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eMedicine - Dermatologic Aspects of Bioterrorism Agents, Anthrax : Article by

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Introduction
Pathophysiology
Clinical Findings
Diagnosis, Treatment, and Vaccination
Biological Warfare Considerations
Treatment and Prophylaxis Recommendations
Summary
Acknowledgments
Multimedia
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Patient Education
Bioterrorism and Warfare Center

Anthrax Introduction

Anthrax Causes

Anthrax Signs and Symptoms

Anthrax Treatment

Biological Warfare


AUTHOR AND EDITOR INFORMATION

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Author: Chad M Hivnor, MD, Chief, Outpatient and Pediatric Dermatology, Dermatology Clinic; San Antonio Unified Services Health Education Consortium; Lackland Air Force Base, Texas

Chad M Hivnor is a member of the following medical societies: American Academy of Dermatology and American Medical Association

Coauthor(s): Nicole M Owens, MD, Assistant Program Director, SAUSHEC Dermatology Residency Program, Assistant Chief, Dermatology Department, Brooke Army Medical Center, Fort Sam Houston

Editors: Takeji Nishikawa, MD, Emeritus Professor, Department of Dermatology, Keio University School of Medicine; Director, Samoncho Dermatology Clinic; Managing Director, The Waksman Foundation of Japan Inc; David F Butler, MD, Professor of Dermatology, Texas A&M University College of Medicine; Director, Division of Dermatology, Scott and White Clinic; Director Dermatology Residency Training Program, Scott and White Clinic; Rosalie Elenitsas, MD, Associate Professor of Dermatology, University of Pennsylvania School of Medicine; Director, Penn Cutaneous Pathology Services, Department of Dermatology, University of Pennsylvania Health System; Joel M Gelfand, MD, MSCE, Medical Director, Clinical Studies Unit, Assistant Professor, Department of Dermatology, Associate Scholar, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania; Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center

Author and Editor Disclosure

Synonyms and related keywords: biological warfare, bioterrorism-induced disease, bioterrorism agents, Bacillus anthracis, B anthracis, pulmonary anthrax, wool-sorter's disease, wool sorter's disease, woolsorter's disease, inhalational anthrax, cutaneous anthrax, gastrointestinal anthrax, GI anthrax, treatment of anthrax, diagnosis of anthrax

INTRODUCTION

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The bioterrorist attacks of late 2001 emphasize the importance of recognizing cutaneous manifestations of bioterrorism agents. After these attacks, 22 anthrax infections were identified in the United States, 11 of which were cutaneous (7 confirmed, 4 suspected).1 Prior to this outbreak, most experts believed that terrorists would aerosolize anthrax spores and cause only inhalational disease.2, 3

Dermatologists played a vital role in diagnosing the initial 3 cases of cutaneous anthrax in New York City in October 2001. They will continue to be involved in diagnosing bioterrorism-related disease because 10 of the top 12 category-A high-priority biological agents that pose a risk to national security also cause cutaneous manifestations; only botulism toxin and Lassa fever virus do not.4

For information on other potential bioterrorism agents, see Dermatologic Aspect of Bioterrorism Agents. Also, the Medscape Disaster Preparedness and Aftermath Resource Center may be of interest.


PATHOPHYSIOLOGY

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Bacillus anthracis is a gram-positive, spore-forming bacillus that derives its name from the Greek word for coal or charcoal, anthrakos. Two plasmids play a significant role in the virulence of the bacteria. The first plasmid encodes a D-glutamic acid capsule that prevents phagocytosis. The second plasmid codes for 3 toxin subunits: protective antigen (PA), edema factor (EF), and lethal factor (LF).5, 6 These factors must combine with PA to exert their effects.7

Seven PA units attach to receptors on the host cell to create a channel that allows EF or LF to enter the cytoplasm directly or by means of endocytosis.6, 8 Once in the cell, EF causes edema and an increase in cyclic adenosine monophosphate levels by affecting water homeostasis.9 LF causes the release of tumor necrosis factor–alpha and interleukin-1 beta.9, 10 Antibodies to PA or mutant PA respectively neutralize or inactivate the toxic effects of either EF or LF. These factors will likely be important for treatment and/or prevention in the future.11, 12

Reports as of 2007 confirm that "PA immunization reduced bacterial growth from the outset and limited infection at the site of inoculation.”13 Other mechanisms of prevention include looking at the sites of mediators of susceptibility to LF in particular.14


CLINICAL FINDINGS

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Cutaneous manifestations

In more than 95% of cases of endemic disease, anthrax spores are transmitted from infected animals or their products to humans with entry via skin abrasions.3

The lesions of cutaneous anthrax have a predictable course. After a variable latency period (range, 1-12 d; mean, 5 d15), a nontender, pruritic macule or papule appears at the site of inoculation. The primary lesion progresses to a vesicle or a bulla after 24-48 hours. The bulla enlarges to 1-2 cm, spontaneously ruptures, and forms an ulcer. A hemorrhagic crust develops and is often accompanied by striking edema (which is worse on the face), erythema, and satellite vesicles. Edema can occur any time during lesion progression (see Media File 6 and Media File 12).

Regional adenopathy, low-grade fever, and malaise often occur within 3-4 days after the primary lesion appears. A 2006 study of mice infected cutaneously with anthrax demonstrated parotid lymph node involvement by the bacteria within 24 hours of percutaneous inoculation and lung and spleen involvement within 36 hours.16 This finding, suggesting that subclinical systemic infection may occur early after cutaneous inoculation, emphasizes the importance of early treatment with prophylactic antibiotics even with cutaneous disease.

The hemorrhagic crust develops into a thick, adherent, brown-black, painless, nontender eschar surrounded by a warm, red, edematous, indurated base. The eschar dries and detaches in 1-2 weeks and reportedly leaves little residual scarring. Edema and painlessness are features that help in differentiating anthrax from other diseases, such as a brown recluse spider bite or ulceroglandular tularemia.

In the absence of antibiotic treatment, 80-90% of lesions heal spontaneously, but 10-20% progress, with resultant malignant edema, septicemia, shock, renal failure, and death. The skin lesions progress despite the administration of antibiotics, which only sterilize the lesion and do not block the effects of the toxins.3

Noncutaneous manifestations

Spores are sometimes transmitted by means of ingestion or inhalation. GI anthrax is exceedingly rare and difficult to diagnose; therefore, resultant mortality rates are high.3 Most cases of GI anthrax are caused by ingestion of under-cooked, infected meat. Patients may present with sore throat, neck swelling, abdominal pain, diarrhea, acute infection, and ulcerative mucosal eschars (posterior oropharynx and intestinal), which can cause perforated viscera. No cases of human GI anthrax have been diagnosed in the United States. A 2006 mouse model demonstrated that Peyer patches are the site of bacterial growth in intragastric inoculation. This model should help study dissemination in this subset of anthrax infection.16

Pulmonary anthrax (wool-sorter's disease) is an extraordinarily rare form of anthrax; only 18 cases were reported in the United States from 1900-1980.17, 18 As demonstrated in the biological weapons facility accident in Sverdlovsk, Russia, most of the morbidity and essentially all the mortality from released anthrax spores are due to inhalational anthrax.19 Between September 2001 and  January 9, 2002, 11 cases of confirmed inhalational anthrax were  diagnosed in the United States.20, 21

On the basis of the findings from the cases in the United States and Sverdlovsk, Russia, clinical manifestations appear 2-43 days after exposure. Initial clinical symptoms are nonspecific and mimic influenzalike infections. Symptoms include malaise and fever with prominent coughing, nausea, and vomiting.9 Other manifestations may include tachycardia, hypoxemia, and elevated transaminase levels. Diagnosis of anthrax on the basis of these symptoms is difficult and may be missed; however, chest radiographs typically reveal mediastinal widening and pleural effusions not commonly seen in influenza. Chest radiograph findings are explained by the 2006 mouse model of anthrax, which found that regardless of means of entry (eg, cutaneous, intravenous, GI), bacteria eventually migrate in large numbers to the lungs and subsequently drain into the mediastinal nodes.16 For more comprehensive information regarding inhalational anthrax, refer to the articles by Inglesby et al,9 Mina et al,20 and Barakat et al21 or the Centers for Disease Control and Prevention.


DIAGNOSIS, TREATMENT, AND VACCINATION

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Diagnosis

The rapid notification to local and state health departments of a potential anthrax infection can prevent excessive morbidity and mortality. Of the recent US bioterrorism-related cases, biopsy was performed in 8 lesions, all of which had the B anthracis cell wall antigen as detected with immunohistochemical (IHC) testing.15, 22, 23, 24 No other serologic or skin test was as sensitive. A 2006 retrospective study by the US Centers for Disease Control and Prevention (CDC) showed that in all 16 cases of bioterrorism, inhalational or cutaneous anthrax showed evidence of B anthracis with IHC testing,25 making this the diagnostic test of choice. In addition to its increased sensitivity, use of IHC testing for diagnosis preserves tissue morphology and requires less handling of hazardous agents used for alternative diagnostic methods.

B anthracis grows on routine culture media; however, cutaneous anthrax lesions are sterilized after only 1-2 days of antibiotic therapy. Tissue culture is, therefore, not helpful for diagnosis in patients taking antibiotics at the time of presentation. The acquisition of a skin biopsy sample for IHC testing is crucial in diagnosing cutaneous anthrax in these patients.10 Even in patients not taking antibiotics, culture and Gram stain results may be negative, but skin biopsy with IHC testing is diagnostic, as was seen in the index-case patient in New York City in 2001.3 Polymerase chain reaction can also be used in formalin-fixed, paraffin-embedded tissue.26 For further information regarding histopathologic diagnosis and IHC of all bioterrorism agents, refer to a 2006 review by Guarner and Zaki.27

The most common misdiagnosis of cutaneous anthrax is a brown recluse spider bite. The main differentiating feature is the exquisite pain associated with the spider bite. Although the primary lesion of anthrax has been called a malignant pustule, this is a misnomer because no pustule is present. Any pustules seen likely represent secondary infection by streptococci or staphylococci.

The most thorough resource for information about diagnosis and treatment is available at the Cutaneous Anthrax Management Algorithm page on the Web site of the American Academy of Dermatology. More information on the diagnosis and treatment of biological agents is also available on the Bioterrorism page on the Web site of the US Food and Drug Administration.

For excellent patient education resources, visit eMedicine's Bioterrorism and Warfare Center. Also, see eMedicine's patient education articles Biological Warfare and Anthrax.

Treatment

Given the potential for systemic dissemination and death from cutaneous anthrax, initiating treatment as soon as possible is vital and should not be delayed until biopsy or culture results are obtained.

Treatment with ciprofloxacin or doxycycline is appropriate until antimicrobial sensitivities are known.3, 15, 28 Stephenson advocates the use of doxycycline instead of ciprofloxacin because B anthracis can develop increasing resistance in vitro to quinolones and macrolides but has minimal resistance to doxycycline.28 Anthrax, however, has shown resistance to doxycycline in vivo, and Russian scientists may have genetically engineered doxycycline-resistant strains of B anthracis.29

The clinical scenarios in which ciprofloxacin is favored over doxycycline are infections involving pregnant or breastfeeding females30 or patients with anthrax meningitis.31 Some have advocated the use of steroids to prevent edema and toxic effects.32 Chloroquine has increased survival in mice challenged with a lethal anthrax dose.33 See summary information in Tables 1 and 2 in Treatment and Prophylaxis Recommendations.

The statement that "incision or debridement should be avoided"34 has no substantiation in the literature. This comment is likely an anecdotal statement from the preantibiotic era. Biopsy with the administration of antibiotics poses a minimal risk and is essential for diagnosis when IHC testing is used.10 Debridement, however, should be avoided in certain cases because it removes the eschar, which serves as a biological dressing.

One study investigating anthrax spore survival and hand hygiene showed that washing with soap and water, 2% chlorhexidine gluconate, and chlorine-containing towels reduced anthrax spore counts, whereas waterless rubs containing ethyl alcohol were not effective.35 Current research is still being focused on the prevention of toxin release, which may be the key in preventing morbidity and mortality. This is particularly being studied for vaccines.

Vaccination

An anthrax vaccine adsorbed (AVA) is licensed by the US Food and Drug Administration. The vaccine is an avirulent, nonencapsulated strain of B anthracis. AVA has been proven safe and effective in preventing anthrax among textile workers, veterinarians, and laboratory workers at risk.36 Findings from one study suggested that the vaccine is also safe in pregnant women.37 AVA protects nonhuman primates against an aerosol challenge with anthrax spores at a rate of 100% at 38 weeks after vaccination and at a rate of 88% at 100 weeks.3, 38 The vaccine had come under severe scrutiny, and the manufacturer suspended production in 1998 for safety checks.39 However, the vaccine was once again approved for production in early 2002, and the Institute of Medicine determined that AVA was safe.36

A tremendous amount of money and effort have been spent on new vaccine development and trials since October 2001. The findings of a Russian study emphasize the importance of future studies. The results showed that genes transferred from Bacillus cereus can enable anthrax bacilli to evade protection in rodents provided by a live attenuated Russian vaccine.3 Young and colleagues described the cellular receptor for the anthrax toxins.40 An antitoxin similar to this receptor should be effective against antibiotic-resistant bacteria. The future lies in antibody-based therapies or vaccinations, which may decrease the duration of the currently recommended 60- to 100-day antibiotic regimen.5, 38 For example, a second-generation recombinant PA intranasal vaccine has shown complete protection against inhalational anthrax in rabbits.41


BIOLOGICAL WARFARE CONSIDERATIONS

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In a biological warfare scenario, anthrax could be disseminated in an odorless and invisible cloud that could travel for many kilometers, depending on wind and other factors.3 During World War II, a number of anthrax spores were detonated on Gruinard Island off the northwest coast of Scotland. Virulent spores were found in several areas of the island 40 years later.3 A total of 280 tons of stabilized 37% formaldehyde and 2000 tons of seawater were required to decontaminate the island. This test showed that spores could be explosively released, kill exposed animals, and retain long-term virulence.3

Japan, the United Kingdom, the Soviet Union, and the United States weaponized this same strain of resilient anthrax spores in the 1950s and the 1960s. In 1969, the United States unilaterally destroyed its stocks of biological weapons. Iraq admitted to the United Nations inspection team in 1995 that they had biological weapons containing anthrax.3, 42

The complete genetic sequence of anthrax is now known. The minimum lethal dose of spores is not known and may be quite low.  Lethality has varied among accidental cases and naturally occurring cases and may have been altered by genetic modification of the bacteria. No cases of inhalational anthrax developed in a group of goat mill workers who inhaled an average of 510 naturally occurring spores over 8 hours. This is in contrast to the Sverdlovsk Russian outbreak of inhalational anthrax in which at least 68 people died from inhalational anthrax. The Russian government admitted in 1992 that the spores were accidentally released from a biological warfare research laboratory when a worker failed to turn on the safety filters before beginning work.19, 29, 43 Based on the number of citizens exposed to the aerosol, the median lethal dose among those dying was only 9 spores, with an amount of less than 1 g of spores probably causing the outbreak.19, 44 Other reports suggest that Russian scientists have engineered a new strain to resist tetracyclines and penicillin.3, 45

A 94-year-old woman from Connecticut and a 61-year-old woman from New York City had no known exposure to anthrax, but they developed inhalational anthrax in late 2001. The minimum lethal dose remains unknown and may be low.

Proper intelligence, early identification of index cases, and preparation in terms of public health measures are the keys to the successful management of future bioterrorism events. Epidemiologic studies and vaccine trials and research must be continued, and the molecular pathogenesis should be further explored.


TREATMENT AND PROPHYLAXIS RECOMMENDATIONS

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Table 1. Treatment of Patients Older Than 2 years With Cutaneous Anthrax Without Systemic Symptoms, Extensive Edema, and Not Located on the Head or Neck. Adapted from the American Academy of Dermatology Web site.

CategoryInitial Oral TherapyDuration (d)
Adults*Ciprofloxacin at 500 mg bid or doxycycline at 100 mg bid100†
Children*Ciprofloxacin at 15 mg/kg q12h (not to exceed 1 g/d)‡ or doxycycline§ in those >8 years and >45 kg at 100 mg q12h; all other children, 2.2 mg/kg q12h100†
Pregnant women*||Ciprofloxacin at 500 mg bid (preferred) or doxycycline at 100 mg bid (Current recommendations favor ciprofloxacin over doxycycline in pregnant women when susceptibilities are known.)100†
Persons who are immunocompromised*Same as for persons who are immunocompetent and for children100†
*Cutaneous anthrax with signs of systemic involvement, extensive edema, or lesions on the head or the neck requires intravenous therapy, and a multiple-drug approach is recommended (see Table 2 below).
†Previous guidelines have suggested treating cutaneous anthrax for 7-14 days, but 100 days is recommended in the setting of this attack, given the likelihood of simultaneous exposure to aerosolized B anthracis.
‡Ciprofloxacin or doxycycline should be considered first-line therapy. Oral amoxicillin at 500 mg tid for adults or at 80 mg/kg/d divided every 8 hours for children is an option for completion of therapy after clinical improvement. The oral amoxicillin dosage is based on the need to achieve appropriate minimum inhibitory concentration levels.
§The American Academy of Pediatrics recommends treatment with tetracyclines for young children who have serious infections (eg, Rocky Mountain spotted fever).
||Although tetracycline or ciprofloxacin is not recommended during pregnancy, they may be indicated for life-threatening illness. Adverse effects on developing teeth and bones are dose related; therefore, doxycycline might be used briefly (7-14 d) before 6 months of gestation.

Table 2. Treatment of Patients With Cutaneous Anthrax With Systemic Symptoms, Extensive Edema, Location on the Head or Neck, or Younger Than 2 Years (same as for inhalational anthrax). Adapted from the American Academy of Dermatology Web site.
CategoryIntravenous Therapy* † Duration (d)
AdultsCiprofloxacin at 400 mg q12h or doxycycline at 100 mg q12h and 1-2 additional antimicrobials† IV treatment initially.‡ Switch to oral antimicrobial therapy when clinically appropriate. See Table 1 above for oral therapy. (IV and oral combined)§
ChildrenCiprofloxacin at 10 mg/kg q12h (not to exceed 1 g/d)|| or doxycycline in those >8 years and >45 kg at 100 mg q12h; all other children 2.2 mg/kg q12h and 1-2 additional antimicrobials† IV treatment initially.‡ Switch to oral antimicrobial therapy when clinically appropriate. See Table 1 above for oral therapy. Continue for 100 days (IV and oral combined).§
Pregnant women#Same as for nonpregnant adults; the high death rate from the infection outweighs the risk posed by the antimicrobial agent. Current recommendations favor ciprofloxacin over doxycycline in pregnant women when susceptibilities are known.IV treatment initially.‡ Switch to oral antimicrobial therapy when clinically appropriate. See Table 1 above for oral therapy. Continue for 100 days (IV and oral combined).§
Persons who are immunocompromisedSame as for adults and children who are immunocompetentSame as for adults and children who are not immunocompromised
*Steroids may be considered as an adjunct therapy for patients with severe edema and for patients with meningitis based on experience with bacterial meningitis from other causes.
†Other agents with in vitro activity include rifampin, vancomycin, penicillin, ampicillin, chloramphenicol, imipenem, clindamycin, and clarithromycin. Because of concerns of constitutive and inducible lactamases in B anthracis, penicillin and ampicillin should not be used alone. Consultation with an infectious diseases specialist is advised.
‡Initial therapy may be altered based on the clinical course of the patient; 1-2 antimicrobial agents (eg, ciprofloxacin, doxycycline) may be adequate as the patient's condition improves.
§Because of the potential persistence of spores after an aerosol exposure, antimicrobial therapy should be continued for 100 days. ||If intravenous ciprofloxacin is not available, oral ciprofloxacin may be acceptable because it is rapidly and well absorbed from the GI tract with no substantial loss by first-pass metabolism. Maximum serum concentrations are attained 1-2 hours after oral dosing but may not be achieved if vomiting or ileus is present.
The American Academy of Pediatrics recommends the use of tetracycline to treat young children with serious infections (eg, Rocky Mountain spotted fever).
#Although tetracycline or ciprofloxacin is not recommended during pregnancy, the use of either of them may be indicated for life-threatening illness. Adverse effects on developing teeth and bones are dose related; therefore, doxycycline might be used for a short time (7-14 d) before 6 months of gestation.


SUMMARY

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Anthrax is a credible biological warfare agent with a high potential for morbidity and mortality. It has 3 toxin subunits that are essential for pathogenesis. The cutaneous findings have a typical but nonspecific course. Edema at any stage and the painless nature of the lesions are key features that differentiate anthrax from other diseases. IHC testing for bacterial antigens by means of biopsy is the best method for diagnosis. If anthrax is suspected, however,  do not wait for a diagnosis before notifying the local authorities and initiating treatment with ciprofloxacin or doxycycline. Potential vaccines and treatments may shorten the present course of treatment of 60-100 days.


ACKNOWLEDGMENTS

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The authors and editors of eMedicine gratefully acknowledge the contributions of previous author, Thomas W. McGovern, MD, to the development and writing of this article.


MULTIMEDIA

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Media file 1:  Cutaneous anthrax showing the typical black eschar. Courtesy of the Public Health Image Library, Centers for Disease Control and Prevention (CDC), Atlanta, Ga.
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Media file 2:  Polychrome methylene blue stain of Bacillus anthracis. Courtesy of Anthrax Vaccine Immunization Program (AVIP) agency, Office of the Army Surgeon General, United States.
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Media file 3:  Cutaneous anthrax. Courtesy of Anthrax Vaccine Immunization Program (AVIP) agency, Office of the Army Surgeon General, United States.
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Media file 4:  Skin lesion of anthrax on the face. Courtesy of the Public Health Image Library, Centers for Disease Control and Prevention (CDC), Atlanta, Ga.
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Media file 5:  Flea bites. Each lesion can mimic the primary lesion of anthrax. The initial red, itchy bump in many diseases is nondiagnostic. The lesions of folliculitis, acne, irritant dermatitis, and many other skin diseases can mimic this first lesion. Courtesy of American Academy of Dermatology.
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Media file 6:  Seven-month-old infant with anthrax. In this infant, the infection progressed rapidly with significant edema developing the day after exposure. This large hemorrhagic lesion developed within 3 more days. The infant was febrile and was admitted to the hospital on the second day after the symptoms appeared.

On September 28, 2001, the infant had visited the mother's workplace. On September 29, nontender massive edema and a weeping erosion developed. On September 30, a 2-cm sore developed over the edematous area. (Note that edema preceded the primary lesion.) On October 2, an ulcer or eschar formed, and the lesion was diagnosed as a spider bite. Hemolytic anemia and thrombocytopenia developed, and the patient was hospitalized. Serum was drawn on October 2; the polymerase chain reaction results were positive for Bacillus anthracis. On October 13, skin biopsy results were positive with immunohistochemical testing for the cell wall antigen.

Note that the initial working diagnosis was a Loxosceles reclusa spider bite with superimposed cellulitis. Courtesy of American Academy of Dermatology with permission of NEJM.
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Media file 7:  Fourth patient with cutaneous anthrax in New York City, October 2001. This dry ulcer was present. Photo used with permission of the patient. Courtesy of American Academy of Dermatology. Courtesy of Sharon Balter of the New York City Department of Health.
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Media file 8:  Note the hemorrhage that is associated with cutaneous anthrax lesions. The early ulcer has a moist base. Courtesy of American Academy of Dermatology.
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Media file 9:  Note the central ulcer and eschar. Courtesy of American Academy of Dermatology.
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Media file 10:  An example of a central ulcer and eschar with surrounding edema. Courtesy of American Academy of Dermatology with permission from Boni Elewski, MD.
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Media file 11:  Note the black eschar. Courtesy of American Academy of Dermatology. Courtesy of Gorgas Course in Clinical Tropical Medicine.
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Media file 12:  Anthrax with facial edema. Courtesy of American Academy of Dermatology.
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Media file 13:  Bioterrorist Agents. Signs and symptoms. Chart courtesy of North Carolina Statewide Program for Infection Control and Epidemiology (SPICE), copyright University of North Carolina at Chapel Hill, www.unc.edu/depts/spice/bioterrorism.html.
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REFERENCES

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Dermatologic Aspects of Bioterrorism Agents, Anthrax excerpt

Article Last Updated: Jun 20, 2008