INTRODUCTION — Anthrax, caused by Bacillus anthracis, is an uncommon illness in the United States. From 1980 through 2000, only seven cases of anthrax were reported to the Centers for Disease Control and Prevention [1]. In 2001, 22 confirmed or suspected cases of bioterrorism-related anthrax occurred in the United States, when B. anthracis spores in powder-containing envelopes were sent through the mail [2-4]. Subsequent sporadic cases have occurred rarely in the United States, such as in individuals exposed to contaminated animal hides while making traditional drums. (See "Microbiology, pathogenesis, and epidemiology of anthrax".)
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 three major anthrax syndromes: cutaneous, inhalation, and gastrointestinal tract anthrax [5-7].
Cutaneous — Cutaneous anthrax is the most common form of the disease. 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 [8-10]. Spores vegetate and multiply, and the antiphagocytic capsule facilitates local spread. (See "Microbiology, pathogenesis, and epidemiology of anthrax".)
The incubation period is usually 5 to 7 days with a range of 1 to 12 days [11,12]. 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 [13]; an outbreak in Algeria was reported with a median incubation period of 19 days [14].
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) [8]. 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 the hallmark of cutaneous anthrax. Rarely, B. anthracis can enter through the palpebral fissure, causing palpebral swelling and necrosis of the eyelids [15].
Systemic symptoms, including fever, malaise, and headache can accompany the cutaneous lesion [11]. In one case during the bioterrorism (BT) event of 2001, a microangiopathic hemolytic anemia, thrombocytopenia, coagulopathy, and renal dysfunction developed in a seven-month-old child; these manifestations resolved following treatment with antibiotics [16].
Historically, the case-fatality rate of cutaneous anthrax is <1 percent with antibiotic therapy; however, without appropriate therapy, mortality can be as high as 20 percent [17].
An outbreak of anthrax occurred in heroin users in Scotland in 2009 and 2010, which caused a skin and soft tissue infection (SSTI) in most patients. (See 'Injection anthrax' below.)
Inhalation — 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 [11,18]. 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 some cases, meningitis.
The incubation period for inhalation anthrax is estimated to be 1 to 7 days but was reported to be as long as 43 days for fatal cases in the 1979 outbreak in Sverdlovsk [13]. 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 one day in 1961 following exposure in a grossly contaminated, dusty carding room in the mill; she previously rarely entered the mill.
During the bioterrorism event in the United States in 2001, the time between known exposure and symptom onset ranged from 4 to 6 days, with a mean of 4.5 days [21,22]. In primate studies, spores have been found in the lungs up to 100 days following exposure [23], and inhalation anthrax has developed up to 58 days following experimental aerosol exposure in primates receiving 30 days of postexposure antibiotics [24].
The course of the disease is usually biphasic. Prodromal symptoms of inhalation anthrax are nonspecific and variable, complicating assessment and diagnosis [5,25,26]. Early symptoms, such as myalgia, fever, and malaise, may mimic those of influenza. However, a variety of symptoms less suggestive of influenza may also be present, such as nausea, hemoptysis, dyspnea, odynophagia, or chest pain [27]. Prodromal symptoms last an average of four to five days and are followed by a rapidly fulminant bacteremic phase with the development of progressive respiratory symptoms, including severe dyspnea, hypoxemia, and shock [9,20].
The fulminant phase is a catastrophic illness that almost uniformly leads to death within days. 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 [13,20,22,27]. For instance, 6 of 11 cases (55 percent) associated with the 2001 BT event in the United States responded to treatment, but none of the five patients who required mechanical ventilation or tracheostomy survived [21]. (See "Treatment of anthrax".)
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. Imaging studies can aid in establishing the diagnosis. Widening of the mediastinum, secondary to mediastinitis, is considered a classic finding in inhalation anthrax (image 1) and 7 of the first 10 cases associated with the 2001 BT event had this finding [22,28].
Other chest radiographic findings seen with inhalation anthrax include hilar abnormalities, pulmonary infiltrates or consolidation, and pleural effusion. One or more of these abnormalities were documented in all 11 cases associated with the 2001 BT event. The abnormalities, however, were often subtle, and chest radiographs obtained early in the course of illness were interpreted as normal in 3 of 11 cases [22,29,30]. (See 'Distinction from common respiratory infections' below.)
As with any form of anthrax, hematogenous spread can result in lesions in other organ systems, including hemorrhagic meningitis and submucosal gastrointestinal lesions [9,19]. Inhalation anthrax is usually fatal; among 71 cases in the world's literature from 1900 to 2005, excluding the six survivors during the 2001 BT event, the mortality rate was 92 percent [27]. (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 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 [31]. 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 [17,32]. 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 [11,33]. The lower estimate is 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.
One series described more than 100 patients in Lebanon with gastrointestinal anthrax [32]. 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.
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 [31,33,34]. The mortality from this disease can be substantial even with parenteral antibiotic treatment [34].
Meningitis — Meningitis has been reported in association with cutaneous, inhalation, and gastrointestinal anthrax cases [35]. About one-half of patients with inhalation anthrax will develop hemorrhagic meningitis [19]. Cerebrospinal fluid analysis reveals an elevated protein (70 percent), low glucose (37 percent), and a positive Gram stain (77 percent) and culture (81 percent) (picture 3) [35]. Parenchymal brain hemorrhage may be so severe that a grossly bloody lumbar puncture may be confused with a traumatic tap. Delirium or coma follows quickly, and refractory seizures, cranial nerve palsies, and myoclonus have been reported [6,35]. 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 [35].
Injection anthrax — Anthrax outbreaks have occurred among people who use injection drugs. In an outbreak of anthrax that occurred among 119 heroin users in Scotland between December 2009 and December 2010, 93 percent of the 47 confirmed cases presented with an SSTI [36]. The typical eschar of cutaneous anthrax was absent in all but one patient, and most patients had disproportionate edema compared with typical cases of cutaneous anthrax and bacterial SSTIs. Twenty-five patients underwent surgical debridement. Twenty-two patients (55 percent) had gastrointestinal involvement, 14 (33 percent) had central nervous system involvement, and 2 (5 percent) had respiratory tract involvement. Some patients developed features of systemic anthrax infection, such as hemorrhagic meningitis, multiorgan failure, and bleeding diathesis.
The epidemiology of injection-related anthrax outbreaks are discussed in detail separately. (See "Microbiology, pathogenesis, and epidemiology of anthrax", section on 'Injection anthrax'.)
DIAGNOSIS — Isolation of Bacillus species is common. However, because of the rarity of anthrax in the United States, most clinical microbiology laboratories do not offer a full array of diagnostic tests for optimal and rapid diagnosis of anthrax. Full identification usually requires sending the isolate to a reference lab, and the index of suspicion in most clinical labs is understandably low. Because of the public health implications of any form of anthrax and the rapid course of inhalation anthrax, when clinicians believe anthrax is possible or likely, they should communicate their suspicions to their supporting laboratories and coordinate the diagnostic evaluation as rapidly as possible with the state health department and, with their assistance, the appropriate Laboratory Response Network (LRN) reference laboratory [37]. (See 'Laboratory Response Network' below.)
Several diagnostic tests are available. Standard culture and susceptibility testing are still relied upon in most clinical settings as for other pathogens, although most clinical laboratories can offer only presumptive identification of B. anthracis with confirmation at a reference laboratory. The organism can be identified by direct observation through immunohistochemical (IHC) staining [38,39]. Standard or real-time polymerase chain reaction can be performed on a variety of specimen types, including blood cultures, tissue samples, and blood samples [40], but this methodology is not widely available in health care settings. As more clinical microbiology labs use matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) systems, direct identification of this pathogen may become more routinely feasible, although the approach presents biosafety concerns and would not reliably identify B. cereus biovar anthracis, which has been described as an animal pathogen in African countries.
Criteria for diagnosis — In 2001, the United States Centers for Disease Control and Prevention (CDC) developed interim case definitions for anthrax.
A confirmed case of anthrax was defined as a clinically compatible case that was laboratory confirmed by the isolation of B. anthracis from the patient or by laboratory evidence based on at least two other supportive tests using nonculture methods for detection of B. anthracis. Supportive laboratory tests include the LRN polymerase chain reaction assay, IHC staining of tissues, and an anti-protective antigen (PA) immunoglobulin (Ig)G detected by an enzyme-linked immunosorbent assay (ELISA) [41].
A suspect case was a clinically compatible illness without isolation of B. anthracis and with only a single supportive test or a clinically compatible case epidemiologically linked to a confirmed exposure to B. anthracis but without corroborative laboratory evidence [41].
Rare strains of B. cereus can cause syndromes indistinguishable from anthrax [42]. There are also strains designated B. cereus biovar anthracis that can behave as anthrax but have different characteristics that could be confusing in a clinical microbiology lab [43]. Isolation of an organism identified as from the B. cereus group in a patient with an illness and epidemiology compatible with anthrax should be considered anthrax until proven otherwise.
The microbiologic diagnosis of B. anthracis is discussed further elsewhere. (See "Microbiology, pathogenesis, and epidemiology of anthrax", section on 'Microbiology'.)
Laboratory Response Network — The LRN was established in 1999 by the 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 select agents including B. anthracis [37]. 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.
Specimen collection and transport — Details of specimen handling and transport should be established through consultation with the local microbiology laboratory, the state health department, and the LRN reference laboratory. In general, the guidelines below should apply:
●Specimens of stool, sputum, pleural fluid, cerebrospinal fluid, and blood stored at 2 to 8ºC
●Swabs at room temperature
●Fresh tissue samples frozen
●Formalin-fixed specimens at room temperature
Blood specimens for polymerase chain reaction 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 1).
DIAGNOSTIC APPROACH 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 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 (BT) 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 [28,44]. In contrast, symptoms more suggestive of an ILI included rhinorrhea and sore throat [44]. 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 [45]. 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 United States Centers for Disease Control and Prevention developed recommendations for the clinical evaluation of persons with possible inhalation anthrax during the 2001 bioterrorism event, which are available online here and here [29].
The following diagnostic testing of patients with suspected inhalation anthrax is recommended:
●Specimens of blood obtained prior to antimicrobial therapy should be sent for routine culture and for polymerase chain reaction (PCR) testing at a Laboratory Response Network (LRN) laboratory
●Pleural fluid, if present, for Gram stain, culture, and PCR
●Cerebrospinal fluid, in patients with meningeal signs, for Gram stain, culture, and PCR
●Acute and convalescent serum samples for serologic testing
●Pleural and/or bronchial biopsies for immunohistochemistry, if other tests are negative
In a mass casualty situation, especially if resources become limited, it may be necessary to use clinical criteria for the diagnosis of meningitis [46,47].
Cutaneous anthrax — The CDC has developed recommendations for the clinical evaluation of persons with possible cutaneous anthrax, which are available online at here and here [29]. In an appropriate epidemiologic setting, the presence of an eschar especially with extensive edema out of proportion to the size of the lesion and the presence of gram-positive rods and few polymorphonuclear leukocytes on Gram stain are strongly suggestive of cutaneous anthrax (picture 4).
The following diagnostic testing of patients with suspected cutaneous anthrax is recommended:
●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
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 [12,38,39].
Gastrointestinal tract anthrax — Information regarding the reliability of diagnostic testing in gastrointestinal tract anthrax is limited. Culture from stool frequently does not yield B. anthracis [31], but Gram stain or culture of oropharyngeal lesions or ascitic fluid may be positive (picture 4) [32]. Blood cultures may also be positive when collected prior to initiating antimicrobial therapy [32]. Serologic testing for antibodies against protective antigen were positive in 7 of 10 oropharyngeal anthrax cases tested [45].
The following diagnostic testing of patients with suspected alimentary tract anthrax is recommended:
●Blood cultures and blood for PCR testing obtained prior to antimicrobial therapy
●Ascites fluid for Gram stain, culture, and PCR testing
●Stool or rectal swab for Gram stain, culture, and PCR testing
●Oropharyngeal lesion, if present, for Gram stain, culture, and PCR testing
●Acute and convalescent serum samples for serologic 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
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 2) 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
Clinical manifestations
●There are three major anthrax syndromes: cutaneous, inhalation, and alimentary tract anthrax. (See 'Clinical manifestations' above.)
●Cutaneous anthrax is the most common form of the disease (picture 1). Naturally occurring cases of cutaneous anthrax develop after spores of Bacillus anthracis are introduced subcutaneously, often as a result of contact with infected animals or animal products. (See 'Cutaneous' above.)
●Cutaneous anthrax begins as a small, painless, but often pruritic papule that quickly enlarges and develops a central vesicle or bulla, followed by erosion, leaving a necrotic ulcer with a black, depressed eschar. Extensive edema of the surrounding tissues is often present along with regional lymphadenopathy and lymphangitis. (See 'Cutaneous' above.)
●Inhalation anthrax results from the inhalation of B. anthracis spores into the alveoli aerosolized through either industrial processing; working with animal products such as wool, hair, or hides that are contaminated with anthrax spores; or intentional release, such as the bioterrorism event of 2001 in the United States. (See 'Inhalation' above.)
●Early clinical symptoms of inhalation anthrax are nonspecific, complicating assessment and diagnosis. Initial symptoms, such as myalgia, fever, and malaise frequently mimic those of influenza. However, anthrax-infected patients become dramatically sicker a few days later with the development of progressive respiratory symptoms, including severe dyspnea and hypoxemia. About one-half of patients with inhalation anthrax will develop hemorrhagic meningitis. (See 'Inhalation' above and 'Meningitis' above.)
●Gastrointestinal tract anthrax presents in two clinical forms, oropharyngeal and gastrointestinal. The disease develops following the consumption of undercooked infected meat from animals with anthrax. (See 'Gastrointestinal tract' above.)
Diagnosis
●Because of the public health implications of anthrax in the United States and the rapid course of disease progression, clinical or laboratory suspicion of anthrax should be followed by rapid testing of clinical samples and early initiation of antibiotic therapy. Immediate notification of the local or state health department and laboratory is essential. (See 'Diagnosis' above.)
●During a potential bioterrorism episode, an important issue is distinguishing inhalation anthrax from more common disorders such as community-acquired pneumonia, influenza, and influenza-like illness. (See 'Distinction from common respiratory infections' above.)
●The most accurate predictors of inhalation anthrax are mediastinal widening (image 1) or pleural effusion on chest radiograph. (See 'Distinction from common respiratory infections' above.)
●Criteria and case definitions established for diagnosis include:
•Confirmed case – A clinically compatible case that is laboratory confirmed by the isolation of B. anthracis from the patient or by laboratory evidence based on at least two other supportive tests using nonculture methods for detection of B. anthracis (Laboratory Response Network polymerase chain reaction assay, immunohistochemistry of tissues, and an anti-protective antigen immunoglobulin G enzyme-linked immunosorbent assay). (See 'Criteria for diagnosis' above.)
•Suspect case – A clinically compatible illness without isolation of B. anthracis and with only a single supportive test or a clinically compatible case epidemiologically linked to a confirmed exposure to B. anthracis but without laboratory confirmation. (See 'Criteria for diagnosis' above.)
●The diagnostic approach is dependent on the clinical syndrome. (See 'Diagnostic approach by clinical syndrome' above.)
