Clinical manifestations and diagnosis of anthrax

INTRODUCTION — Anthrax, usually caused by Bacillus anthracis, is an uncommon illness; the presentation can vary depending on the route of exposure. Consideration of the possibility of anthrax in patients with consistent clinical syndromes is important because of the potential for rapid disease progression and the public health implications.

The clinical manifestations and diagnosis of anthrax will be reviewed here. The pathogenesis, epidemiology, treatment, and prevention of anthrax are discussed separately. (See "Microbiology, pathogenesis, and epidemiology of anthrax" and "Treatment of anthrax" and "Prevention of anthrax".)

CLINICAL MANIFESTATIONS — There are four major anthrax syndromes: cutaneous anthrax, inhalation anthrax, gastrointestinal tract anthrax, and the more rare primary anthrax meningitis [1-4]. Anthrax has also been associated with injection drug use; in that setting, the clinical presentation is distinct from typical cutaneous anthrax.

Cutaneous — Cutaneous anthrax is the most common form of the disease.

●Route of infection – Naturally occurring cases of cutaneous anthrax develop after spores of B. anthracis are introduced subcutaneously, often as a result of contact with infected animals or animal products. Cuts or abrasions increase susceptibility to cutaneous infection [5-7]. Spores germinate and multiply, and the antiphagocytic capsule facilitates local spread. (See "Microbiology, pathogenesis, and epidemiology of anthrax".)

●Incubation period – The incubation period is usually 5 to 7 days with a range of 1 to 12 days [8,9]. However, during an anthrax outbreak in Sverdlovsk, Union of Soviet Socialist Republics, cutaneous cases developed up to 13 days following the aerosol release of spores [10]; an outbreak in Algeria was reported with a median incubation period of 19 days [11].

●Local features – Over 90 percent of cutaneous anthrax lesions occur in exposed areas such as the face, neck, arms, and hands. The disease begins as a small, painless, but often pruritic papule and quickly enlarges and develops a central vesicle or bulla, followed by erosion, leaving a painless necrotic ulcer with a black, depressed eschar (picture 1) [5]. Extensive edema of the surrounding tissues, due to toxin release, is often present along with regional lymphadenopathy and lymphangitis (picture 2). An eschar with extensive surrounding edema is highly suggestive of anthrax. Less often, B. anthracis can enter through the palpebral fissure, causing palpebral swelling and necrosis of the eyelids [12].

●Systemic symptoms and complications – Systemic symptoms, including fever, malaise, and headache can accompany the cutaneous lesion, although they do not occur in the majority of cases. In a systematic review that included 340 adults hospitalized with cutaneous anthrax, fever or chills were reported in 39 percent, fatigue and flu-like symptoms in 11 percent, and headache in 10 percent [13]; the proportion of children with such systemic symptoms was slightly lower.

Complications include airway obstruction from head and neck involvement, sepsis syndrome, and meningitis. Overall, secondary meningitis has been reported in approximately 10 percent of patients hospitalized with cutaneous anthrax [13]. It is important to identify patients at risk for adverse outcomes. These include those with head and neck involvement, signs of sepsis, or signs of meningitis. (See "Sepsis syndromes in adults: Epidemiology, definitions, clinical presentation, diagnosis, and prognosis", section on 'Clinical presentation' and "Clinical features and diagnosis of acute bacterial meningitis in adults", section on 'Clinical features'.)

Thus, fever or chills, hypotension, nausea or vomiting, altered mental status, headache, meningeal signs, other neurologic signs, papilledema, seizure, leukocytosis, bacteremia, coagulopathy, adenopathy and extensive edema are risk factors for meningitis or death [14]. Thoracic edema and anxiety also may be risk indicators.

●Mortality rate – Without appropriate therapy, mortality is quite high. However, where reasonably good health care is available, mortality is much lower. For example, in a cooperative study of treatment duration in Turkey, there were no deaths among 66 patient with uncomplicated cutaneous anthrax (no shock, sepsis, meningitis or pulmonary involvement) [15]. In a review of 85 cases from Eastern Turkey, there were two fatalities (2.4 percent), both in people with delayed admission and severe head and neck disease [16]. A review of 71 patients in Peru reported a mortality rate of 4.2 percent; all three deaths were in patients with meningoencephalitis [17].

Inhalation

●Route of infection – Inhalation anthrax results from the inhalation of B. anthracis spore-containing particles. This may occur when anthrax spores are aerosolized while working with contaminated animal products such as wool, hair, or hides. It has also resulted from inhalation of weaponized and intentionally released spore preparations.

Inhaled airborne particles >5 microns in size are either physically trapped in the nasopharynx or cleared by the mucociliary escalator system. In comparison, inhaled particles <5 microns in size can be deposited on alveolar ducts or alveoli [8,18]. B. anthracis spores are phagocytosed by alveolar macrophages and transported to mediastinal lymph nodes. There, they germinate, multiply, and release toxins, causing hemorrhagic necrosis of the thoracic lymph nodes draining the lungs, which results in a hemorrhagic mediastinitis and, in occasional cases, a necrotizing pneumonia [19]. The organisms then become bloodborne, causing bacteremia and, in many cases, meningitis.

●Incubation period – The median incubation period for inhalation anthrax is estimated to be seven to nine days [13]. However, both very short and very long incubation periods have been reported. In the 1979 outbreak in Sverdlovsk, the reported incubation period was as long as 43 days for fatal cases [10]. In contrast, information from a single case report suggests that the incubation period can be as short as one day [20]. This case report describes an office worker at a textile mill who developed inhalation anthrax within one day in 1961 following exposure in a grossly contaminated, dusty carding room in the mill; she previously rarely entered the mill.

In primate studies, spores have been found in the lungs up to 100 days following exposure [21], and inhalation anthrax has developed up to 58 days following experimental aerosol exposure in primates receiving 30 days of postexposure antibiotics [22].

●Prodromal phase – The course of the disease is usually biphasic. Prodromal symptoms of inhalation anthrax are nonspecific and variable, complicating assessment and diagnosis [1,23,24]. Early symptoms, such as myalgia, fever, and malaise, are common and may mimic those of a viral respiratory infection. However, a variety of symptoms less suggestive of a viral infection may also be present, such as nausea, hemoptysis, dyspnea, odynophagia, or chest pain [25]. Prodromal symptoms last an average of four to five days.

●Fulminant phase – The fulminant phase is a catastrophic illness characterized by rapidly progressive respiratory symptoms, including severe dyspnea and hypoxemia, and shock [6,20]. This results in a very high mortality rate within days.

As with any form of anthrax, hematogenous spread can result in lesions in other organ systems, including hemorrhagic meningitis and submucosal gastrointestinal lesions [6,19]. Approximately one-third to one-half of patients with inhalation anthrax develop secondary meningitis [13,19].

●Imaging findings – Imaging studies can aid in establishing the diagnosis; almost all patients have some radiographic abnormality. Pleural effusion is common. Widening of the mediastinum, secondary to mediastinitis, is considered a classic finding in inhalation anthrax (image 1) [26]. In a systematic review of 90 adults hospitalized with inhalational anthrax, these findings were reported in 71 and 46 percent at presentation, respectively [13]. Other chest radiographic findings seen with inhalation anthrax include hilar abnormalities, pulmonary infiltrates, and consolidation. Imaging abnormalities, however, can often be subtle, particularly early in the course of illness [27-29]. (See 'Distinction from common respiratory infections' below.)

●Mortality – Inhalation anthrax is usually fatal; among 71 cases in the world's literature from 1900 to 2005, excluding the 6 survivors during the 2001 bioterrorism event, the mortality rate was 92 percent [25]. It does not appear that modern intensive care has changed the outcome once the fulminant phase is reached. However, antibiotic therapy can be successful if initiated during the prodromal phase of the disease [10,20,25,27]. The challenge for the clinician is to appropriately treat patients during the prodromal stage, even though anthrax is a rare disease with a nonspecific and variable presentation. (See "Treatment of anthrax".)

Gastrointestinal tract — Gastrointestinal tract anthrax presents as one of two clinical forms, oropharyngeal or gastrointestinal anthrax. B. anthracis has been reported to infect all regions of the alimentary tract from the mouth to the ascending colon. The disease develops following the consumption of undercooked meat from animals infected with anthrax and tends to occur in family clusters or point-source outbreaks.

●Gastrointestinal form – Gastrointestinal involvement is likely to be more common than oropharyngeal disease, but its incidence is probably underestimated because it occurs mostly in medically underserved areas. The incubation period is estimated to be one to six days [30]. Following ingestion, the spores infect the alimentary tract epithelium. Necrotic ulcers, often similar to eschars on the skin, are surrounded by extensive edema of the infected intestinal segment and its adjacent mesentery; mesenteric lymph nodes may be enlarged and hemorrhagic [31]. Ulcerations can occur in the stomach, esophagus, and duodenum and may result in gastrointestinal hemorrhage. The case-fatality rate of gastrointestinal anthrax is estimated to range from 4 to 60 percent [8,32]. In a review of cases published between 1880 and 2018, the overall mortality was 74 percent [13]. However, this nonselective review likely included many patients who received no treatment. The low mortality rate estimate (4 percent) was derived from point-source outbreaks studied by public health officials in Uganda and Thailand, where large numbers of people ate uncooked meat from animals that died of anthrax. Most of the people who ate the uncooked meat became sick with gastroenteritis, which cleared with oral antibiotics. It may be that many of these patients did not have anthrax.

One series described more than 100 patients in Lebanon with gastrointestinal anthrax; these patients received medical care [31]. The illness generally started with asthenia, headache, low-grade fevers, facial flushing, and conjunctival injection. This was followed by abdominal pain of variable intensity, nausea, vomiting, and, to a lesser extent, diarrhea. Typically, patients at this point had ascites and intravascular depletion. Later, the abdominal pain tended to become more severe, and patients had progression of ascites and hypotension. At surgery, segmental disease was usually found in the distal small bowel and/or proximal colon. Although they do not cite the survival rate, most patients (even those who required surgery) survived.

●Oropharyngeal form – The oropharyngeal form of anthrax is less frequent and also develops following consumption of undercooked, contaminated meat. Edematous lesions develop, which progress over one to two weeks to necrotic ulcers covered with a pseudomembrane. Edema and painful swelling may develop in the oropharynx and neck, accompanied by cervical lymphadenopathy, pharyngitis, and fever [30,32,33]. The mortality from this disease can be substantial even with parenteral antibiotic treatment [33].

Meningitis — Primary meningitis (meningitis as the presenting syndrome without clear route of exposure) is a rare form of anthrax. In contrast, secondary meningitis through bacteremic spread occurs in about a third of patients with other forms of systemic anthrax and has been associated with cutaneous, inhalation, and gastrointestinal cases [4].

Clinical features include fever, headache, and meningeal signs [13]. Delirium or coma follows quickly after presentation. Refractory seizures, cranial nerve palsies, and myoclonus have been reported [2,34].

Anthrax meningitis is frequently associated with intracranial hemorrhage [4]. This is typically identified by imaging (computed tomography or magnetic resonance imaging) or lumbar puncture. Cerebrospinal fluid (CSF) analysis reveals an elevated protein (70 percent), low glucose (37 percent), and a positive Gram stain (77 percent) and culture (81 percent) (picture 3) [34]. Parenchymal brain hemorrhage may be so severe that a grossly bloody lumbar puncture may be confused with a traumatic tap. A review of 44 well-documented cases found that 75 percent of patients died within 24 hours of presentation, with an overall survival of only 6 percent [34].

Injection anthrax — Anthrax has been associated with injection drug use [35]. Although the injection site is usually the route of infection, the clinical presentation is distinct from the typical syndrome of cutaneous anthrax. Skin and soft tissue findings include substantial edema and swelling at injection site, blistering and skin necrosis, and lack of the classic eschar [36].

Systemic symptoms are also commonly reported. In a systematic review that included 59 adults hospitalized with anthrax associated with injection drug use, fever or chills were reported in 49 percent, fatigue and flu-like symptoms in 27 percent, and diaphoresis in 20 percent [13]. In another review, nonspecific gastrointestinal symptoms such as nausea, vomiting, and abdominal pain were reported in over half of confirmed cases and various neurologic symptoms in approximately one-third [36].

Among reported cases of adults hospitalized with injection-associated anthrax between 1960 and 2018, the mortality rate was 33 percent [13].

The epidemiology of injection-related anthrax outbreaks is discussed in detail separately. (See "Microbiology, pathogenesis, and epidemiology of anthrax", section on 'Injection anthrax'.)

DIAGNOSTIC EVALUATION

Contacting public health officials — The possibility of anthrax should be suspected in patients with a consistent clinical syndrome and consistent epidemiology (eg, exposure to animals or animal hides or clusters of similar cases that could portend a bioterrorism event). In the United States, when anthrax is suspected, clinicians should contact their local or state health department immediately to notify them and review specimen collection and submission guidelines. Non-culture testing is typically performed at a reference laboratory. (See 'Specimen handling and transport to a reference lab' below.)

Evaluation by clinical syndrome

Inhalation anthrax

Distinction from common respiratory infections — It is important to distinguish potential inhalation anthrax cases from more common disorders such as community-acquired pneumonia (CAP), influenza, and influenza-like illnesses (ILI). As mentioned above, this may be difficult. If the patient has influenza, respiratory syncytial virus, or coronavirus disease 2019 (COVID-19), a positive test can allay concerns about anthrax. The epidemiologic setting is important, especially with regards to occupational history and hobbies (eg, drum maker) or if there is an association with other cases, as in the occurrence of a suspected bioterrorism event.

The bioterrorism event of 2001 illustrated the importance of screening for inhalation anthrax because the window of opportunity for successful treatment is narrow once symptoms appear. Clinical signs more frequently associated with inhalation anthrax compared with CAP or ILI included shortness of breath, nausea, vomiting, altered mental status, pallor or cyanosis, and hematocrit >45 percent [26,37]. In contrast, symptoms more suggestive of an ILI included rhinorrhea and sore throat [37]. Unexplained mediastinal widening on chest radiography in a compatible clinical setting should raise the possibility of inhalation anthrax. Other radiographic findings are probably not specific enough to be helpful in an unsuspected sporadic case, but such findings can be helpful in an outbreak situation or if there was a known risk of exposure. In the 2001 outbreak, pleural effusion was more common in patients with inhalation anthrax than in those with CAP [38]. Although chest radiographs are almost always abnormal in patients with inhalation anthrax, these findings are sometimes subtle, and they may be initially overlooked. Thus, the diagnosis of inhalation anthrax cannot be ruled out even if a chest radiograph is interpreted as normal early in the course of illness.

Approach to testing — Diagnostic testing should be performed on specimens from patients being evaluated for inhalation anthrax, including patients with a known exposure or high risk of exposure, patients with a clear epidemiologic link presenting with symptoms of inhalation anthrax, and patients with a clinical presentation suggestive of anthrax in the absence of an alternate diagnosis.

The following diagnostic testing is recommended for patients with suspected inhalation anthrax (table 1) [39]. Specimens submitted for culture should ideally be collected prior to antimicrobial therapy. Non-culture testing is typically performed at a reference laboratory. (See 'Specimen handling and transport to a reference lab' below.)

●Blood for routine culture and for polymerase chain reaction (PCR) testing

●Acute and convalescent serum samples for serologic testing

●Plasma to test for anthrax lethal factor toxin (this can also be performed on acute serum)

●Pleural fluid, if present, for Gram stain, culture, PCR, and testing for anthrax lethal factor toxin

●Pleural and/or bronchial biopsies for PCR and immunohistochemistry, if other tests are negative

Evaluation of cerebrospinal fluid (CSF) is also warranted in patients with systemic anthrax (including inhalational anthrax). (See 'Meningitis' below.)

Cutaneous anthrax — The possibility of cutaneous anthrax should be suspected in a patient with a cutaneous eschar (picture 1), especially with extensive edema disproportionate to the lesion size, and potential exposure (eg, to animals or animal hides or in the setting of clusters of similar cases). Gram-positive rods and few polymorphonuclear leukocytes on Gram stain are strongly suggestive of cutaneous anthrax (picture 4).

The following diagnostic testing is recommended for patients with suspected cutaneous anthrax (table 1) [39]. Specimens submitted for culture should ideally be collected prior to antimicrobial therapy. Non-culture testing is typically performed at a reference laboratory. (See 'Specimen handling and transport to a reference lab' below.)

●Lesion specimens:

•For vesicular lesions, two swabs of vesicular fluid from an unopened vesicle, one for Gram stain and culture, the second for PCR testing.

•For eschars, the edge should be lifted and two swabs rotated underneath and submitted, one for Gram stain and culture, the second for PCR testing.

•For ulcers, the base of the lesion should be sampled with two saline-moistened swabs and submitted, one for Gram stain and culture, the second for PCR testing.

●Biopsy – In addition, a full-thickness punch biopsy of a papule or vesicle including adjacent skin from all patients should be submitted in 10 percent formalin for histopathology and immunohistochemistry. In patients not receiving antibiotic therapy or on therapy for <24 hours, a second biopsy specimen should be submitted for Gram stain, culture, and PCR testing [9,40,41].

●Acute and convalescent serum samples for serologic testing.

●Plasma to test for anthrax lethal factor toxin (this can also be performed on acute serum).

●In patients with evidence of systemic illness (eg, fever, tachycardia, hypotension), blood for culture and PCR testing.

Evaluation of CSF is also warranted in patients with signs of secondary meningitis or other features of systemic infection (eg, sepsis). (See 'Meningitis' below.)

Gastrointestinal tract anthrax — Information regarding the reliability of diagnostic testing in gastrointestinal tract anthrax is limited. The following diagnostic testing is recommended for patients with suspected gastrointestinal tract anthrax (table 1) [39]. Specimens submitted for culture should ideally be collected prior to antimicrobial therapy. Non-culture testing is typically performed at a reference laboratory. (See 'Specimen handling and transport to a reference lab' below.)

●Blood for culture and PCR testing

●Acute and convalescent serum samples for serologic testing

●Plasma to test for anthrax lethal factor toxin (this can also be performed on acute serum)

●Ascites fluid for Gram stain, culture, PCR testing, and testing for anthrax lethal factor toxin

●Rectal swab for Gram stain, culture, and PCR testing

●Oropharyngeal lesion, if present, for Gram stain, culture, and PCR testing

If the patient undergoes surgery, affected tissue can be obtained for Gram stain, culture, and PCR testing; immunohistochemistry can be performed on formalinized tissue.

Evaluation of CSF is also warranted in patients with systemic anthrax (including gastrointestinal anthrax). (See 'Meningitis' below.)

Culture from stool frequently does not yield B. anthracis [30], but Gram stain or culture of oropharyngeal lesions or ascitic fluid may be positive (picture 4) [31]. Blood cultures may also be positive when collected prior to initiating antimicrobial therapy [31]. Serologic testing for antibodies against protective antigen were positive in 7 of 10 oropharyngeal anthrax cases tested [38].

Meningitis — All patients with systemic anthrax should undergo evaluation for meningitis. In particular, the possibility of anthrax meningitis should be suspected in any patient with known or suspected anthrax at another clinical site who has severe nausea or vomiting, altered mental status, headache, meningeal signs, other neurologic signs, papilledema, or seizure. It should also be suspected in patients not known to have anthrax and who have undiagnosed hemorrhagic meningitis.

In addition to the blood, serum, and plasma testing recommended for all patients with systemic anthrax (see 'Approach to testing' above), diagnostic testing for patients with suspected anthrax meningitis includes (table 1):

●CSF for culture and PCR testing

In a mass-casualty situation, especially if resources become limited preventing lumbar puncture and CSF testing on all patients, it may be necessary to make the presumptive diagnosis of meningitis on signs and symptoms alone [42,43].

Specimen handling and transport to a reference lab — Details of specimen handling and transport should be established through consultation with the local microbiology laboratory, the state health department, and the Laboratory Response Network (LRN) reference laboratory. In general, the guidelines below should apply:

●Specimens of stool, sputum, pleural fluid, CSF, and blood stored at 2 to 8°C

●Swabs at room temperature

●Fresh tissue samples frozen

●Formalin-fixed specimens at room temperature

Blood specimens for PCR testing should optimally be collected in tubes containing ethylenediaminetetraacetic acid (EDTA) or citrate as anticoagulant and not heparin. Isolates of Bacillus can be transported on most nonselective laboratory media at room temperature. Specific information on specimen types, volumes, and transport conditions is summarized in the table (table 2).

The LRN was established in 1999 by the Centers for Disease Control and Prevention (CDC), the Association of Public Health Laboratories (APHL), the Federal Bureau of Investigation (FBI), and the United States Army Medical Research Institute of Infectious Diseases (USAMRIID) for the rapid identification of selected agents, including B. anthracis [44]. The LRN is part of a linked hierarchy of sentinel, reference, and national-level laboratories. There are LRN reference laboratories (generally state public health laboratories) in all 50 states. These laboratories can be accessed through the local health departments.

DIAGNOSIS — The diagnosis of anthrax is made by the growth of B. anthracis on culture of a clinical specimen. Isolation of a B. cereus group organism from a patient with a compatible clinical syndrome and epidemiology should also be considered anthrax until proven otherwise. Depending on the syndrome, blood, skin lesion specimens, pleural fluid, cerebrospinal fluid (CSF), rectal swab, ascitic fluid or tissue can be cultured. The diagnosis is also supported by a positive polymerase chain reaction (PCR) on one of these specimens, positive serologic testing, or detection of lethal toxin in a patient with a compatible clinical syndrome; these non-culture tests are generally available only through reference laboratories. Testing for anthrax is discussed elsewhere. (See 'Diagnostic evaluation' above.)

Clinicians who suspect anthrax should communicate closely with their clinical laboratory to ensure appropriate microbiologic workup of any Bacillus isolate and to send the isolate to a reference laboratory for definitive identification. In the United States, this should be accomplished by immediately notifying the state health department and, with their assistance, the appropriate Laboratory Response Network (LRN) reference laboratory [44]. (See 'Specimen handling and transport to a reference lab' above.)

B. anthracis grows rapidly on routine culture media. However, several issues pose challenges to the microbiologic diagnosis of anthrax in the clinical laboratory. Clinical laboratories may not routinely work up an isolated Bacillus species since these organisms most commonly reflect contamination. Furthermore, B. anthracis belongs to the Bacillus cereus group, and species within this group are so closely related that routine testing does not reliably distinguish them [45]. Additionally, rare strains of B. cereus can harbor virulence plasmids and cause syndromes indistinguishable from anthrax [46-49].

Finally, the  (MALDI-TOF MS) systems that most laboratories use to identify microbes may not specifically identify B. anthracis. In the United States, two systems are the most widely used. The Biomerieux system classifies B. anthracis as “B. cereus group.” The Bruker system uses two panels, neither of which identifies B. anthracis. Although Bruker offers a supplemental panel that can identify B. anthracis, it does not come standard with the system.

Standard susceptibility testing is still relied upon as for other pathogens [50], and susceptibility testing should be carried out while the organism is being worked up by a reference lab.

OTHER EVALUATION — For patients with suspected or documented systemic anthrax, the initial evaluation also focuses on potential complications of infection. This work-up is detailed in the table (table 3) and includes:

●Routine laboratory testing: Complete blood count, electrolytes, kidney function tests, liver enzymes, and coagulation tests

●Electrocardiogram

●Chest imaging

●Lumbar puncture for cell count, glucose, total protein, Gram stain, culture, and polymerase chain reaction (PCR) testing

●Echocardiogram

Ongoing monitoring for patients with systemic anthrax is also warranted. This is discussed elsewhere. (See "Treatment of anthrax", section on 'Monitoring'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Anthrax".)

SUMMARY AND RECOMMENDATIONS

●Clinical syndromes – There are four major anthrax syndromes:

•Cutaneous anthrax – This is the most common form of anthrax. It begins as a small, painless, but often pruritic papule that quickly enlarges and develops a central vesicle or bulla, followed by erosion, resulting in a necrotic ulcer with a black, depressed eschar (picture 1). There is often extensive surrounding edema, regional lymphadenopathy, and lymphangitis (picture 2). (See 'Cutaneous' above.)

•Inhalation anthrax – Early clinical symptoms are nonspecific and include myalgia, fever, and malaise, which can mimic a viral respiratory infection. After an average of four to five days, patients become dramatically sicker with progressive respiratory symptoms, including severe dyspnea, hypoxemia, and shock.

•Gastrointestinal tract anthrax – This is characterized by necrotic ulcers with surrounding edema in the mucosa of the gastrointestinal tract, which can result in hemorrhage. Patients also present with abdominal pain, nausea, and vomiting. An oropharyngeal form involves lesions in the mouth and throat, with painful edema in the neck, pharyngitis, and cervical lymphadenopathy. (See 'Gastrointestinal tract' above.)

•Anthrax meningitis – Meningitis rarely occurs as the presenting syndrome but occurs in about a third of patients with systemic anthrax. It is associated with parenchymal brain hemorrhage that can result in grossly bloody cerebrospinal fluid (CSF) and rapid progression to delirium or coma. (See 'Meningitis' above.)

●Diagnostic evaluation – The possibility of anthrax should be suspected in patients with a consistent clinical syndrome (as above) and consistent epidemiology (eg, exposure to animals or animal hides or clusters of similar cases that could portend bioterrorism event). In the United States, when anthrax is suspected, clinicians should contact their local or state health department immediately to notify them and review specimen collection and submission. Diagnostic testing includes culture and polymerase chain reaction (PCR) testing of blood and specimens from affected clinical sites, acute and convalescent serologic testing, and testing for lethal factor toxin on plasma (table 1). All patients with systemic anthrax (ie, all forms of anthrax other than limited cutaneous disease) should be evaluated for meningitis. (See 'Diagnostic evaluation' above.)

●Diagnosis – The diagnosis of anthrax is made by the growth of B. anthracis on culture of a clinical specimen. Isolation of a B. cereus group organism from a patient with a compatible clinical syndrome and epidemiology should also be considered anthrax until proven otherwise. The diagnosis is also supported by a positive PCR from clinical specimens, detection of lethal toxin in blood or body fluid, or positive serologic testing. (See 'Diagnosis' above.)