplasm where they exert their effects.^{10 12 18}

EF is a calmodulin-dependent adenyl cyclase that converts adenosine triphosphate to cyclic adenosine monophosphate (cAMP). Thus, intracellular levels of cAMP increase and lead to the edema often seen in anthrax.¹⁹ Edema toxin also plays a role in inhibiting both phagocytic and oxidative burst activities of polymorphonuclear leukocytes. Generally, bacterial toxins that are capable of increasing cAMP tend to decrease the immune response of phagocytes, thereby contributing to the development of infection.¹⁸

The action of LF continues to be a matter of study. At high concentrations, LF has been shown to cause lysis of macrophages; at lower concentrations, it may play a role in the increased expressions of tumor necrosis factor (TNF) and interleukin-1 (IL-1).^{12 18} This observation has lead to the interesting theory that IL-1 and/or other proinflammatory mediators are stored within the macrophage early in the course of anthrax infection, when toxin levels are lower than the critical concentration required for lysis. Later, as the infection progresses and the number of bacteria increases, a threshold for lysis is reached and large amounts of preformed mediators are released in the circulation. This rapid release of inflammatory mediators may account for the sudden death seen in anthrax victims.^{12 19} Data supporting the role of IL-1 and TNF were provided by Hanna et al^11,12,18 who reported that antibodies to TNF and IL-1 were protective against a lethal dose of anthrax toxin in mice.

To test the hypothesis that macrophages are important cellular mediators in this disease, mice were depleted of macrophages by a regimen of silica injections. Silica-treated animals became resistant to lethal toxin. There was a 100% survival in the silica- treated group compared to the < 10% survival in the control group. Restoration of lethal toxin sensitivity was achieved by reinjection of cultured macrophages into the experimental group, but not by injection of other cell lines.^{18 20} More recently, the Vande Woude team has found that LF proteolytically cleaves and inactivates an enzyme in one of the key signaling pathways in cells, the mitogen-activated protein kinase pathway, which helps control cell growth, embryonic development, and maturation of oocytes into eggs.²¹ Researchers, however, have not yet shown that this effect contributes to LF toxicity.

	Clinical Manifestations

TOP Abstract Introduction Historical Background Epidemiology Microbiology Pathogenesis Clinical Manifestations Inhalational Anthrax Diagnosis and Treatment Prevention Conclusion References

 
Cutaneous anthrax is initiated when spores of B anthracis are introduced into the skin through cuts or abrasions or by biting flies. The spores germinate within hours, and the vegetative cells multiply and produce anthrax toxin. Macrophages are thought to be central to germination and toxin release. Edema and necrosis ensues with little purulence noted, which is likely due to the inhibitory function of edema toxin on leukocytes.

The signs and symptoms of cutaneous anthrax become apparent within 5 days of exposure, beginning as small, painless, often puritic papules. Within 24 to 48 h, the papules enlarge and become vesicular (usually, 1 to 2 cm in diameter). Edema out of proportion to vesicular size surrounds the lesion. Fever, malaise, and regional adenopathy are often associated features. Gram’s stains of the vesicular fluid may show rare leukocytes and Gram-positive rods. The lesion generally ruptures near the end of the first week; the remaining ulcer progresses to a black eschar responsible for the name of this disease (anthrax is derived from the Greek word for coal, the characteristic color and appearance of the eschar). The eschar sloughs in 2 to 3 weeks.^{7 10 12} If it is recognized and treated promptly, the disease is rarely fatal.

Pharyngeal and GI anthrax occur following the ingestion of contaminated and undercooked meat. Pharyngeal ulcers and edema of the neck occur with multiplication of the anthrax bacilli. In rare instances, head and neck lesions have led to airway compromise. After intestinal absorption, bacteria are transported to mesenteric and other regional lymph nodes where there is multiplication and dissemination, development of hemorrhagic adenitis, ascites, and bacteremia. Like cutaneous anthrax, the GI form of the disease presents within 5 days of ingestion of contaminated meat. Severe abdominal pain, hematemesis, hematochezia, and (rarely) watery diarrhea are presenting features. Early diagnosis is difficult, resulting in high mortality.^{10 12 15 16}

	Inhalational Anthrax

TOP Abstract Introduction Historical Background Epidemiology Microbiology Pathogenesis Clinical Manifestations Inhalational Anthrax Diagnosis and Treatment Prevention Conclusion References

 
Inhalational anthrax was, until recently, a disease mainly of historical interest, with sporadic cases reported mostly among wool handlers and persons in close contact with infected animals. It may now warrant closer attention because the threat of biological warfare has once again been raised.

Aerosolized anthrax spores > 5 µm in size are deposited in the upper airways (pharynx, larynx, and trachea) and effectively trapped or cleared by the mucociliary system. Spores between 2 and 5 µm in size are able to reach the alveolar ducts and alveoli. These spores are engulfed by pulmonary macrophages and transported to mediastinal and hilar lymph nodes. Following a period of germination, a large amount of anthrax toxin is produced. Regional lymph nodes are quickly overwhelmed and the toxin finds its way into the systemic circulation, resulting in edema, hemorrhage, necrosis, and septic shock; death soon follows.²² Since the organisms are initially transported to mediastinal lymph nodes, a major site of involvement is the mediastinum. Edema and lethal toxin cause massive hemorrhagic mediastinitis that is typical of inhalational anthrax.

The minimum infectious inhaled dose in humans has not yet been determined. The minimum infectious inhaled dose in chimpanzees is 40,000 to 65,000 spores.²³ The US Department of Defense estimates that the lethal dose for 50% of test subjects for humans is between 8,000 and 10,000 spores.³ A review of previous outbreaks suggests that prior exposure to radiation, alcoholism, and underlying pulmonary disease are important risk factors for inhalational anthrax.¹¹ It has been suggested that inhalational anthrax is more prevalent in adults, although the evidence in the literature supporting this claim is equivocal.

Inhalational anthrax is usually biphasic in nature. The incubation period lasts up to 6 days. The initial stage, continuing for an average of 4 days, begins with the insidious onset of myalgia, malaise, fatigue, nonproductive cough, occasional sensation of retrosternal pressure, and fever. There may be a transient improvement in symptomatology after the first few days. The second stage, lasting 24 h and often culminating in death, develops suddenly with the onset of acute respiratory distress, hypoxemia, and cyanosis. The patient may have mild fever; alternatively, there may be hypothermia with the development of shock. Diaphoresis is often present; enlarged mediastinal lymph nodes may lead to partial tracheal compression and alarming stridor. Auscultation of the lungs is remarkable for crackles and signs of pleural effusions.²⁴ There may be meningeal involvement in up to 50% of cases; it is usually bloody and may be associated with subarachnoid hemorrhage. Decreased level of consciousness, meningismus, and coma may be present (Table 1) .^{3 12} A chest radiograph typically shows widening of the mediastinum and pleural effusions, whereas the parenchyma may appear normal.

Much of our knowledge about the pathology of inhalational anthrax comes from animal models. Fritz et al²⁶ observed the pathologic changes in a rhesus monkey model of inhalational anthrax. Clinical signs and symptoms were noted within 3 to 8 days of inhalation of a lethal dose. The major changes at the gross or light microscopy levels were edema, hemorrhage, and necrosis. Hemorrhage was seen in mediastinal, mesenteric, and tracheobronchial lymph nodes; meninges; lungs; and small intestinal serosa (Table 2) . All monkeys had heavy loads of bacteria at the time of death. In general, the leukocyte response was mild in nature.

Historically, inhalational anthrax was uniformly fatal. This observation was based on case series prior to the advent of ICUs. There were 11 survivors in the Sverdlovsk series, suggesting that supportive care in an intensive care setting is an important treatment strategy. Mortality, however, remains exceptionally high, in large part due to delays in diagnosis.

	Diagnosis and Treatment

TOP Abstract Introduction Historical Background Epidemiology Microbiology Pathogenesis Clinical Manifestations Inhalational Anthrax Diagnosis and Treatment Prevention Conclusion References

 
Diagnosis of inhalational anthrax during the first stage is difficult. The symptoms and signs of disease are similar to the common cold or a viral infection and are often mistaken for the latter diagnoses. Advanced disease may be recognizable by virtue of the shock-like symptoms and characteristic chest radiograph abnormality, but by then, the disease progression is rapid and treatment is ineffectual.

Gram’s stains and cultures should be obtained on blood samples of patients in whom anthrax is suspected. Sputum from patients seldom yields positive smears or cultures. Serologic diagnosis of anthrax can be made by means of a microhemagglutination test specific for the PA component of the toxin. These tests are available through state health department laboratories. Suspicious Gram’s stains should be reported to the CDC for further evaluation.^{14 15}

Antibiotics and supportive care in an intensive care setting are the mainstay of therapy. Antitoxin used in the Sverdlovsk epidemic is no longer available for human use. The anthrax bacillus is highly susceptible to penicillin, amoxicillin, chloramphenicol, doxycycline, erythromycin, streptomycin, and ciprofloxacin, but resistant to third-generation cephalosporins (Table 3 ).²⁸

ICUs are especially useful in the hemodynamic monitoring of patients and management of septic and hemorrhagic shock, the final common pathway linking all these patients. In addition, progressive respiratory insufficiency may necessitate the use of ventilatory support.

	Prevention

TOP Abstract Introduction Historical Background Epidemiology Microbiology Pathogenesis Clinical Manifestations Inhalational Anthrax Diagnosis and Treatment Prevention Conclusion References

 
Prevention of anthrax depends largely on the use of vaccines. As mentioned previously, virulent strains of B anthracis contain two large plasmids: the "toxin" plasmid, pXO1, and the "capsule" plasmid, pXO2. Strains that contain only one plasmid are avirulent. This forms the basis for effective vaccine production. The first vaccine, produced by Pasteur in 1881, was a heat-attenuated strain (pXO1 ^-/pXO2 ⁺) that formed capsules but could not produce toxin. It provided a much lower level of immunity than did the toxigenic vaccine strains.²⁹

The anthrax vaccine in use today has its root in the 1930s when Sterne developed a live, toxin producing, unencapsulated (attenuated) vaccine (pXO1 ⁺/pXO2 ^-). The vaccine was used in livestock as a single dose with a yearly booster.²⁹ Although the Sterne vaccine is effective for use in many domestic animals (cattle, sheep, pigs, camels, and buffalo), progressive disease caused by the vaccine has been observed in goats and llama. Its use in humans has been limited, mainly due to safety issues. It is sometimes associated with tissue necrosis at the site of inoculation, and there have been rare fatalities.^{10 30}

The first vaccine for human use was developed in 1943 at the Soviet Sanitary Technical Institute. It is a live spore vaccine similar to Sterne’s vaccine. Administered in the shoulders by scarification, a yearly booster is recommended. The efficacy of this vaccine is not well established, although Soviet studies show a fivefold to 15-fold reduced risk in occupationally exposed workers.^{12 31}

The United Kingdom and US vaccines (the latter manufactured by the Michigan Department of Public Health) developed in the 1950s and early 1960s are produced from cell-free filtrates of bacilli. The US vaccine is produced under conditions of rapid growth in order to maintain a low EF and LF content and to increase the PA content. The preparation is then alum-precipitated to formulate the vaccine.^{29 30}

There are few comparative studies assessing the efficacy of anthrax vaccines. In one study published in 1962, Brachman et al³² performed a single-blinded placebo-controlled trial looking at workers in four tanneries in the northeastern US. PA vaccine made from sterile culture filtrate produced by the US Army was administered in three doses to 379 workers. The remaining 414 received a placebo. Overall, the vaccine was found to be 92.5% effective in preventing cases of anthrax. The incidence of anthrax in the four tanneries was 1,200 per 100,000 persons per year. Instances of cutaneous and inhalational anthrax were not reported separately. In addition, the study did not have sufficient statistical power to assess protection against inhalational anthrax. Thirty-five percent of the recipients reported some type of reaction to the vaccine. These were all minor, consisting of local erythema, edema, and induration at the site of inoculation, lasting 24 to 48 h. Systemic reactions occurred in 0.5% of all cases. Manufacturer labeling for the current US vaccine cites a 30% rate of mild local reactions and a 4% rate of moderate local reactions with a second dose.¹²

The dosing schedule recommended for the Michigan Vaccine, based on the Brachman study, consists of 0.5 mL of vaccine administered subcutaneously at 0, 2, and 4 weeks, and 6, 12, and 18 months, followed by yearly boosters. This is recommended for individuals who have a high risk of occupational exposure to anthrax.

Although there are no human studies available that look specifically at the effectiveness of anthrax vaccines against inhalation of anthrax spores, several animal studies exist. In one study, rhesus monkeys received two doses of vaccine prior to exposure to a lethal dose of aerosolized anthrax spores. All monkeys in the nonvaccinated group died within 5 days of exposure, whereas the vaccinated monkeys were protected up to 2 years.¹² These studies suggest that at minimum, two doses of vaccine should be effective against an aerosol exposure to anthrax. A protective antibody response usually does not develop until 7 days after the second dose.

Recent advances in molecular biology techniques promise more effective vaccines. New purified PA vaccines are combined with adjuvants derived from the cell wall of the bacille Calmette-Guèrin (BCG) strain of the tubercle bacillus in an effort to increase the cellular response to PA.³³ These vaccines await clinical trials, and their efficacy is yet unknown.

Control of disease in animals by vaccination and sanitary practices is a major step in preventing disease in man. Restrictions in importing wool and other animal products from endemic countries and the proper burial of infected animals have reduced the instances of woolsorter’s disease in industrialized countries. In the setting of a terrorist threat, protective suits and specialized gas masks that protect against 1- to 5-µm aerosolized particles should be used by field workers and health-care providers. Vaccination of high-risk subjects is an important consideration. In settings where prevention is not possible, recent animal studies highlight the role of postexposure prophylaxis. Friedlander et al³⁴ exposed six groups of monkeys to a lethal dose of aerosolized anthrax. After 1 day of exposure, groups were treated with one of the following: IM saline solution (control), vaccine alone, IM penicillin G, ciprofloxacin, doxycycline, or doxycycline and vaccine. Antibiotics were administered through orogastric tubes and continued for 30 days. Survivors were rechallenged with aerosolized anthrax 131 to 142 days after initial exposure. Monkeys that received no antibiotics had the worst survival rates: 9 of 10 in the control group and 8 of 10 that received vaccination alone died. On the other hand, only 3 of the group that received penicillin alone, 1 of 9 that received ciprofloxacin alone, 1 of 10 in the doxycycline group, and none of the monkeys that received the combination vaccine and doxycycline died. The results of this study suggest that prolonged use of antibiotics in combination with vaccination after exposure to inhalational anthrax seems a prudent course of therapy.

A recent report from the CDC, published in Morbidity and Mortality Weekly, recommends vaccination and the use of oral fluoroquinolones (ciprofloxacin, 500 mg bid; levofloxacin, 500 mg qd; or ofloxacin, 400 mg bid) for postexposure prophylaxis in adults. Doxycycline is an acceptable alternative. Prophylaxis should continue until exposure to B anthracis is excluded or for a period of 4 weeks if exposure is confirmed. Three doses of vaccine should be administered during the 4-week period (at time 0, 2, and 4 weeks after exposure).³⁵ If a vaccine is not available, the antibiotic treatment should continue for at least 60 days. In contrast to CDC recommendations, the Working Group on Civilian Biodefense advocates the initial use of IV antibiotics, especially in settings where only a small number of people are exposed and resources are not limited.³⁶ Oral therapy should replace IV therapy when clinical improvement is noted. Fluoroquinolones are generally not recommended during pregnancy or for children < 18 years of age due to the observed association with arthropathy in adolescent animals and similar reports in a small number of children.³⁶ However, in regard to the treatment of inhalational anthrax and the balancing of potential risks and benefits, the CDC and the Working Group on Civilian Biodefense recommend ciprofloxacin for postexposure prophylaxis in children and pregnant women until antibiotic susceptibility is determined.^{35 36}

	Conclusion

TOP Abstract Introduction Historical Background Epidemiology Microbiology Pathogenesis Clinical Manifestations Inhalational Anthrax Diagnosis and Treatment Prevention Conclusion References

 
Inhalational anthrax is a rare and rapidly fatal disease. In the present day environment of political unrest, the use of anthrax as a biological agent of mass destruction by disgruntled groups both at home and abroad may become an unfortunate reality. It is important for health-care providers in general and for pulmonary and critical-care specialists in particular to have a sound understanding of the clinical presentations and treatment of anthrax. Early diagnosis is difficult, and a high index of suspicion is required. Mild "flu-like" symptoms progress rapidly to respiratory distress, septic shock, and multiple organ failure. Hemorrhagic mediastinitis, diffuse hemorrhagic lymphadenitis, widespread edema, and mediastinal widening on chest radiography are characteristic features. Immediate and prolonged antibiotic use, vaccination, and the adequate management of respiratory distress and septic and hemorrhagic shock in the ICU are the mainstay of therapy. Many antibiotics are effective; however, resistance to third- generation cephalosporins has been noted. Despite all these efforts, the morbidity and mortality from this disease may still remain high.

	Footnotes

 
Abbreviations: cAMP = cyclic adenosine monophosphate; CDC = Centers for Disease Control and Prevention; EF = edema factor; IL-1 = interleukin-1; km = kilometers; LF = lethal factor; PA = protective antigen; TNF = tumor necrosis factor; US = United States

This work was supported by the Mr. and Mrs. C.F. Chan Fund and the Mr. and Mrs. Samuel Reeves and Family Fund.

Received for publication March 2, 1999. Accepted for publication May 25, 1999.

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TOP Abstract Introduction Historical Background Epidemiology Microbiology Pathogenesis Clinical Manifestations Inhalational Anthrax Diagnosis and Treatment Prevention Conclusion References

 

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