Anthrax results from infection with Bacillus anthracis, a Gram-positive, spore-forming, rod-shaped organism that exists in its host as a vegetative bacillus and in the environment as a spore. In nature, anthrax is a zoonotic disease of herbivores that is ubiquitous in the soil of many geographic regions; sporadic human disease results from environmental or occupational contact with endospore-contaminated animal products (Dixon et al., 1999). The cutaneous form of anthrax is the most common presentation of naturally-occurring disease; gastrointestinal and inhala-tional forms are exceedingly rare. Cutaneous anthrax occurred regularly in the first half of the twentieth century in association with contaminated hides and wools used in the garment industry, but it is uncommonly seen in current-day industrialized countries due to importation restrictions. The last known case of naturally occurring inhalational anthrax in the US occurred in 1976 (Suffin et al., 1978).

It is ironic that, as American policies and regulations alleviated the risk of industrial outbreaks of anthrax, latter-day governmental policies may have shifted that risk to bioterror-related outbreaks. What was once an occupational disease of slaughterhouse workers, ranchers, and mill workers has now become an occupational hazard of politicians, journalists, postal workers, and the public at large (Witkowski and Parish, 2002). Prevailing wisdom had previously held that a large-scale bioterrorism attack with anthrax would employ aerosolized endospores and result in outbreaks of inhalational disease. The attacks in the US in 2001 illustrate the difficulties in predicting modes and outcomes in bioterrorism: the attacks were on a relatively small scale, and while endospores were used, the delivery method -envelopes - resulted in a significant proportion of cutaneous cases (Inglesby et al., 2002). However, as with the Sverdlovsk outbreak in 1979, the serious morbidity and mortality in the US attacks were related to inhalational disease. Thus, it still seems warranted to plan for larger-scale events with aerosolized agents.

The clinical presentations and differential diagnoses of cutaneous and inhala-tional anthrax are described in Table 12.5. The lesion of cutaneous anthrax may be similar in appearance to other lesions, including cutaneous forms of other agents of bioterrorism such as tularemia or glanders; however, it may be distinguished by epidemiologic as well as certain clinical features. Unless secondarily infected, anthrax is traditionally a painless lesion and associated with significant local edema. The bite of Loxosceles reclusa, the brown recluse spider, shares many of the local and systemic features of anthrax, but is typically painful from the outset and lacks such significant edema (Freedman et al., 2002). Cutaneous anthrax is associated with systemic disease and its attendant mortality in up to 20 percent of untreated cases, although with appropriate antimicrobial therapy mortality is less than 1 percent (Inglesby et al., 1999).

Once the inhaled endospores reach the terminal alveoli of the lungs, generally requiring particle sizes of 1-5 |m, they are phagocytosed by macrophages and transported to regional lymph nodes, where they germinate into vegetative bacteria and subsequently disseminate hematogenously (Dixon et al., 1999). Spores may remain latent for extended periods of time in the host, up to 100 days in experimental animal exposures (Henderson et al, 1956). This correlates with the potential for prolonged clinical incubation periods after exposure to endospores; cases of inha-lational anthrax occurred up to 43 days after exposure in the Sverdlovsk experience (Meselson et al., 1994). The calculated incubation period based on the known dates of exposure in 6 of the 11 cases of inhalational anthrax from 2001 ranged from 4 to 6 days (Jernigan et al., 2001), and from 1 to 10 days for the cutaneous cases (Bell et al., 2002). Studies in non-human primates suggest the incubation period is influenced by exposure inoculum (Dixon et al, 1999; Inglesby et al, 2002).

Prior to the US anthrax attacks in October 2001, most of the clinical data concerning inhalational anthrax derived from Sverdlovsk - the largest previous outbreak recorded. Although there is much overlap among the clinical manifestations noted in both outbreaks, more detailed data are available from the recent US experience. Mailed letters containing anthrax spores in late September and early October of 2001 from a still-unidentified terrorist source(s) resulted in 22 cases of bioterrorism-associated anthrax (Lucey, 2005). Of these, 11 were of the cutaneous form; 11 were confirmed persons with inhalational anthrax, 5 (45 percent) of whom died. Although this contrasts with a case-fatality rate of greater than 85 percent reported from Sverdlovsk, the reliability of reported data from this outbreak is questionable (Inglesby et al., 2002).

Patients almost uniformly presented an average of 3.3 days after symptom onset, with fevers, chills, malaise, myalgias, non-productive cough, chest discomfort, dyspnea, nausea or vomiting, tachycardia, peripheral neutrophilia, and liver enzyme elevations (Jernigan et al., 2001; Barakat et al., 2002). Many of these findings are non-diagnostic and overlap considerably with those of influenza and other common viral respiratory tract infections, rendering clinical diagnosis problematic in the absence of a known outbreak. Recently compiled data suggest that shortness of breath, mental status abnormalities, nausea, and vomiting are significantly more common in anthrax, whereas rhinorrhea and sore throat are uncommonly seen in anthrax, but noted in the majority of viral respiratory infections (CDC, 2001; Hupert et al., 2003).

Other common clinical manifestations of inhalational anthrax, as informed by the 2001 outbreak, include abdominal pain, headache, mental status abnormalities, and hypoxemia. Abnormalities on chest radiography appear to be universally present, although these may only be identified retrospectively in some cases (Jernigan et al., 2001). Pleural effusions appear to be the most common abnormality; infiltrates, consolidation, and/or mediastinal adenopathy/widening are also noted in the majority. The latter is thought to be an early indicator of disease, but computed tomography was more sensitive than chest radiography for this finding.

Clinical manifestations of inhalational anthrax generally evolve to a fulminant septic picture with progressive respiratory failure and shock. B. anthracis is routinely isolated in blood cultures if obtained before the initiation of antimicrobials.

Pleural fluid is typically hemorrhagic; bacteria can either be isolated in culture or documented by antigen-specific immunohistochemical stains of this material in the majority of patients (Jernigan etal., 2001). The average time from hospitalization until death was three days (range 1-5 days) in the US series, consistent with other reports of the clinical virulence of this infection. Autopsy data typically reveal hemorrhagic mediastinal lymphadenitis and disseminated meta-static infection. Pathology data from the Sverdlovsk outbreak confirm meningeal involvement, typically hemorrhagic meningitis, in 50 percent of disseminated cases (Abramova et al., 1993). Meningitis was the presenting manifestation in the index anthrax case in 2001 (Bush et al., 2001).

The diagnosis of inhalational anthrax should be entertained in the setting of a consistent clinical presentation in the context of a known exposure, a possible exposure, or epidemiologic factors suggesting bioterrorism (e.g. clustered cases of a rapidly progressive illness). The diagnosis should also be considered in a single individual with a consistent or suggestive clinical illness in the absence of another etiology. The early recognition and treatment of inhalational anthrax is likely to be associated with a survival advantage (Jernigan et al., 2001); however, patients appear to evolve rapidly to a late stage of infection in which survival appears unlikely (Lucey, 2005). Therefore, prompt empiric antimicrobial therapy should be initiated if infection is clinically suspected.

Combination parenteral therapy is appropriate in the ill person for a number of reasons - to cover the possibility of antimicrobial resistance, to target specific bacterial functions (e.g. the theoretical effect of clindamycin on toxin production), to ensure adequate drug penetration into the central nervous system, and perhaps to favorably affect survival (Jernigan et al., 2001; Lucey, 2005). In the future, it is likely that novel therapies such as toxin inhibitors or receptor antagonists will be available, in combination with antimicrobials, to treat anthrax (Artenstein et al., 2004; Opal et al., 2005; see also Friedlander, 2001). Detailed therapeutic and postexposure prophylaxis recommendations for adults, children, and special groups have been recently reviewed elsewhere (Inglesby et al., 2002; Lucey, 2005). Anthrax vaccine adsorbed has been proved to be effective in preventing cutaneous anthrax in human clinical trials, and in preventing inhalational disease after aerosol challenge in non-human primates (Friedlander et al., 1999). The current vaccine has generally been found to be safe, but requires six doses over 18 months with the need for frequent boosting. Its availability is currently limited, although it is hoped that second-generation anthrax vaccines, currently in clinical trials, will prove effective.

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