Infectious Disease Pathology
Case 1 -
Centers for Disease Control and Prevention
Click on each slide thumbnail image for an enlarged view
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
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.
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.
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
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.
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.
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
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.
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