Cutaneous anthrax is the most common naturally occurring form of anthrax infection in humans. It occurs following exposure to infected animals grazing on contaminated land or exposure to contaminated animal products, such as hides and wool. Other forms of anthrax are inhalational anthrax and gastrointestinal anthrax, which may also occur as animal-derived infections.1–4 The term anthrax derives from the Greek word for coal, and refers to the black skin lesion typically found in cutaneous anthrax.1 Cutaneous anthrax is caused by Bacillus anthracis, aerobic rod-shaped bacterial microorganisms (1–10 μm) that form spores (1 μm), the infective agents of B anthracis. Widely distributed throughout the world, the temperature-resistant spores exist in the soil and may survive for decades in ambient conditions. When the spores contaminate skin lacerations or abrasions, they are ingested by and germinate inside macrophages. Subsequently, vegetative bacilli multiply extracellularly.
The 3 major virulence factors of anthrax—lethal toxin, edema toxin, and its polyglutamyl capsule—are produced by plasmids, activated only in vegetative forms of B anthracis. Lethal toxin and edema toxin are binary exotoxins, formed by 2 of 3 proteins produced by the X01 plasmid (protective antigen, lethal factor, and edema factor). Protective antigen is common to both exotoxins and enables them to enter cells across the cellular membrane. Lethal toxin is a zinc metalloprotease that causes the release of large quantities of inflammatory cytokines (tumor necrosis factor-α and interleukin-1β), leading to serious local and systemic manifestations and resulting in shock and death. Edema toxin works through unregulated adenylate cyclase activity, which causes marked tissue edema through the exodus of water from cells and the impairment of neutrophil function, propagating the infection. The third important virulence factor is B anthracis's polyglutamyl capsule, coded by genes of the X02 plasmid, which prevents phagocytosis of vegetative forms, thus allowing their proliferation.1–4
Culture examinations for infectious microorganisms are commonly performed at community hospital laboratories, which are considered Level A. In culture, B anthracis is characterized by nonhemolytic, white-to-gray, ground-glass colonies with undulating borders that retain their shape when manipulated. These colonies are nonmotile in testing media and microscopically reveal Gram-positive rods forming central or subterminal spores. These characteristic microorganisms, considered “presumptive B anthracis,” should be sent to a Level B laboratory (usually a state laboratory), where additional tests will determine true B anthracis.5
The medical staff of Robert Wood Johnson University Hospital at Hamilton (RWJUHH), Hamilton, NJ, treated 3 patients for anthrax infection in October 2001.6–8 One patient is presented here to exemplify diagnostic features and therapeutic decisions in an individual with cutaneous anthrax.
A middle-aged woman presented to RWJUHH with a localized, slightly tender skin ulceration of the forehead (3 × 2 × 0.5 cm). The lesion had indurated, elevated borders and a necrotic red to brown, but not black, center (Figure 1). The patient had no complaints of shortness of breath and she was afebrile, with facial edema and right cervical lymphadenopathy. Laboratory data showed a normal differential count on peripheral blood examination. The patient's blood cultures, skin lesion swab culture, and bilateral nasal swab cultures were negative for B anthracis.
The skin lesion had appeared approximately 6 days before the patient presented at the hospital; she had no history of trauma. Initially, the patient noted an erythematous papule on her forehead, associated with facial edema. Later, the papule evolved into a vesicle with ulceration. When the skin lesion became larger and the facial swelling worsened, the patient consulted her primary care physician, who prescribed oral ciprofloxacin, 500 mg BID. At that time, the skin lesion swab culture was negative for B anthracis or other microorganisms.
The gross skin lesion did not initially point to cutaneous anthrax because it did not have the typical black eschar and the patient did not have a documented exposure. However, the diagnosis of cutaneous anthrax was considered because this patient event occurred in Hamilton Township, NJ, in October 2001, when letters contaminated with B anthracis spores had been sorted at Hamilton's postal processing and distribution facility.
The patient did not remember any recent contact with animal skin or meat processing. She was not a post office employee, although she may have been in contact with contaminated mail at home or at work, where she was an office secretary. No one in her family developed similar lesions. The differential diagnosis included spider bite because she had recently cleaned some infrequently used areas of her home.
During this time, RWJUHH treated 2 post office employees for anthrax: 1 for cutaneous anthrax and 1 for inhalational anthrax. In the fall of 2001, 6 of 22 cases that occurred nationally were diagnosed and treated in New Jersey, including the 3 cases treated at RWJUHH. At the same time, more than 1000 post office workers related to Hamilton's facility were examined and treated prophylactically (ciprofloxacin) at the Occupational Health Department of RWJUHH, an action that most likely prevented any anthrax-related deaths in New Jersey.8,9
At RWJUHH, the patient was placed on intravenous (IV) ciprofloxacin (400 mg BID) and ceftazidime (1 g every 6 hours); ceftazidime was discontinued later when IV vancomycin (1 g every 12 hours) was added. Dry forehead dressings were changed daily.
The patient's lymphadenopathy and facial edema improved. Despite antibiotic treatment, the skin lesion persisted and enlarged. As a result, the lesion was completely removed surgically. Frequently repeated microbiologic studies performed before surgery had shown no B anthracis growth—only light, normal skin flora growth in the ulcerated area. Although macroscopic black discoloration was not apparent, microscopic morphology showed eschar formation over edematous viable tissue. Surface skin flora growth had most likely changed the gross appearance of the otherwise typical anthrax lesion in the eschar phase.
Because Gram's stain of the excised tissue showed a focal group of Gram-positive, spore-forming, rod-shaped bacterial microorganisms suggestive of B anthracis (Figure 2), the specimen was sent to the Centers for Disease Control and Prevention (CDC). The CDC laboratory reported positive histologic staining for B anthracis antigen in the paraffin block and polymerase chain reaction (PCR) positivity in the frozen portion of lesional tissue.7
With the surgical wound healing without complications, the patient was discharged 5 days after surgery; she continued to take oral ciprofloxacin. The skin edema and lymphadenopathy resolved completely, as observed during office follow-up. No respiratory, meningeal, or other systemic symptoms were detected. Three years later, the surgical scar was imperceptible.
Thirty-five months after diagnosis and treatment, the patient's serum was evaluated for antibodies to B anthracis-protective antigen protein. Evaluation was performed with the QuickELISA Anthrax-PA Kit (Immunetics, Boston, MA), using a Sigma Microplate Reader II (Awareness Technology, Palm City, FL). The sample was tested using a positive control obtained from the CDC pooled serum of the anthrax vaccine recipients. The cutoff was established as the mean negative control net optical density (OD, 450 nm ± 1), with a targeted cutoff of 0.11 to 0.25. Low positive controls (<1.0) were greater than the cutoff, with strong positive controls (>1.0). The patient sample, tested in duplicate, was at the high end of the low positive range (0.648–0.995). The patient, therefore, showed presence of B anthracis-protective antigen antibodies 3 years after the infectious episode.
In cutaneous anthrax, a painless papule appears 1 to 12 days after spores infect the skin through lacerations or abrasions, as observed in the above case report. During the next 1 to 2 days, a vesicle containing B anthracis microorganisms develops, characteristically surrounded by prominent edema. Later, the vesicle ruptures. An ulcer then forms, covered with black eschar, and the lesion enlarges. If secondary bacterial infection occurs, however, the lesion may remain as a purulent ulcer and not evolve into black eschar. Tissue edema may significantly increase if the lesion is located in facial or cervical areas, and regional lymphadenopathy may be present. Low-grade fever and malaise are usual symptoms. Approximately 2 weeks later, the lesion heals and the eschar falls off, commonly leaving no significant scarring; however, bacteremia, followed by septic shock, may be a complication.
Cutaneous anthrax ultimately requires intensive antibiotic treatment. Use of appropriate antibiotics does not shorten the course of cutaneous anthrax, but prevents progression to systemic illness. With antibiotic treatment, mortality decreases dramatically to approximately 1%; mortality without antibiotic treatment is estimated at 5% to 20%.2–4
Differential diagnosis of eschar includes arachnid bite, vasculitis, tularemia, scrub typhus, rickettsial spotted fevers, rat-bite fever, and ecthyma gangrenosum.2 Contact with possibly infected animals or animal products or exposure to bioterrorism-related contamination are important diagnostic factors.
Diagnostic procedures are available to demonstrate the causative bacteria. In addition, a cutaneous anthrax management algorithm is available from the American Academy of Dermatology, (AAD), which includes the AAD's current recommendations for disease treatment steps, as follows:
- Examination of exudate from skin vesicles yields either Gram-positive spore-forming rods of B anthracis on Gram's stain or growth of B anthracis microorganisms in cultures on sheep blood or chocolate agar.
- During the eschar stage, swabs should be taken from under the gently lifted edge of the eschar. Otherwise, swabs from the base of the ulcer should be examined if neither vesicle nor eschar is present.
- Two full-thickness, 4-mm punch biopsies of the lesion may also be considered. One specimen, fixed or unfixed, may be obtained for histologic examination, immunohistochemistry studies, and PCR examination, and 1 sterile unfixed specimen can be obtained for Gram's stain or other staining and microbiology cultures.
- When a vesicle is present, both the vesicle edge and the adjacent nonvesicular skin should be included in the biopsy.
- If eschar is present, both the center and the erythematous area immediately adjacent to the edge of the eschar should be included.4,10
Lesions may not yield bacterial growth after treatment with antibiotics. Moreover, because skin lesions are caused by exotoxins, absence of B anthracis does not rule out cutaneous anthrax. Blood cultures may be helpful in establishing anthrax diagnosis, and they are always recommended when anthrax is in the differential diagnosis. Preferably, cultures should be done before initiation of antibiotic treatment. Examination for rising serum antibody titers can also be performed. Nasal swab examination should not be considered a clinically valid test for anthrax exposure.4,8
Microscopic examination of week-old cutaneous anthrax lesions reveals coagulative hemorrhagic necrosis involving the epidermis and superficial dermis and associated with prominent edema of underlying viable tissue (Figure 3). Focal stromal hemorrhages, rare foci of degenerated acute inflammatory infiltrates, and marked and occasionally atypical mononuclear inflammatory infiltrates in perivascular and periadnexal location are present. Focal islands of regenerating epidermis line the superficial layer of edematous viable tissue under a necrotic layer of eschar, with a lack of granulation tissue formation. Histopathologic findings explain the common absence of significant scarring as the result of eschar healing.7
ANTHRAX AS A BIOLOGIC WEAPON
All forms of anthrax—cutaneous, inhalational, and gastrointestinal—may result when B anthracis is used as a biologic weapon.
A biphasic illness, inhalational anthrax probably accounts for the highest mortality. The initial phase is characterized by malaise, confusion, myalgia, chest and abdominal pain, and mild fever. There is rapid progression in the fulminant phase of respiratory distress, characterized by fever, acute dyspnea, cyanosis, and shock, followed by death. Radiologic examination shows mediastinal widening due to massively enlarged lymph nodes. Hemorrhagic pleural effusions and pulmonary infiltrates may be present. Anthrax meningitis may also be a lethal complication of the systemic spread of B anthracis.6
The differential diagnosis of early inhalational anthrax symptoms includes influenza-like illness. Although some cases of influenza-like illness are caused by bacteria, most are caused by viruses. They are usually associated with rhinorrhea, contrary to inhalational anthrax. Nevertheless, prominent influenza-like symptoms with mediastinal widening and pleural effusions should be vigorously treated as inhalational anthrax until proven otherwise.11
Gastrointestinal anthrax may follow ingestion of undercooked meat, either spore-containing or contaminated by a large number of vegetative bacilli. Patients with gastrointestinal anthrax complain of nausea, vomiting, abdominal pain, bloody diarrhea; they are febrile and dehydrated. Symptoms progress to an acute abdomen due to massive edema involving the intestinal wall. Secondary obstruction, hemorrhagic mesenteric lymphadenitis and ascites, and mucosal ulcerations and wall perforations lead to hemorrhage, sepsis, and shock. Oropharyngeal anthrax is a form of gastrointestinal anthrax, and it is characterized by pharyngitis with 1 or more eschars, neck swelling, and lymphadenopathy.1–4
To make a timely diagnosis and cure the patient, a blood culture should be obtained and a fecal sample and peritoneal fluid should be collected for cultures. Because early diagnosis may be difficult, mortality is high.1–4
If it is suspected that a patient was exposed to anthrax as a biologic weapon, the local Department of Health should be notified immediately and specific instructions should be obtained. Currently, the CDC recommends the Food and Drug Administration-approved anthrax vaccine for preexposure prophylaxis only when there is a risk for repeated exposures, such as in military and laboratory personnel. Additional recommendations regarding prophylaxis, diagnosis, and treatment of anthrax are available on the CDC Web site.12,13
Medical treatment is recommended for the various forms of anthrax, which should be followed as published according to the patient's age and clinical status. Initial treatment should be changed based on the patient's susceptibility results or clinical course. Blood cultures should be obtained before antibiotic treatment is started, and a consultation with an infectious disease specialist is suggested.2,14
Adults with cutaneous anthrax should be treated with oral ciprofloxacin, 500 mg BID, or oral doxycycline, 100 mg BID, for 7 to 10 days. With signs of systemic involvement, extensive edema, and lesions on the head or neck, cutaneous anthrax requires hospitalization and treatment similar to inhalational anthrax: IV ciprofloxacin, 400 mg every 12 hours, and a multidrug approach that takes into consideration patient age; pregnancy status; compromised immune status; optimal therapy if the strain has proved susceptible; and other circumstances, such as drug hypersensitivity or exhaustion of drug supplies. Corticosteroids may be necessary to treat life-threatening edema or may be used as adjuvant treatment for facial and neck lesions and for systemic or central nervous system involvement.2,14
In case of a bioterrorism attack, treatment should be continued for at least 60 days (perhaps 120 days after a large exposure) due to potential persistence of inhaled aerosolized B anthracis spores.2,14
Because of possible bacterial spread, surgery should be avoided during a vesicular period, unless the lesion has been proved to be sterile by preceding microbiologic examination in which swab utilization did not yield B anthracis growth. Surgical procedures may include tissue biopsy to determine diagnosis. Surgery of large necrotic lesions may be performed when the diagnosis is clinically uncertain, including when (1) the gross appearance of the lesion is atypical, (2) there is no history of possible B anthracis exposure, and (3) there is patient concern regarding a disfiguring scar. Conservative antibiotic treatment is recommended when the lesion, with vesicle, ulcer, or eschar, is diagnosed as cutaneous anthrax. Locally, dry dressings protect the skin lesion against superimposed infection. Topical therapy is not effective. Self-limited healing of the cutaneous lesion is a rule, without complications and permanent scarring in most cases treated with antibiotics. If secondary infection of anthrax-related necrosis occurs, however, it may be treated surgically, according to individual presentation and specific clinical indications.2,4,10
Although there have been no documented person-to-person anthrax transmissions, clinical specimens should be isolated and handled as potentially infectious; protective eyewear, closed-front laboratory coats, and gloves should be used. Dressings that had covered draining cutaneous lesions should be treated as hazardous waste. All areas exposed to possible vegetative forms of anthrax should be decontaminated by cleansing with hypochlorite solution. To decontaminate any surface possibly contaminated by spores, leave the disinfectant on the surface for 1 hour. All instruments should be autoclaved. Avoid any action that could create aerosol or droplet dispersal of the suspicious examined or discarded material.3,8
Most cutaneous anthrax cases heal spontaneously, with no permanent scarring. Histopathologic findings show epidermalization of viable tissue without granulation tissue formation in the eschar phase of the skin lesion. Therefore, conservative treatment is recommended for uncomplicated cutaneous anthrax. Because systemic spread of the disease can be fatal, antibiotic treatment is important, with ciprofloxacin or doxycycline the preferred antibiotics. Diagnostic surgical biopsy may be used, and surgical treatment may be needed for secondarily infected cases. Treatment decisions, however, should be made by the physician and the patient, based on the individual case presentation.
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