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Anthrax: ENT manifestations and current concepts
ORIGINAL ARTICLES Anthrax: ENT manifestations and current concepts ARI WIRTSCHAFTER, MD, SREEKANT CHERUKURI, MD, and MICHAEL S. BENNINGER, MD, Detroit, Michigan
In light of recent events, anthrax has once again taken center stage in the world of science and the world in which we live. Because patients with anthrax may initially present to otolaryngology clinics, it is important for the otolaryngologist to know how to diagnose and treat this entity. This article will present current information on epidemiology, microbiology, pathogenesis/clinical manifestations, diagnosis, and treatment with a particular interest in the head and neck region. (Otolaryngol Head Neck Surg 2002;126:8-13.)
rich in organic matter, and dramatic changes in soil microenvironment seen with abundant rainfall or drought.1 There are 4 clinical types of human anthrax: cutaneous, inhalational, gastrointestinal, and oropharyngeal.3 Cutaneous anthrax accounts for more than 90% of the cases worldwide.3 Before the recent events, the last reported case of inhalational anthrax in the United States was in 1976.4 Gastrointestinal anthrax has never been reported in this country.2 Oropharyngeal anthrax is the least common form of anthrax, with approximately 30 cases reported worldwide in association with 2 separate outbreaks in Thailand and Turkey.5,6
In light of recent events, anthrax has once again taken
MICROBIOLOGY
center stage in the world of science and the world in which we live. From ancient plagues in Egypt to Koch’s postulates of bacteriology to the first successful antibacterial vaccine created by Louis Pasteur, anthrax has played a pivotal role in history.1,2 More recently, it has been developed into a biological weapon, and possibly a weapon of mass destruction. In the 7 weeks following the September 11 tragedies, 7 cases of inhalation anthrax (3 fatal) and 8 cases of cutaneous anthrax have plagued the United States. It is imperative that all physicians, including otolaryngologists, understand this entity and know how to treat it.
Bacillus anthracis is an aerobic, nonhemolytic, nonmotile, sporulating gram-positive rod (Fig 1). This organism, which primarily resides in soil, is resistant to drying, heat, ultraviolet light, gamma radiation, and many disinfectants. Herbivores, who contract systemic anthrax from spore-infested soil, can transmit this to human beings by contact with the infected animal or their products.7 Virulence requires a 3-component protein exotoxin and a poly-D-glutamic acid capsule whose production is dependent on 2 plasmids (pX01 and pX02, respectively).1 The first component of the exotoxin, called protective antigen, binds to a cell surface receptor. Following proteolytic cleavage, the protective antigen serves as a binding site for the other 2 components, edema factor and/or lethal factor. The protective antigen’s name is derived from its use in anthrax vaccines. The second component of the exotoxin, the edema factor, is a calmodulin-dependent adenyl cyclase. When injected subcutaneouly, it has been found to cause edema in experimental animals.1 The third component, lethal factor, is a protease that cleaves mitogen-activated protein (MAP), kinase kinases 1 and 2. It is this component that causes death, although the specific mechanism is unknown. In order for the organism to be successful, it must have its poly-D-glutamic acid capsule, which is weakly antigenic and antiphagocytic. Strains with a pX02 deletion and thus no capsule are avidly phagocytosed by polymorphonuclear leukocytes.1
EPIDEMIOLOGY
Bacillus anthracis is primarily found in tropical environments in Africa, Asia, South and Central America, and the Caribbean.3 Highly endemic countries such as Pakistan, Iran, and Iraq continue to have epizootic anthrax. Although specific reasons for an agricultural outbreak are not fully understood, certain conditions make it more favorable such as soil pH above 6.0, soil
From the Department of Otolaryngology–Head and Neck Surgery, Henry Ford Hospital. Reprint requests: Michael S Benninger, MD, Chairman, Department of Otolaryngology–Head and Neck Surgery, Henry Ford Hospital, 2799 West Grand Blvd, Detroit, MI 48202; e-mail, [email protected] Copyright © 2002 by the American Academy of Otolaryngology– Head and Neck Surgery Foundation, Inc. 0194-5998/2002/$35.00 + 0 23/1/121513 doi:10.1067/mhn.2002.121513 8
PATHOGENESIS/CLINICAL MANIFESTATIONS
As mentioned, there are 4 clinical types of human anthrax.3 Dissemination of spores depends on which
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Table 1. Differential diagnosis of oropharyngeal anthrax Peritonsillar abscess Parapharyngeal space abscess Strep pharyngitis Ludwig’s/Vincent’s angina Diphtheria
area is affected. All types can lead to septicemia, shock, and death. Cutaneous Anthrax
Cutaneous anthrax develops after the introduction of spores into the subcutaneous tissues through cuts or abrasions. This occurs primarly at areas of exposed skin such as face, neck, and extremities. Although the interval between exposure and infection is not definitively known, it is usually between 2 and 3 days after the inciting event and has been reported as long as 12 days.7,8 Once infected, the spores germinate and spread via the antiphagocytic properties of the capsule. Release of the exotoxin results in local edema and eventually tissue necrosis.4,7 The initial lesion is a pruritic macule or papule that enlarges into a round ulcer by the second day. A clear or serosanguineous fluid containing numerous organisms is released from 1 to 3 mm vesicles in the surrounding area. The ulcer matures into a painless, depressed, black eschar that dries and falls off over the next 1 to 2 weeks. It is from the appearance of this black eschar that anthrax (Greek for “coal”) derives its name.2 There can be significant edema around the site of the ulcer. Fig 2 demonstrates a cutaneous lesion on the side of the neck. In contrast to the skin lesion, the regional lymphadenopathy that develops is painful.7 One particular concern of lesions in the head and neck region is that edema in this location can tract rapidly along soft tissue plains and patients can develop shortness of breath and possibly even airway obstruction.2,9 Patients may require corticosteroids, intubation, or even tracheostomy to avoid asphyxiation.2,3 Khajehdehi9 describes a young Iranian village woman with cutaneous anthrax of neck who developed rapid swelling of the face, neck, shoulders, chest, and breasts with associated respiratory difficulty. She did not require intubation but it took 2 weeks for her edema to completely resolve. Another interesting case of cutaneous anthrax in the head and neck region involved the nose. A patient who was working with infected sheepskins became severely toxic with nasal discharge. Just beneath his nostril, he had an 8-mm round raised lesion with depressed glis-
Fig 1. Gram stain of Bacillus anthracis shows gram positive rods. (Image courtesy of Dr. William A. Clark, Public Health Image Library, Center for Disease Control, Atlanta, Georgia.)
Fig 2. Cutaneous anthrax lesion on the side of the neck. Note the surrounding vesicles. (Image courtesy of Public Health Image Library, Centers for Disease Control, Atlanta, Georgia.)
tening center. Culture from the nasal discharge revealed Bacillus anthracis. He developed signs of severe systemic toxicity and even required a lumbar puncture to rule-out anthrax meningitis. Ultimately, he responded well to antibiotics and steroids and was discharged.10 Anthrax meningitis is a rare complication of primarily the cutaneous form of anthrax although inhalational and gastrointestinal types have also been associated with it. Symptoms associated with this entity include: fever, headache, nuchal rigidity, agitation, seizures, and delirium. This complication is almost universally fatal, in spite of treatment, and death usually ensues within 1 to 6 days.2
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Table 2. Treatment protocol for inhalation, gastrointestinal, and oropharyngeal anthrax* Category
Adults
Children
Initial therapy (IV)
Ciprofloxacin 400 mg q 12 hrs or Doxycycline 100 mg q 12 hrs AND 1 or 2 additional antimicrobials Ciprofloxacin 10-15 mg/kg q 12 hrs (not to exceed 1g/day) or Doxycycline**: 8 yrs and 45 kg: 100 mg Q 12 hrs 8 yrs and 45 kg: 2.2 mg/kg Q 12 hrs 8 yrs: 2.2 mg/kg Q 12 hrs AND One or two additional antimicrobials
Duration
Switch to oral when clinically appropriate: Ciprofloxacin 500 mg po BID or Doxycycline 100 mg po BID 60 days total antibiotic duration Switch to oral when clinically appropriate: Ciprofloxacin 10-15 mg/kg po Q 12 hrs or Doxycycline (po regimen same as IV) 60 days total antibiotic duration
*For latest CDC recommendations, go to www.cdc.gov. **The American Academy of Pediatrics recommends treatment of young children with tetracyclines for serious infections.
Cutaneous anthrax is ultimately fatal in up to 20% of untreated cases due to systemic manifestations.7 Death is rare if appropriately treated with antibiotics; however, treatment does not alter the course of the skin manifestations of the disease.7 Excising the lesion may hasten systemic dissemination and is contraindicated. Most lesions will not leave any permanent scarring as well.2 Inhalation Anthrax
Inhalational anthrax, also called “Woolsorter’s disease,” follows the inhalation of endospores from infected animals. The dissemination of airborne anthrax is highly dependent on the size of the spores. Those that are greater than 5 µm cannot affect the lungs because they are either trapped in the nasopharynx or cleared by the mucociliary escalator system. If, however, the spores are between 2 and 5 µm, then they can lodge in the alveolar ducts or alveoli.4,11 There they are phagocytosed by macrophages and transported to mediastinal lymph nodes where they proliferate and can cause hemorrhagic mediastinitis. This process may take up to 60 days.4,7 Initial symptoms such as fever, cough, headache, vomiting, weakness, and abdominal or chest pain may mimic common ailments such as influenza. This stage, which may last from hours to days, may even improve prior to the more serious and often fatal second-stage. As hemorrhagic mediastinitis develops, patients develop acute onset of fever, dyspnea, and diaphoresis. Septicemia and shock will occur, and up to half of patients will develop meningitis. Mortality is approximately 90%, but these figures are based on medical science that was available 30 years ago.7 Advances in mechanical ventilation, antibiotic therapy, and other treatment modalities may significantly lower these numbers today along with a high index of suspicion for an outbreak.4
Gastrointestinal Anthrax
Gastrointestinal anthrax is acquired from grossly contaminated and undercooked meat. Bacteria can invade the mucosal and submucosal lymphatics, and ulceration is always seen.2 Symptoms such as nausea, vomiting, and melanotic or bloody diarrhea usually present 2 to 5 days after ingestion and may progress rapidly to ascites, acute abdomen, and sepsis.2,7 There tend to be multiple cases within the same household. Mortality from this entity approaches that of inhalation anthrax due to the difficulty in early diagnosis.2 Oropharyngeal Anthrax
Oropharyngeal anthrax also develops after ingestion of infected meat and subsequent invasion of mucosal and submucosal lymphatics. This entity was first formally documented in the otolaryngology literature by Navacharoen et al12 in 1985. He described an otherwise healthy 59-year-old Thai male admitted to Chiang Mai Hospital with a sore throat and neck swelling 5 hours after ingestion of a local dish of water buffalo. On examination, the patient was noted to have marked inflammation of the soft palate, uvula, and left tonsil with associated necrotic tissue. There was extensive, nonpitting edema over the mandible and neck on the affected side, which extended down to chest and axilla. Gram stain from the lesion on the tonsil showed gram-positive bacilli and cultures later identified the organism as Bacillus anthracis. In spite of appropriate treatment with intravenous penicillin G, the patient died 10 hours after admission.12 In addition to fever, dysphagia, and neck pain, patients with oropharyngeal anthrax may also complain of hoarseness, cough, globus sensation, and difficulty breathing. Neck swelling has been reported up to 6 cm in size. Intraoral examination typically reveals inflam-
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Table 3. Treatment protocol for cutaneous anthrax* Category
Adults Children
Initial therapy (oral)
Duration
Ciprofloxacin 500 mg BID or Doxycycline 100 mg BID Ciprofloxacin 10-15 mg/kg q 12 hrs (not to exceed 1g/day) or Doxycycline**: 8 yrs and 45 kg: 100 mg Q 12 hrs 8 yrs and 45 kg: 2.2 mg/kg Q 12 hrs 8 yrs: 2.2 mg/kg Q 12 hrs
60 days 60 days
*For latest CDC recommendations, go to www.cdc.gov. Multi-drug regimen is recommended for cutaneous anthrax with systemic symptoms, extensive edema, or for lesions on the head and neck. **The American Academy of Pediatrics recommends treatment of young children with tetracyclines for serious infections.
matory lesions (red-purple ulcerations) or asymmetric swelling of the oral cavity or oropharynx. If localized to the tonsillar region, it may mimic a peritonsillar abscess; however, there is no pus. Other sites of lesions include the posterior pharyngeal wall, hard and soft palate, and base of tongue. A gray pseudomembrane may also be present as seen in diphtheria.5,6 Sirisanthana reported that early lesions were edematous and congested, progressing to central necrosis and ulceration after 1 week.5 Table 1 lists a differential diagnosis for oropharyngeal anthrax. All oropharyngeal cases must be carefully observed, because rapid edema may develop and necessitate endotracheal intubation or even tracheostomy. Corticosteroids may be indicated in addition to appropriate antibiotic therapy. In general, these lesions tend to have a more favorable outcome than gastrointestinal anthrax.2,7,11 DIAGNOSIS
Successful diagnosis of anthrax is dependent on a high level of suspicion. Changes in the geopolitical climate coupled with unusual outbreaks of flu-like symptoms should cause alarm. Initial diagnosis will come from gram stain and culture of blood or the affected area.7 Nasal swabs have been an effective means of revealing exposure to anthrax spores. Hail et al13 studied sampling of various sites of rhesus monkeys after exposing them to lethal doses of aerosolized anthrax. He found that swabs from the nares provided the greatest yield of anthrax colony-forming units up to 1 week after exposure. A M’Fadyean stain will demonstrate a pink capsule surrounding dark-blue, often square-ended bacilli.3 It is important to notify the laboratory of suspected anthrax as isolation of Bacillus in the United States usually represents Bacillus cereus, an infection seen with reheating rice.7,14 In the case of oropharyngeal anthrax, definitive diagnosis can be made from a throat swab of the affected side. In general, however, many patients will
present with systemic symptoms and die before culture results are available. Alternatively, inhalation anthrax may be diagnosed with a simple chest x-ray. Specifically, a widened mediastinum in an otherwise healthy individual with flu-like symptoms is considered pathognomonic for anthrax.2 Definitive testing is available at the US Army Medical Research Institute of Infectious Diseases (USAMRIID) located in Fort Detrick, Maryland. Such testing includes enzyme-linked immunosorbent assay for protective antigen and polymerase chain reaction (PCR).7 There is also an anthraxin skin test that consists of a subdermal injection of attenuated organisms. This test was positive in 81.8% of cases in the first 3 days and 97% to 99% positive in the next 2 to 3 weeks, making it a valuable acute as well as retrospective diagnostic tool.2,15 Treatment. Although much of the current media attention has focused on the use of ciprofloxacin for anthrax, numerous antibiotics are effective against this organism, including penicillin, chloramphenicol, tetracycline, erythromycin, streptomycin, macrolides, aminoglycosides, vancomycin, first generation cephalosporins, and other fluoroquinolones.4,7 Cutaneous anthrax is highly susceptible to penicillin and in one study of 25 patients; cultures were negative within 5 hours of initiation of treatment.4,16 However, because anthrax in the face of bioterrorism may have been genetically altered to be resistant to penicillin, the Centers for Disease Control (CDC) currently recommends ciprofloxacin and doxycycline as first-line therapy for all forms of anthrax.7 Other agents listed above may be used as suspectibilities are identified, but penicillin and ampicillin are not currently recommended to be used alone. Multi-drug therapy is recommended for initial treatment of inhalational, gastrointestinal, and oropharyngeal anthrax. Cutaneous anthrax with systemic involvement, extensive edema, and lesions on the head and neck also require multi-drug therapy. The duration of treatment is not definitively known. The CDC currently recommends a 60-day course,
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Table 4.
Postexposure prophylaxis protocol for prevention of inhalation anthrax*
Category
Adults Children
Initial therapy (oral)
Duration
Ciprofloxacin 500 mg BID or Doxycycline 100 mg BID Ciprofloxacin 10-15 mg/kg q 12 hrs (not to exceed 1g/day) or Doxycycline**: >8 yrs and >45 kg: 100 mg Q 12 hrs >8 yrs and 45 kg: 2.2 mg/kg Q 12 hrs 8 yrs: 2.2 mg/kg Q 12 hrs
60 days 60 days
*For latest CDC recommendations, go to www.cdc.gov. **The American Academy of Pediatrics recommends treatment of young children with tetracyclines for serious infections.
because the primary exposure is most likely an aerosol in a setting of bioterrorism. Indeed, spores may not germinate for up to 60 days. Inhalational, gastrointestinal, and oropharyngeal forms are initially treated intravenously and can be later switched to an oral equivalent when clinically appropriate.7 In contrast, cutaneous anthrax is initially treated orally, unless signs of systemic infection are present. It is important to remember that in spite of effective treatment, the skin lesions will follow their natural course.7 Tables 2 and 3 summarize the current CDC guidelines. Postexposure prophylaxis with 30 days of antibiotics including penicillin, ciprofloxacin, or doxycycline have been shown to be effective in monkeys.4 Those animals that received prophylactic antibiotics in addition to the anthrax vaccine were protected from the disease when rechallenged in comparison with those who did not receive the vaccine.4 Nevertheless, the CDC currently recommends a 60-day regimen of ciprofloxacin or doxycycline as summarized in Table 4. There is currently no recommendation regarding the use of the anthrax vaccine in the postexposure setting. If the vaccine becomes available, a shorter course of antibiotics coupled with vaccinations at 0, 2, and 4 weeks might be an option.7 Physicians should stay aware regarding contemporary antibiotic treatment of anthrax, as antibiotic susceptibility may change. Current recommendations regarding antibiotic treatment should be available from the CDC, FDA, and individual state health authorities.
placebo-controlled trial, the US vaccine has been shown effective against cutaneous anthrax.7,17 In rhesus monkeys, inoculation of this vaccine at 0 and 2 weeks was 100% protective against aerosolized anthrax at 8 and 38 weeks, and 88% effective at 100 weeks.7,18 The AVA vaccine is given in a 6-dose series: 0, 2, 4 weeks, and 6, 12, 18 months. Currently, only military personnel and those working around anthrax in laboratories are eligible for vaccination. There are not sufficient quantities for mass vaccination. Vaccination is recommended for postexposure prophylaxis, although there are no specific guidelines or quantities available, as of yet, for the civilian population.7 FUTURE DIRECTIONS
Scientists have recently created a synthetic compound that neutralizes anthrax toxin in rats called polyvalent inhibitor (PVI). This compound prevented natural anthrax proteins from binding to protective antigen, thus preventing release of edema factor and lethal factor. When rats were injected with PVI, they were protected against exposure 10 times the lethal dose of anthrax toxin. Control rats died within hours.19 A second group of researchers reported that variations in a mouse gene Kif1C protected mice from the effects of anthrax toxin.20 These studies are, perhaps, years away from being applicable to human beings. Nevertheless, these treatments combined with advances in antibiotics, vaccinations, and intensive care may help to prevent the fatal effects of anthrax.
VACCINATIONS
Both the United States and Russia have developed vaccines to anthrax. The Russian version is a live, toxigenic, unencapsulated avirulent animal strain similar to one used in veterinary medicine. Western civilization has deemed the live vaccine unsuitable for human injection.7 The American version, developed in Michigan, utilizes a cell-free, nonencapsulated strain of B anthracis, designated “anthrax vaccine adsorbed” (AVA). Immunity is generated against the protective antigen. In a small,
REFERENCES 1. Laforce, F Marc. Pathogenesis and epidemiology of anthrax. In: Rose BD, editor. Up to date. Wellesley, MA:2001. 2. Dixon TC, Meselson M, Guillemin J, et al. Anthrax. N Engl J Med 1999;341:815-26. 3. Walker DH. Anthrax. In: Tropical infectious diseases principles, pathogens, and practice. Philadelphia: 1999. p.486-91. 4. Laforce, F Marc. Clinical features and treatment of anthrax. In: Up To Date, Rose, BD, editor. Up to date. Wellesley, MA:2001. 5. Sirisanthana R, Navachareon N, Tharaichitkul P, et al. Outbreak of oral-oropharyngeal anthrax: an unusual manifestation of
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6. 7. 8. 9. 10. 11. 12. 13.
human infection with bacillus anthracis. Am J Trop Med Hyg 1984;33:144-50. Doganay M, Almac A, Hanagasi R. Primary throat anthrax. A report of six cases. Scand J Infect Dis 1986;18:415-9. Inglesby TV, Henderson DA, Bartlett JG, et al. Anthrax as a biological weapon: medical and public health management. JAMA 1999;218:1735-45. Meselson M, Guillemin J, Hugh-Jones M, et al. The Sverdlovsk anthrax outbreak of 1979. Science 1994;266:1202-7. Khajehdehi P. Toxemic shock, hematuria, hypokalemia, and hypoproteinemia in a case of cutaneous anthrax. Mt Sinai J Med 2001;68:213-5. Katz AM. Nasal anthrax in Boston. Pharos 1995;58:48-9. Shafazand S, Doyle R, Ruoss S, et al. Inhalational anthrax: epidemiology, diagnosis, and management. Chest 1999;116: 1369-76. Navacharoen N, Sirisanthana T, Navacharoen W, et al. Oropharyngeal anthrax. The Journal of Laryngology and Otology 1985;99:1293-5. Hail AS, Rossi CA, Ludwig GV, et al. Comparison of noninvasive sampling sites for early detection of bacillus anthracis spores
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14. 15. 16. 17. 18.
19. 20.
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from rhesus monkeys after aerosol exposure. Military Medicine 1999;164:833-7. Levinson W, Jawetz E. Gram positive rods. In: Medical microbiology & immunology, 3rd edition. London; 1994. p. 81. Shlyakhov E, and Rubinstein E. Evaluation of the anthraxin skin test for diagnosis of acute and past human anthrax. Eur J Clin Microbiol Infect Dis 1996;15:242-5. Ronaghy HA, Azadeh B, Kohout E, et al. Penicillin therapy of human cutaneous anthrax. Curr Ther Res 1972;14:721. Brachman PS, Gold H, Plotkin SA, et al. Field evaluation of human anthrax vaccine. Am J Public Health 1962;52:632-45. Ivins BE, Fellows P, Pitt ML, et al. Efficacy of standard human anthrax vaccine against bacillus anthracis aerosol spore challenge in rhesus monkeys. Salisbury Med Bull 1996;87:125-6. Mourez M, Kane RS, Mogridge J, et al. Designing a polyvalent inhibitor of anthrax toxin. Nature Biotechnology 2001;19: 958-61. Watters JW, Dewar K, Lehoczky J, et al. Kif1C, a kinesin-like motor protein, mediates mouse macrophage resistance to anthrax lethal factor. Current Biology 2001;11:1503-11.
In light of recent events, anthrax has once again taken center stage in the world of science and the world in which we live. Because patients with anthrax may initially present to otolaryngology clinics, it is important for the otolaryngologist to know how to diagnose and treat this entity. This article will present current information on epidemiology, microbiology, pathogenesis/clinical manifestations, diagnosis, and treatment with a particular interest in the head and neck region. (Otolaryngol Head Neck Surg 2002;126:8-13.)
rich in organic matter, and dramatic changes in soil microenvironment seen with abundant rainfall or drought.1 There are 4 clinical types of human anthrax: cutaneous, inhalational, gastrointestinal, and oropharyngeal.3 Cutaneous anthrax accounts for more than 90% of the cases worldwide.3 Before the recent events, the last reported case of inhalational anthrax in the United States was in 1976.4 Gastrointestinal anthrax has never been reported in this country.2 Oropharyngeal anthrax is the least common form of anthrax, with approximately 30 cases reported worldwide in association with 2 separate outbreaks in Thailand and Turkey.5,6
In light of recent events, anthrax has once again taken
MICROBIOLOGY
center stage in the world of science and the world in which we live. From ancient plagues in Egypt to Koch’s postulates of bacteriology to the first successful antibacterial vaccine created by Louis Pasteur, anthrax has played a pivotal role in history.1,2 More recently, it has been developed into a biological weapon, and possibly a weapon of mass destruction. In the 7 weeks following the September 11 tragedies, 7 cases of inhalation anthrax (3 fatal) and 8 cases of cutaneous anthrax have plagued the United States. It is imperative that all physicians, including otolaryngologists, understand this entity and know how to treat it.
Bacillus anthracis is an aerobic, nonhemolytic, nonmotile, sporulating gram-positive rod (Fig 1). This organism, which primarily resides in soil, is resistant to drying, heat, ultraviolet light, gamma radiation, and many disinfectants. Herbivores, who contract systemic anthrax from spore-infested soil, can transmit this to human beings by contact with the infected animal or their products.7 Virulence requires a 3-component protein exotoxin and a poly-D-glutamic acid capsule whose production is dependent on 2 plasmids (pX01 and pX02, respectively).1 The first component of the exotoxin, called protective antigen, binds to a cell surface receptor. Following proteolytic cleavage, the protective antigen serves as a binding site for the other 2 components, edema factor and/or lethal factor. The protective antigen’s name is derived from its use in anthrax vaccines. The second component of the exotoxin, the edema factor, is a calmodulin-dependent adenyl cyclase. When injected subcutaneouly, it has been found to cause edema in experimental animals.1 The third component, lethal factor, is a protease that cleaves mitogen-activated protein (MAP), kinase kinases 1 and 2. It is this component that causes death, although the specific mechanism is unknown. In order for the organism to be successful, it must have its poly-D-glutamic acid capsule, which is weakly antigenic and antiphagocytic. Strains with a pX02 deletion and thus no capsule are avidly phagocytosed by polymorphonuclear leukocytes.1
EPIDEMIOLOGY
Bacillus anthracis is primarily found in tropical environments in Africa, Asia, South and Central America, and the Caribbean.3 Highly endemic countries such as Pakistan, Iran, and Iraq continue to have epizootic anthrax. Although specific reasons for an agricultural outbreak are not fully understood, certain conditions make it more favorable such as soil pH above 6.0, soil
From the Department of Otolaryngology–Head and Neck Surgery, Henry Ford Hospital. Reprint requests: Michael S Benninger, MD, Chairman, Department of Otolaryngology–Head and Neck Surgery, Henry Ford Hospital, 2799 West Grand Blvd, Detroit, MI 48202; e-mail, [email protected] Copyright © 2002 by the American Academy of Otolaryngology– Head and Neck Surgery Foundation, Inc. 0194-5998/2002/$35.00 + 0 23/1/121513 doi:10.1067/mhn.2002.121513 8
PATHOGENESIS/CLINICAL MANIFESTATIONS
As mentioned, there are 4 clinical types of human anthrax.3 Dissemination of spores depends on which
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Table 1. Differential diagnosis of oropharyngeal anthrax Peritonsillar abscess Parapharyngeal space abscess Strep pharyngitis Ludwig’s/Vincent’s angina Diphtheria
area is affected. All types can lead to septicemia, shock, and death. Cutaneous Anthrax
Cutaneous anthrax develops after the introduction of spores into the subcutaneous tissues through cuts or abrasions. This occurs primarly at areas of exposed skin such as face, neck, and extremities. Although the interval between exposure and infection is not definitively known, it is usually between 2 and 3 days after the inciting event and has been reported as long as 12 days.7,8 Once infected, the spores germinate and spread via the antiphagocytic properties of the capsule. Release of the exotoxin results in local edema and eventually tissue necrosis.4,7 The initial lesion is a pruritic macule or papule that enlarges into a round ulcer by the second day. A clear or serosanguineous fluid containing numerous organisms is released from 1 to 3 mm vesicles in the surrounding area. The ulcer matures into a painless, depressed, black eschar that dries and falls off over the next 1 to 2 weeks. It is from the appearance of this black eschar that anthrax (Greek for “coal”) derives its name.2 There can be significant edema around the site of the ulcer. Fig 2 demonstrates a cutaneous lesion on the side of the neck. In contrast to the skin lesion, the regional lymphadenopathy that develops is painful.7 One particular concern of lesions in the head and neck region is that edema in this location can tract rapidly along soft tissue plains and patients can develop shortness of breath and possibly even airway obstruction.2,9 Patients may require corticosteroids, intubation, or even tracheostomy to avoid asphyxiation.2,3 Khajehdehi9 describes a young Iranian village woman with cutaneous anthrax of neck who developed rapid swelling of the face, neck, shoulders, chest, and breasts with associated respiratory difficulty. She did not require intubation but it took 2 weeks for her edema to completely resolve. Another interesting case of cutaneous anthrax in the head and neck region involved the nose. A patient who was working with infected sheepskins became severely toxic with nasal discharge. Just beneath his nostril, he had an 8-mm round raised lesion with depressed glis-
Fig 1. Gram stain of Bacillus anthracis shows gram positive rods. (Image courtesy of Dr. William A. Clark, Public Health Image Library, Center for Disease Control, Atlanta, Georgia.)
Fig 2. Cutaneous anthrax lesion on the side of the neck. Note the surrounding vesicles. (Image courtesy of Public Health Image Library, Centers for Disease Control, Atlanta, Georgia.)
tening center. Culture from the nasal discharge revealed Bacillus anthracis. He developed signs of severe systemic toxicity and even required a lumbar puncture to rule-out anthrax meningitis. Ultimately, he responded well to antibiotics and steroids and was discharged.10 Anthrax meningitis is a rare complication of primarily the cutaneous form of anthrax although inhalational and gastrointestinal types have also been associated with it. Symptoms associated with this entity include: fever, headache, nuchal rigidity, agitation, seizures, and delirium. This complication is almost universally fatal, in spite of treatment, and death usually ensues within 1 to 6 days.2
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Table 2. Treatment protocol for inhalation, gastrointestinal, and oropharyngeal anthrax* Category
Adults
Children
Initial therapy (IV)
Ciprofloxacin 400 mg q 12 hrs or Doxycycline 100 mg q 12 hrs AND 1 or 2 additional antimicrobials Ciprofloxacin 10-15 mg/kg q 12 hrs (not to exceed 1g/day) or Doxycycline**: 8 yrs and 45 kg: 100 mg Q 12 hrs 8 yrs and 45 kg: 2.2 mg/kg Q 12 hrs 8 yrs: 2.2 mg/kg Q 12 hrs AND One or two additional antimicrobials
Duration
Switch to oral when clinically appropriate: Ciprofloxacin 500 mg po BID or Doxycycline 100 mg po BID 60 days total antibiotic duration Switch to oral when clinically appropriate: Ciprofloxacin 10-15 mg/kg po Q 12 hrs or Doxycycline (po regimen same as IV) 60 days total antibiotic duration
*For latest CDC recommendations, go to www.cdc.gov. **The American Academy of Pediatrics recommends treatment of young children with tetracyclines for serious infections.
Cutaneous anthrax is ultimately fatal in up to 20% of untreated cases due to systemic manifestations.7 Death is rare if appropriately treated with antibiotics; however, treatment does not alter the course of the skin manifestations of the disease.7 Excising the lesion may hasten systemic dissemination and is contraindicated. Most lesions will not leave any permanent scarring as well.2 Inhalation Anthrax
Inhalational anthrax, also called “Woolsorter’s disease,” follows the inhalation of endospores from infected animals. The dissemination of airborne anthrax is highly dependent on the size of the spores. Those that are greater than 5 µm cannot affect the lungs because they are either trapped in the nasopharynx or cleared by the mucociliary escalator system. If, however, the spores are between 2 and 5 µm, then they can lodge in the alveolar ducts or alveoli.4,11 There they are phagocytosed by macrophages and transported to mediastinal lymph nodes where they proliferate and can cause hemorrhagic mediastinitis. This process may take up to 60 days.4,7 Initial symptoms such as fever, cough, headache, vomiting, weakness, and abdominal or chest pain may mimic common ailments such as influenza. This stage, which may last from hours to days, may even improve prior to the more serious and often fatal second-stage. As hemorrhagic mediastinitis develops, patients develop acute onset of fever, dyspnea, and diaphoresis. Septicemia and shock will occur, and up to half of patients will develop meningitis. Mortality is approximately 90%, but these figures are based on medical science that was available 30 years ago.7 Advances in mechanical ventilation, antibiotic therapy, and other treatment modalities may significantly lower these numbers today along with a high index of suspicion for an outbreak.4
Gastrointestinal Anthrax
Gastrointestinal anthrax is acquired from grossly contaminated and undercooked meat. Bacteria can invade the mucosal and submucosal lymphatics, and ulceration is always seen.2 Symptoms such as nausea, vomiting, and melanotic or bloody diarrhea usually present 2 to 5 days after ingestion and may progress rapidly to ascites, acute abdomen, and sepsis.2,7 There tend to be multiple cases within the same household. Mortality from this entity approaches that of inhalation anthrax due to the difficulty in early diagnosis.2 Oropharyngeal Anthrax
Oropharyngeal anthrax also develops after ingestion of infected meat and subsequent invasion of mucosal and submucosal lymphatics. This entity was first formally documented in the otolaryngology literature by Navacharoen et al12 in 1985. He described an otherwise healthy 59-year-old Thai male admitted to Chiang Mai Hospital with a sore throat and neck swelling 5 hours after ingestion of a local dish of water buffalo. On examination, the patient was noted to have marked inflammation of the soft palate, uvula, and left tonsil with associated necrotic tissue. There was extensive, nonpitting edema over the mandible and neck on the affected side, which extended down to chest and axilla. Gram stain from the lesion on the tonsil showed gram-positive bacilli and cultures later identified the organism as Bacillus anthracis. In spite of appropriate treatment with intravenous penicillin G, the patient died 10 hours after admission.12 In addition to fever, dysphagia, and neck pain, patients with oropharyngeal anthrax may also complain of hoarseness, cough, globus sensation, and difficulty breathing. Neck swelling has been reported up to 6 cm in size. Intraoral examination typically reveals inflam-
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Table 3. Treatment protocol for cutaneous anthrax* Category
Adults Children
Initial therapy (oral)
Duration
Ciprofloxacin 500 mg BID or Doxycycline 100 mg BID Ciprofloxacin 10-15 mg/kg q 12 hrs (not to exceed 1g/day) or Doxycycline**: 8 yrs and 45 kg: 100 mg Q 12 hrs 8 yrs and 45 kg: 2.2 mg/kg Q 12 hrs 8 yrs: 2.2 mg/kg Q 12 hrs
60 days 60 days
*For latest CDC recommendations, go to www.cdc.gov. Multi-drug regimen is recommended for cutaneous anthrax with systemic symptoms, extensive edema, or for lesions on the head and neck. **The American Academy of Pediatrics recommends treatment of young children with tetracyclines for serious infections.
matory lesions (red-purple ulcerations) or asymmetric swelling of the oral cavity or oropharynx. If localized to the tonsillar region, it may mimic a peritonsillar abscess; however, there is no pus. Other sites of lesions include the posterior pharyngeal wall, hard and soft palate, and base of tongue. A gray pseudomembrane may also be present as seen in diphtheria.5,6 Sirisanthana reported that early lesions were edematous and congested, progressing to central necrosis and ulceration after 1 week.5 Table 1 lists a differential diagnosis for oropharyngeal anthrax. All oropharyngeal cases must be carefully observed, because rapid edema may develop and necessitate endotracheal intubation or even tracheostomy. Corticosteroids may be indicated in addition to appropriate antibiotic therapy. In general, these lesions tend to have a more favorable outcome than gastrointestinal anthrax.2,7,11 DIAGNOSIS
Successful diagnosis of anthrax is dependent on a high level of suspicion. Changes in the geopolitical climate coupled with unusual outbreaks of flu-like symptoms should cause alarm. Initial diagnosis will come from gram stain and culture of blood or the affected area.7 Nasal swabs have been an effective means of revealing exposure to anthrax spores. Hail et al13 studied sampling of various sites of rhesus monkeys after exposing them to lethal doses of aerosolized anthrax. He found that swabs from the nares provided the greatest yield of anthrax colony-forming units up to 1 week after exposure. A M’Fadyean stain will demonstrate a pink capsule surrounding dark-blue, often square-ended bacilli.3 It is important to notify the laboratory of suspected anthrax as isolation of Bacillus in the United States usually represents Bacillus cereus, an infection seen with reheating rice.7,14 In the case of oropharyngeal anthrax, definitive diagnosis can be made from a throat swab of the affected side. In general, however, many patients will
present with systemic symptoms and die before culture results are available. Alternatively, inhalation anthrax may be diagnosed with a simple chest x-ray. Specifically, a widened mediastinum in an otherwise healthy individual with flu-like symptoms is considered pathognomonic for anthrax.2 Definitive testing is available at the US Army Medical Research Institute of Infectious Diseases (USAMRIID) located in Fort Detrick, Maryland. Such testing includes enzyme-linked immunosorbent assay for protective antigen and polymerase chain reaction (PCR).7 There is also an anthraxin skin test that consists of a subdermal injection of attenuated organisms. This test was positive in 81.8% of cases in the first 3 days and 97% to 99% positive in the next 2 to 3 weeks, making it a valuable acute as well as retrospective diagnostic tool.2,15 Treatment. Although much of the current media attention has focused on the use of ciprofloxacin for anthrax, numerous antibiotics are effective against this organism, including penicillin, chloramphenicol, tetracycline, erythromycin, streptomycin, macrolides, aminoglycosides, vancomycin, first generation cephalosporins, and other fluoroquinolones.4,7 Cutaneous anthrax is highly susceptible to penicillin and in one study of 25 patients; cultures were negative within 5 hours of initiation of treatment.4,16 However, because anthrax in the face of bioterrorism may have been genetically altered to be resistant to penicillin, the Centers for Disease Control (CDC) currently recommends ciprofloxacin and doxycycline as first-line therapy for all forms of anthrax.7 Other agents listed above may be used as suspectibilities are identified, but penicillin and ampicillin are not currently recommended to be used alone. Multi-drug therapy is recommended for initial treatment of inhalational, gastrointestinal, and oropharyngeal anthrax. Cutaneous anthrax with systemic involvement, extensive edema, and lesions on the head and neck also require multi-drug therapy. The duration of treatment is not definitively known. The CDC currently recommends a 60-day course,
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Table 4.
Postexposure prophylaxis protocol for prevention of inhalation anthrax*
Category
Adults Children
Initial therapy (oral)
Duration
Ciprofloxacin 500 mg BID or Doxycycline 100 mg BID Ciprofloxacin 10-15 mg/kg q 12 hrs (not to exceed 1g/day) or Doxycycline**: >8 yrs and >45 kg: 100 mg Q 12 hrs >8 yrs and 45 kg: 2.2 mg/kg Q 12 hrs 8 yrs: 2.2 mg/kg Q 12 hrs
60 days 60 days
*For latest CDC recommendations, go to www.cdc.gov. **The American Academy of Pediatrics recommends treatment of young children with tetracyclines for serious infections.
because the primary exposure is most likely an aerosol in a setting of bioterrorism. Indeed, spores may not germinate for up to 60 days. Inhalational, gastrointestinal, and oropharyngeal forms are initially treated intravenously and can be later switched to an oral equivalent when clinically appropriate.7 In contrast, cutaneous anthrax is initially treated orally, unless signs of systemic infection are present. It is important to remember that in spite of effective treatment, the skin lesions will follow their natural course.7 Tables 2 and 3 summarize the current CDC guidelines. Postexposure prophylaxis with 30 days of antibiotics including penicillin, ciprofloxacin, or doxycycline have been shown to be effective in monkeys.4 Those animals that received prophylactic antibiotics in addition to the anthrax vaccine were protected from the disease when rechallenged in comparison with those who did not receive the vaccine.4 Nevertheless, the CDC currently recommends a 60-day regimen of ciprofloxacin or doxycycline as summarized in Table 4. There is currently no recommendation regarding the use of the anthrax vaccine in the postexposure setting. If the vaccine becomes available, a shorter course of antibiotics coupled with vaccinations at 0, 2, and 4 weeks might be an option.7 Physicians should stay aware regarding contemporary antibiotic treatment of anthrax, as antibiotic susceptibility may change. Current recommendations regarding antibiotic treatment should be available from the CDC, FDA, and individual state health authorities.
placebo-controlled trial, the US vaccine has been shown effective against cutaneous anthrax.7,17 In rhesus monkeys, inoculation of this vaccine at 0 and 2 weeks was 100% protective against aerosolized anthrax at 8 and 38 weeks, and 88% effective at 100 weeks.7,18 The AVA vaccine is given in a 6-dose series: 0, 2, 4 weeks, and 6, 12, 18 months. Currently, only military personnel and those working around anthrax in laboratories are eligible for vaccination. There are not sufficient quantities for mass vaccination. Vaccination is recommended for postexposure prophylaxis, although there are no specific guidelines or quantities available, as of yet, for the civilian population.7 FUTURE DIRECTIONS
Scientists have recently created a synthetic compound that neutralizes anthrax toxin in rats called polyvalent inhibitor (PVI). This compound prevented natural anthrax proteins from binding to protective antigen, thus preventing release of edema factor and lethal factor. When rats were injected with PVI, they were protected against exposure 10 times the lethal dose of anthrax toxin. Control rats died within hours.19 A second group of researchers reported that variations in a mouse gene Kif1C protected mice from the effects of anthrax toxin.20 These studies are, perhaps, years away from being applicable to human beings. Nevertheless, these treatments combined with advances in antibiotics, vaccinations, and intensive care may help to prevent the fatal effects of anthrax.
VACCINATIONS
Both the United States and Russia have developed vaccines to anthrax. The Russian version is a live, toxigenic, unencapsulated avirulent animal strain similar to one used in veterinary medicine. Western civilization has deemed the live vaccine unsuitable for human injection.7 The American version, developed in Michigan, utilizes a cell-free, nonencapsulated strain of B anthracis, designated “anthrax vaccine adsorbed” (AVA). Immunity is generated against the protective antigen. In a small,
REFERENCES 1. Laforce, F Marc. Pathogenesis and epidemiology of anthrax. In: Rose BD, editor. Up to date. Wellesley, MA:2001. 2. Dixon TC, Meselson M, Guillemin J, et al. Anthrax. N Engl J Med 1999;341:815-26. 3. Walker DH. Anthrax. In: Tropical infectious diseases principles, pathogens, and practice. Philadelphia: 1999. p.486-91. 4. Laforce, F Marc. Clinical features and treatment of anthrax. In: Up To Date, Rose, BD, editor. Up to date. Wellesley, MA:2001. 5. Sirisanthana R, Navachareon N, Tharaichitkul P, et al. Outbreak of oral-oropharyngeal anthrax: an unusual manifestation of
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human infection with bacillus anthracis. Am J Trop Med Hyg 1984;33:144-50. Doganay M, Almac A, Hanagasi R. Primary throat anthrax. A report of six cases. Scand J Infect Dis 1986;18:415-9. Inglesby TV, Henderson DA, Bartlett JG, et al. Anthrax as a biological weapon: medical and public health management. JAMA 1999;218:1735-45. Meselson M, Guillemin J, Hugh-Jones M, et al. The Sverdlovsk anthrax outbreak of 1979. Science 1994;266:1202-7. Khajehdehi P. Toxemic shock, hematuria, hypokalemia, and hypoproteinemia in a case of cutaneous anthrax. Mt Sinai J Med 2001;68:213-5. Katz AM. Nasal anthrax in Boston. Pharos 1995;58:48-9. Shafazand S, Doyle R, Ruoss S, et al. Inhalational anthrax: epidemiology, diagnosis, and management. Chest 1999;116: 1369-76. Navacharoen N, Sirisanthana T, Navacharoen W, et al. Oropharyngeal anthrax. The Journal of Laryngology and Otology 1985;99:1293-5. Hail AS, Rossi CA, Ludwig GV, et al. Comparison of noninvasive sampling sites for early detection of bacillus anthracis spores
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from rhesus monkeys after aerosol exposure. Military Medicine 1999;164:833-7. Levinson W, Jawetz E. Gram positive rods. In: Medical microbiology & immunology, 3rd edition. London; 1994. p. 81. Shlyakhov E, and Rubinstein E. Evaluation of the anthraxin skin test for diagnosis of acute and past human anthrax. Eur J Clin Microbiol Infect Dis 1996;15:242-5. Ronaghy HA, Azadeh B, Kohout E, et al. Penicillin therapy of human cutaneous anthrax. Curr Ther Res 1972;14:721. Brachman PS, Gold H, Plotkin SA, et al. Field evaluation of human anthrax vaccine. Am J Public Health 1962;52:632-45. Ivins BE, Fellows P, Pitt ML, et al. Efficacy of standard human anthrax vaccine against bacillus anthracis aerosol spore challenge in rhesus monkeys. Salisbury Med Bull 1996;87:125-6. Mourez M, Kane RS, Mogridge J, et al. Designing a polyvalent inhibitor of anthrax toxin. Nature Biotechnology 2001;19: 958-61. Watters JW, Dewar K, Lehoczky J, et al. Kif1C, a kinesin-like motor protein, mediates mouse macrophage resistance to anthrax lethal factor. Current Biology 2001;11:1503-11.