Case 1 -

Cutaneous Anthrax Wun-Ju Shieh Centers for Disease Control and Prevention

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Clinical Summary A 38-year-old female working in a media company in New York City noticed a painless small papule on her left clavicle that was not erythematous nor pruritic. Three days later, the lesion became erythematous, with surrounding edema and measured approximately 1 cm in diameter. The following day, she took an oral antibiotic that remained from a previous prescription because of mild headache and malaise, and also applied topical Bacitracin on the skin lesion. After two days of self-treatment with no apparent improvement, the patient visited a local infectious disease physician. The skin lesion was 5 cm in diameter, with a raised border and central depression. It was associated with significant edema obscuring her clavicle and intense erythema involving the upper left chest and shoulder. Several small satellite vesicles surrounded the lesion and left cervical lymphadenopathy were noted on physical examination. A small amount of serous fluid from the wound was sent for Gram stain and culture, which yielded no growth. The initial diagnosis was an arthropod bite with secondary infection and ciprofloxacin was prescribed. She returned to the clinic two days later with no significant gross change of the lesion. A complete blood count and serum electrolyte obtained at that time were within normal limit. After one week of continuous antibiotic treatment, the lesion had improved significantly. However, after seeing pictures of similar lesion on the internet, the patient visited another infectious disease physician for second opinion. A skin biopsy was taken for histopathologic evaluation and subsequent diagnostic workup. She was continued on ciprofloxicin for another week with complete resolution of the lesion. Case 1 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Case 1 - Figure 1 Skin biopsy from the edge of the eschar shows intact epidermis. Superficial ulceration and fibrinopurulent membrane typically associated with acute lesion of cutaneous anthrax were not seen. H & E stain, original magnification x 12.5. Case 1 - Figure 2 The adjacent dermis shows edema, focal hemorrhage, and perivascular mononuclear cell infiltrates. H & E stain, original magnifications x 12.5 Case 1 - Figure 3 A higher magnification of the dermis illustrates the edema and intense perivascular mononuclear inflammatory cell infiltrates. H & E stain, original magnifications x 50. Case 1 - Figure 4 This higher magnification further demonstrates the polymorphous nature of the perivascular inflammatory cell infiltrate dominated by mononuclear phagocytes and lymphocytes with focal hemorrhage. H & E stain, original magnification x 158. Diagnosis: Cutaneous anthrax Description: The patient reported handling "threat" letters at work after developing the skin lesion. Bacterial cultures of specimens from the lesion and from a suspicious letter both tested negative for B. anthracis, and the patient was administered ciprofloxacin. After learning of a patient with inhalational anthrax in Florida, the patient contacted the New York City Department of Health, and a skin biopsy was obtained 9 days after antibiotic treatment. The biopsy was negative for B. anthracis by PCR. Skin biopsy from the edge of eschar showed intact epidermis; the dermis showed edema, focal hemorrhage, and perivascular mononuclear cell infiltrates. Superficial ulceration and fibrinopurulent membrane typically associated with acute lesions of cutaneous anthrax were not seen. Gram stain and Steiner's silver stain did not reveal any bacterial organism. Immunohistochemical (IHC) tests using an indirect immunoalkaline phosphatase technique were performed. The primary antibodies used in the tests included a monoclonal mouse anti-B. anthracis (cell wall) antibody and a monoclonal mouse anti-B. anthracis (capsule) antibody. Focal, rare immunohistochemical staining of B. anthracis antigen was present in the dermis that established the diagnosis of cutaneous anthrax. Discussion: This case represents an unusual example of cutaneous anthrax caused by infection with the spore-forming bacterium Bacillus anthracis. There are two unusual features associated with the presentation of this case. Firstly, the causative agent was transmitted through an intentional release of the spores instead of the usual route of contact with infected animals or through agricultural practice. Secondly, the skin biopsy was taken after nine days of antibiotic treatment, and the histopathogic features at this late stage of lesion are rarely described in the literature. In patients with classic presentation, skin lesion usually begins as a raised itchy bump that resembles an insect or spider bite. The lesion develops into a vesicle within 1-2 days and then a painless ulcer with a characteristic eschar in the center. Lymph nodes in the adjacent area may become swelling; fever and chills may develop along with lymphadenopathy. About 20% of untreated cases of cutaneous anthrax may result in death due to spread of the bacteria throughout the body and the release of deadly toxins in the blood stream. However, fatality has become rare with appropriate antimicrobial therapy, such as ciprofloxacin. Epidemiology Anthrax is an acute infectious disease caused by the spore-forming bacterium Bacillus anthracis. While anthrax commonly affects hoofed animals such as sheep and cattle, humans can get infection as well. Human anthrax can occur in three forms: cutaneous, inhalational, and gastrointestinal. B. anthracis spores can live in the soil for many years, and humans usually become infected with anthrax by handling products from infected animals or by inhaling anthrax spores from contaminated animal products. Anthrax can also be contracted by eating undercooked meat from infected animals. Although cutaneous anthrax occurs ubiquitously throughout the world, its incidence in the United States has been very low owing to improvements in animal husbandry and the handling of animal products. Since 1950, human anthrax in the United States was confined to those occupationally at risk. There were 235 confirmed cases reported from 1955 to 2002, and most of them were cutaneous anthrax. Before autumn 2001, all cases of cutaneous anthrax in the United States were related to agricultural or industrial exposures. However, the epidemiology and laboratory diagnosis of cutaneous anthrax changed after October 2001 because of the intentional release of B. anthracis spores through the U.S. postal system and the subsequent identification of anthrax in 22 patients, including 11 with cutaneous disease. Pathogenesis After the spores of B. anthracis are ingested or inhaled, the bacteria will infect macrophages, germinate, and then continue to multiply. In cutaneous anthrax, the bacteria can proliferate at the site of infection as well as at the regional lymph nodes that drain the infected site. Edema toxins and lethal toxins produced by the bacteria usually cause extensive edema and local necrosis respectively, contributing to the gross pathology of cutaneous anthrax. In untreated cases, bacteremia and toxemia may ensue and lead to widespread destruction of tissues and organs. Diagnosis Traditionally, cutaneous anthrax was diagnosed by microbiologic methods and skin biopsy was seldom taken for histopathologic examination. Although culture and Gram stain of specimens from suspicious skin lesions are still the essential methods for diagnosing cutaneous anthrax, their sensitivity decreases significantly if the patient has received antibiotic treatment prior to specimen collection. In general, the longer the duration of illness and treatment course, the less chance of detecting B. anthracis organism by culture and special stains. The organism is best demonstrated when the lesion is in the vesicular stage, so swab exudates for Gram stain and culture should be performed before initiation of antibiotic therapy. The encapsulated bacilli in the skin may be seen by H&E if the skin biopsy is taken before initiation of antibiotic treatment. In cases within one week of antibiotic treatment, the bacilli in skin biopsy may be highlighted by special stains, and Steiner's silver stain generally is more useful than Gram stain for demonstrating these bacilli in the cutaneous lesion. Because IHC testing of skin biopsies can detect bacterial antigens in tissues regardless of the treatment, it provides a more sensitive and specific way to establish the diagnosis of cutaneous anthrax. Using two monoclonal antibodies against different epitopes of B. anthracis further enhances the sensitivity and specificity of IHC assays. Microscopic examination of the skin biopsies usually shows necrosis, hemorrhage, acantholysis, bullous formation, and ulceration in the epidermis. Various degrees of edema, coagulation necrosis, hemorrhage, and vasculitis are commonly seen in the dermis. Polymorphonuclear infiltrates were often present with prominent spongiosis in the lower epidermis of biopsies taken prior to treatment or at the early phase of treatment. The dermis is usually markedly edematous, with separation of collagen bundles, and often contained an intense perivascular inflammatory infiltrate. Inflammatory infiltrate may vary from case to case and can be predominantly mononuclear if the biopsy is taken after one or two weeks of treatment. Other laboratory methods, such as serology and PCR assay, are also important investigational tools. Serology is very useful for surveillance and diagnosis of cutaneous anthrax, but the results require several weeks because of the need to test paired serum specimens. PCR assay is a sensitive and specific method to detect bacterial DNA in clinical samples, but it does not provide a morphologic correlation with the result. Based on the study results described in the report associated with the 2001 cutaneous anthrax outbreak, a skin biopsy should be obtained whenever cutaneous anthrax is suspected, preferably before initiation of antibiotic treatment, and evaluated by IHC testing. Dividing a single biopsy specimen for multiple tests is not recommended because of the focal nature of immunostaining. Treatment Ciprofloxacin and doxycycline are first-line therapy for cutaneous anthrax. Intravenous therapy with a multidrug regimen is recommended for cutaneous anthrax with signs of systemic involvement, for extensive edema, or for lesions on the head and neck. In cutaneous anthrax, antimicrobial treatment may render lesions culture negative in 24 hours, although progression to eschar formation still occurs. Corticosteroids can be considered for extensive edema or swelling of the head and neck region associated with cutaneous anthrax. Cutaneous anthrax is typically treated for 7 to10 days; however, in the scenario of bioterrorism attack, the risk for simultaneous aerosol exposure appears to be high. Although an effective immune response may be produced after primary infection, a potential for reactivation of latent infection may also exist. Therefore, persons with cutaneous anthrax associated with bioterrorism attack should be treated for 60 days. Selected references: Jernigan DB, Raghunathan PL, Bell BP, et al: Investigation of bioterrorism-related anthrax, United States, 2001: epidemiologic findings. Emerg Infect Dis 2002, 8:1019-1028. Tatti KM, Greer P, White E, et al: Morphologic, immunologic, and molecular methods to detect bacillus anthracis in formalin-fixed tissues. Appl Immunohistochem Mol Morphol. 2006 Jun;14(2):234-43. Shieh WJ, Guarner J, Paddock C, et al: The critical role of pathology in the investigation of bioterrorism-related cutaneous anthrax. Am J Pathol. 2003 Nov;163(5):1901-10. Shlyakhov E, Rubinstein E: Evaluation of the anthraxin skin test for diagnosis of acute and past human anthrax. Eur J Clin Microbiol Infect Dis 1996, 15:242-245. Lebowich RJ, McKillip, B.G., and Conboy, J.R.: Cutaneous Anthrax. A pathological study with clinical correlation. American Journal of Clinical Pathology 1943, 13:505. Gold H: Anthrax. A report of 117 cases. American Medical Associaton Archives of International Medicine 1955, 96:387. Sidel V, Cohen HW, Gould RM: From woolsorters to mail sorters: anthrax past, present, and future. Am J Public Health 2002, 92:705-706. Carucci JA, McGovern TW, Norton SA, et al: Cutaneous anthrax management algorithm. J Am Acad Dermatol 2001, 21:21.