Diagnosis
Clinical Manifestations
Skin infection Skin disease is the most common manifestation of anthrax, and half of the victims (11 of 22) in the United States bioterrorist attack presented with cutaneous disease. In the absence of exposure to animals or animal products, the diagnosis of cutaneous anthrax should immediately raise the possibility of a bioterrorist attack. One to 7 days after inoculation of spores into the skin, a small papule develops and progresses to a vesicle over the ensuing few days. Erythema and nonpitting edema often surround the vesicle. Initially, the vesicular fluid is serous and contains large numbers of organisms. Once the vesicle ruptures, a black eschar becomes evident at the base of the ulcer [see Figure 5]. Anthrax derives its name, which is taken from the Greek word for coal, from these characteristic black lesions. Despite the erythema and swelling, lesions are not painful but may be mildly pruritic. Lymphangitis, lymphadenopathy, fever, and malaise may accompany the skin infection. After 1 to 2 weeks, the skin lesion dries and a permanent scar is formed. Lesions occur primarily on exposed regions of the body. The arms are the most frequent site of infection; the face and neck are also commonly involved. Lesions are usually single but may occur at multiple sites as a result of simultaneous inoculations.
Respiratory infection (Woolsorters’ disease) Unlike cutaneous anthrax, which is rarely fatal, inhalational anthrax is usually a fulminant disease with a high mortality. The index case in the United States bioterrorist attack presented as typical inhala-tional anthrax, followed quickly by sepsis and meningitis.63 The pulmonary form of disease is usually biphasic in its presenta-tion.64 From 1 to 5 days after inhalation of spores, the patient has symptoms suggestive of a viral syndrome: nonproductive cough, malaise, fatigue, myalgia, and mild fever. Occasionally, the sensation of chest heaviness is reported. Other manifestations reported in the United States bioterrorist cases included sweats, often drenching; nausea and vomiting; abdominal pain; headache; confusion; and sore throat.65 Rhonchi may be heard on pulmonary auscultation. Within 2 to 4 days, symptoms temporarily resolve but are rapidly followed by the second, more severe stage of the disease. This stage involves the sudden onset of severe respiratory distress with dyspnea, cyanosis, and diffuse diaphoresis, accompanied by fever, tachycardia, and tachypnea. On pulmonary auscultation, moist, crepitant rales are evident, and findings are consistent with pleural effusion. Chest x-ray often demonstrates a widened mediastinum. Infiltrates or consolidation may also be seen, and pleural effusions are commonly found.65 Death often occurs within 24 hours and may be preceded by septic shock. A Russian patient was described as dying suddenly, in midsentence. Recent experience in the United States suggests that early aggressive antibiotic therapy may modify the outcome, and death rates were reduced from above 85% to below 50%.56 Autopsy usually reveals hemorrhagic necrosis of the thoracic lymph nodes, drainage from the lungs, and hemorrhagic mediastinitis. A high index of suspicion is critical because any delay in diagnosis and treatment greatly increases the likelihood of a fatal outcome.
Gastrointestinal infection Gastrointestinal anthrax has not been reported in the United States. It occurs primarily in developing countries, usually after ingestion of contaminated meat. The incubation period is usually 3 to 5 days. Patients initially have nausea, vomiting, anorexia, and fever. Acute abdominal pain, hematemesis, and bloody diarrhea follow rapidly. Findings on examination suggest an acute surgical abdomen, and there is moderate leukocytosis with immature band forms. Rapid progression to toxemia and shock leads to death within 2 to 5 days after the initial onset of symptoms.
An oropharyngeal form of anthrax has also been described. Inflammatory lesions that resemble the cutaneous lesions develop on the posterior pharynx, hard palate, or tonsils. Tissue necrosis and edema are accompanied by sore throat, dysphagia, fever, regional lymphadenopathy, and toxemia.
Meningitis Anthrax meningitis can result from bacteremia precipitated by cutaneous, respiratory, or gastrointestinal infection. This complication is relatively rare, occurring in fewer than 5% of patients. In the index case in the United States bioterrorist attack, the patient presented to the emergency department with confusion, and gram-positive rods were identified in his CSF.63 The onset of meningeal symptoms usually occurs simultaneously with the primary lesion or within several days after its onset. Meningitis is hemorrhagic and rapidly fatal (within 6 days).
Patient History and Laboratory Tests
A careful epidemiologic history is the single most important means of suggesting the diagnosis. A history of contact with herbivores or products from these animals, particularly if the products come from outside the United States, should raise the possibility of anthrax. The sudden appearance of several cases of severe acute febrile illness with a fulminant fatal outcome should raise the possibility of a bioterrorist attack. Certain occupational groups are at higher risk of being exposed to anthrax spores disseminated in the mail: post-office workers, members of the news media, and politicians and their staffs. Therefore, the occupational history can provide a critical clue for recognizing early in-halational and cutaneous anthrax.
The physical appearance of the skin lesions is characteristic, and Gram stains and cultures of the ulcer base are frequently positive. A history of exposure to dust from a contaminated animal product can usually be obtained in the prodromal phase of the respiratory illness, when symptoms are mild. In the absence of a thorough history, the disease is initially mistaken for a viral respiratory illness or bronchitis. Patients with gastrointestinal disease have a history of eating undercooked, often spoiled, meat.
Gram stain of the peripheral blood may reveal gram-positive bacilli, and in cases of meningitis, the CSF Gram stain is often positive. Blood cultures are positive in most cases of inhalational anthrax, and specimens for culture should be drawn immediately. The microbiology laboratory must be alerted to the possibility of anthrax, or the organism may be identified only as a Bacillus species and the pathogen misinterpreted as a contaminant. In the United States, the public health Laboratory Response Network, consisting of 81 clinical laboratories, has been established to specifically identify bioweapon pathogens, and all suspected samples should be referred to one of these laboratories for confirmatory diagnosis.
In addition to microbiologic-study results, a chest x-ray showing a widened mediastinum, infiltrates, and pleural effusions suggests inhalational anthrax. A chest CT scan is also helpful in this disease, revealing hyperdense hilar and mediastinal nodes, mediastinal edema, and infiltrates and pleural effusions. Thora-centesis may reveal hemorrhagic pleural fluid.
A variety of rapid-assay kits are available to detect B. anthracis spores on environmental surfaces. However, none of these kits has been independently evaluated or endorsed by the CDC or the Food and Drug Administration, and many false positive results were reported during the United States bioterrorist attack.56
Enzyme-linked immunosorbent assays are available that measure antibody titers against lethal and edema toxins. A fourfold rise in titers over 4 weeks or a single titer of 1:32 is considered positive. This assay is not helpful during the acute illness. In patients receiving antibiotic prophylaxis, the antibody response may be blunted.
Treatment and prognosis
Antibiotic therapy should be immediately initiated in all patients deemed at high risk who have fever or a systemic illness consistent with inhalational anthrax. Any delay in therapy increases the risk of a fatal outcome. First-line antibiotics are intravenous ciprofloxacin or doxycycline combined with one or two other antibiotics with activity against the pathogen [see Table 1]. Because anthrax strains may have constitutive and inducible P-lactamases, monotherapy with penicillin or ampicillin is not recommended. When meningitis is suspected, doxycycline should not be used, because of its poor CNS penetration. Once the patient is stable, oral antibiotics can be given, with ciprofloxacin (500 mg twice daily) or doxycycline (100 mg twice daily) being the treatment of choice. Because of the risk of delayed germination of spores in the host, therapy should be continued for 60 days. Oral ciprofloxacin or doxycycline for 60 days is recommended for cutaneous disease. Excision of skin lesions is con-traindicated because of the increased risk of precipitating bac-teremia. However, after appropriate antibiotic therapy, excision and skin grafting may be necessary.66
Before antibiotics became available, cutaneous disease was associated with a mortality of 10% to 20%. With appropriate antibiotic treatment, fewer than 1% of patients die. Despite appropriate antibiotics and respiratory support, inhalational anthrax in the past was almost always fatal. However, experiences in Russia and the United States demonstrated that with early systemic antibiotic therapy, mortality can be reduced to approximately 50%. Gastrointestinal disease also is associated with a high mortality (25% to 100%).
Prevention
Postexposure prophylaxis is critical for the prevention of secondary cases. The selection of patients for prophylaxis depends on the environmental setting and the conditions of the spore release. Nasal swab cultures are insensitive and should not be used to determine whether an individual should receive prophylactic antibiotics. Nasal swab cultures are recommended only as an epidemiologic tool to determine the extent of exposure in a specific area or building. In cases of suspected exposure to B. anthracis, the preventive regimens of choice are oral fluoro-quinolones (e.g., ciprofloxacin, 500 mg twice daily; levofloxacin, 500 mg a day; or ofloxacin, 400 mg twice daily) or, if fluoro-quinolones are contraindicated, doxycycline (100 mg twice daily). Prophylaxis should be continued until exposure is excluded. If exposure is confirmed, prophylaxis should be continued for 60 days. In persons thought to be heavily exposed, prophylaxis for 100 days may be considered.67
A killed vaccine derived from a component of the anthrax exotoxin is available and is recommended for all industrial workers at risk for exposure to contaminated animal products. As a result of increased concerns about biologic warfare and bioterrorism, military personnel are now vaccinated. Postexpo-sure vaccination, although not approved by the FDA, has been shown to provide additional protection in animal studies and is recommended as an option by the CDC. In such cases, the vaccine is considered an investigational new drug and should be administered with informed consent.68
Anecdotal reports in the lay press have associated anthrax vaccine with a high incidence of serious reactions. Nevertheless, although mild localized reactions occur in up to 30% of anthrax vaccine recipients, to date, with the exception of two cases of optic neuritis,69 and one of delayed anaphylaxis,70 serious adverse reactions have not been reported.
For decontamination after anthrax exposure, exposed skin should be washed extensively with soap and water. Because of the potential danger of secondary aerosolization, decontamination of exposed environments is recommended. Decontamination is technically difficult and requires expert analysis that takes into account the nature of the exposure and the environmental conditions.
Infections and Disorders Due to Other Bacillus Species
Bacillus organisms are found in soil, dust, decaying organic matter, and water. Some species are part of the normal flora, particularly in patients who have had prolonged hospitalizations. Despite their widespread distribution, these organisms rarely cause infection and are more often isolated as a contaminant. Risk factors associated with serious Bacillus infections include use of intravascular catheters; intravenous drug abuse; sickle cell disease; and immunosuppression caused by malignancy, neu-tropenia, corticosteroid therapy, or AIDS.72 Because these organisms are frequently resistant to third-generation cephalosporins, prolonged antibiotic treatment regimens that include these agents may select out for Bacillus organisms.
B. cereus is the most frequent Bacillus species to cause invasive infection, followed by B. subtilis [see Table 4].
Diagnosis
Clinical Manifestations
With the exception of B. cereus eye infections, Bacillus infections are rare and cannot be clinically distinguished from those caused by other pyogenic organisms. Pneumonia can develop in the compromised host, and necrotizing pneumonia caused by B. cereus has been reported in patients with acute leukemia and hepatic malignancy. Fatal pseudomembranous tracheobronchitis and pneumonia have been reported in a patient with aplastic anemia.73
Bacterial endocarditis caused by Bacillus species is a well-recognized complication of intravenous drug abuse. The tricuspid valve is most often involved, and the course of illness tends to be indolent. Bacillus species are among many pathogens that infect prosthetic valves.74 Indwelling catheters may become colonized with Bacillus organisms, resulting in positive blood culture results.
High-grade bacteremia can be complicated by fatal menin-goencephalitis in the immunocompromised host.75 Necrotizing fasciitis can be caused by B. cereus.
In rare cases, meningitis may result from Bacillus bacteremia, but more often, it has followed inadvertent inoculation of organ-isms into the CSF during spinal anesthesia.76 Because of their hardy growth characteristics, Bacillus species are common laboratory contaminants. Pseudobacteremia caused by contamination of alcohol swabs and rubber stoppers on blood culture bottles and pseudomeningitis caused by Bacillus contamination of commercial culture media have been reported.77
Table 4 Clinical Syndromes Caused by Bacillus Species
|
Species |
Clinical Syndrome |
|
B. alvei |
Meningitis, pneumonia, empyema, bacteremia |
|
B. cereus |
Ophthalmitis, bacteremia, pneumonia, osteomyelitis, endocarditis, soft tissue infection |
|
B. sphaericus |
Peritonitis, pleuritis, lung infection, meningitis, bacteremia |
|
B. subtilis |
Meningitis, otitis, mastoiditis, urinary tract infection, bacteremia, endocarditis, ventricular shunt infection |
Motor vehicle accidents in which injuries result from direct contact with the road may result in B. cereus soft tissue and bone infections that necessitate extensive surgical debridement and amputation for cure. Close-range gunshot wounds and injection of contaminated heroin have also been complicated by B. cereus soft tissue infection.78,79
Ocular infections B. cereus is a primary pathogen for ocular infections. This species is one of the most common agents associated with posttraumatic endophthalmitis. When B. cereus is the causative agent, an intraocular foreign body is often present. Injuries caused by metal fragments and injuries associated with contamination by soil and dust increase the risk of infection by B. cereus. The onset of infection is rapid and leads to destruction of the vitreous and retinal tissue, causing loss of vision 12 to 48 hours after inoculation. Patients frequently become systemically ill, with fever and leukocytosis. Endophthalmitis and panoph-thalmitis can also be related to intravenous drug abuse. Early diagnosis and treatment are critical for preventing permanent structural changes and blindness.80
Food poisoning B. cereus produces two enterotoxins, diar-rheal toxin and emetic toxin, that are responsible for two food-poisoning syndromes. The emetic form is associated primarily with the ingestion of contaminated fried rice.81 From 1 to 6 hours after ingestion, the person experiences vomiting and symptoms identical to those of staphylococcal food poisoning. A case of fulminant fatal hepatic failure and rhabdomyolysis associated with ingestion of B. cereus emetic toxin has also been reported.82 The diarrheal form has a longer incubation period (10 to 12 hours), and manifestations are related to lower rather than upper gastrointestinal symptoms. Symptoms include abdominal pain, profuse watery diarrhea, tenesmus, and nausea. This syndrome is usually self-limited and lasts 12 to 24 hours. Outbreaks are generally associated with ingestion of contaminated meat, vegetables, and mayonnaise.83
Treatment
B. cereus is resistant to penicillin and other P-lactam antibiotics, including cephalosporins; it is sensitive to vancomycin, gentamicin, imipenem, and ciprofloxacin. Clindamycin, erythro-mycin, chloramphenicol, and tetracycline have also been shown to be active. Other Bacillus species are susceptible to penicillins and cephalosporins. Pending speciation and susceptibility testing, vancomycin or clindamycin with or without gentamicin is the empirical treatment of choice when infection with Bacillus species is suspected [see Table 1].
If Bacillus bacteremia develops in immunocompromised patients with long-term indwelling catheters, antibiotic therapy must be instituted and the catheter removed to prevent recurrence of the infection.84 In addition to antibiotic treatment, the deep-seated soft tissue infection associated with necrotizing fasciitis requires aggressive surgical debridement.85
For intraocular infections, systemic therapy is usually supplemented with intravitreous clindamycin and gentamicin administered by an ophthalmologist. Intravitreous dexamethasone and early vitrectomy have been recommended for the management of sight-threatening endophthalmitis by B. cereus.80
For patients with food poisoning, antibiotics are not required, because the disease is self-limited. Supportive care may include intravenous fluids if the patient becomes severely dehydrated.
Infections Due to the Erysipelothrix Organism
Human infections by the Erysipelothrix organism are rare and are always caused by E. rhusiopathiae (formerly E. insidiosa). This aerobic gram-positive bacillus grows on routine nonselective media and is nonhemolytic, nonmotile, and catalase negative. Because of the cell wall’s high lipid content (about 30%), E. rhusiopathiae is resistant to desiccation and may tolerate salting, pickling, and smoking. The organism is capable of growing over a broad temperature range (4° to 42° C) and is widespread in nature. E. rhusiopathiae can infect mammals, birds, fish, shellfish, and insects. Human infection results from handling dead infected animal parts. Infection can also result from cat bites.86 Most cases of skin infection occur during the summer and early fall. Infection is almost always the result of occupational exposure of slaughterhouse workers, butchers, fishers, farmers, and veterinarians. The organism is usually traumatically inoculated. Bacilli remain extracellular and are often located deep in the skin near capillaries, where the organism can gain entry into the bloodstream.
Diagnosis
Clinical Manifestations
Erysipeloid Between 2 and 7 days after skin inoculation, a purplish-red, nonvesicular area arises with a sharply defined, raised, serpiginous border. Lesions most often develop on the face and hands. Proximal regions of the hand and fingers are involved, whereas the distal phalanges are usually spared. Lesions spread peripherally at a slow pace (1 cm/day). Over time, the central part of the lesion begins to heal, resulting in a pale center surrounded by a fiery-red outer border. Lesions itch or burn and are rarely associated with lymphangitis or lymphadenitis. Fever and systemic complaints are rare.
Endocarditis Endocarditis is rare but may occur on both deformed and normal heart valves. The onset is acute or subacute and most often involves the aortic valve. In approximately 40% of cases, a skin lesion is noted just before or at the time of diagnosis, suggesting the possibility of E. rhusiopathiae.88 Often, the skin lesion has healed by the time endocarditis becomes apparent. Mental-status changes associated with multiple cerebral hemorrhages may also accompany this form of endocarditis.89
Patient History and Laboratory Tests
An appropriate epidemiologic history will suggest the diagnosis. Morphologically, the skin lesions resemble erysipelas (caused by group A streptococci). However, the rate of progression of Erysipelothrix infection is considerably slower, and unlike erysipelas, this skin lesion is not associated with tenderness or lymphadenopathy. Injection and culturing of nonbacteriostatic normal saline is rarely successful. Biopsy of a full-thickness skin specimen from the advancing border of the lesion and culturing in glucose-containing broth result in the highest yields. PCR assays for erysipelas have proved to be useful in swine and have been applied to humans.90 Diagnosis of endocarditis depends on isolation of the organism from blood cultures.
Treatment
The treatment of choice for erysipeloid is penicillin; a single injection of 600,000 units of penicillin G benzathine generally is curative. For penicillin-allergic patients, oral erythromycin (250 to 500 mg every 6 hours) is effective. This skin infection is usually self-limited and lasts about 3 weeks; however, antibiotic treatment hastens the healing. Bacterial endocarditis is best treated with intravenous penicillin G. For penicillin-allergic patients, intravenous cefazolin or ceftriaxone is recommended [see Table 1].90,91 Most strains are resistant to vancomycin, which therefore should not be used for empirical therapy for endocarditis if E. rhusiopathiae is a possibility. Despite appropriate therapy, the mortality associated with endocarditis is 30% to 40%.
