Approach
Anthrax is a notifiable condition, and public health officials should be notified once a diagnosis is confirmed. The diagnostic approach depends on whether cutaneous, inhalation, ingestion, or injection anthrax is suspected. Suspicion of anthrax must be conveyed to the laboratory, as Bacillus species are otherwise often disregarded as contaminants and do not undergo further testing.
Clinical presentation
The clinical presentation depends on the anthrax subtype.
Cutaneous anthrax
In patients with an occupational exposure (contact with animals or their products), cutaneous anthrax is suspected if, 2-6 days later, a painless, itchy papule forms.[45] Within 24-36 hours, the lesion becomes vesicular and develops central necrosis, massive oedema, and eschar formation. In late stages, a necrotic black eschar may form. Regional lymphadenopathy is common.
Inhalation anthrax
Cases of inhalation anthrax are clinically non-specific, and an epidemiological link or high index of suspicion is critical to diagnosis.
If a patient presents with a history of an occupational exposure and presents with a 2- to 5-day illness with fevers, sweats, fatigue, non-productive cough, chest discomfort, nausea, vomiting, diarrhoea, abdominal pain, headaches, myalgias, and sore throat, suspicion should be high.[45] Symptoms of congestion and coryza are notably absent.
Physical examination findings in cases of inhalation anthrax are non-specific and rarely aid in diagnosis. Decreased breath sounds may suggest characteristic pleural effusions, but clinical signs of pneumonia are variable or may be lacking.[37]
Initial symptoms are followed by rapid cardiopulmonary collapse within 1-3 days. The initial flu-like syndrome can be followed by a brief period of apparent resolution prior to deterioration. Hypotension is common.
Ingestion anthrax
This type, of which there are two subtypes (oropharyngeal and gastrointestinal), is exceedingly rare and is usually reported within the context of an outbreak.
Patients present with fevers, abdominal pain, ascites, nausea, and vomiting 2-5 days after spore ingestion.[46] Oropharyngeal mucosal ulceration or pseudomembrane formation may be additional manifestations of B anthracis spore ingestion.[47]
Injection anthrax
This type of anthrax may be difficult to recognise and treat, and the differential includes other common skin and soft-tissue infections that injection-drug users often develop.
Injection anthrax has been reported in intravenous heroin users. Anthrax-contaminated heroin may also be ingested or inhaled (snorted).
Symptoms of injection anthrax are similar to cutaneous anthrax; however, infection may be deep under the skin or in the muscle where the drug was injected. Patients typically present with massive oedema around the injection site, often leading to compartment syndrome or necrotising fasciitis. Necrotic skin lesions may be absent, and complications occur more often. No eschar is apparent, and pain is often not described.[20]
Anthrax meningitis
Approximately 14% to 37% of patients develop meningitis, depending on the route of transmission. All patients with signs and symptoms of systemic anthrax should be evaluated for meningitis. Meningitis may complicate any form of anthrax and may also be a primary manifestation.[1]
Primary symptoms include fever, headache (which is often described as severe), nausea, vomiting, and fatigue. Meningeal signs (e.g., meningismus), altered mental status, and other neurological signs such as seizures or focal signs are usually present.[2]
Clinical presentation in children
Anthrax in children requires special consideration, as the presentation and progression of illness can be different from that in adults, including a higher risk of dissemination and subsequent meningoencephalitis, even after a focal infection.[48] Furthermore, febrile respiratory illnesses are common and could mimic early symptoms of anthrax.
One systematic review found that, although there have been very few case reports of children with inhalational anthrax, most children present with fever, cough, dyspnoea, and abnormal lung findings on examination.[49]
Similar to adults, children with gastrointestinal anthrax can present with upper respiratory tract disease characterised by dysphagia and oropharyngeal findings or lower respiratory tract disease characterised by fever, abdominal pain, and vomiting.
Children with inhalational disease may have atypical presentations, including primary meningoencephalitis.
With paediatric cutaneous anthrax, the incubation period is typically 1-12 days and the skin lesion progresses from a pruritic papule into a depressed black eschar surrounded by moderate to severe oedema over 2-6 days.[48] The lesion is typically painless and can be accompanied by fever, malaise, headache, and painful lymphadenopathy.
Initial investigations
Anthrax is diagnosed in adults and children using a combination of microbiology and pathology testing methods. The Centers for Disease Control and Prevention (CDC) also recommend the following tests to confirm the diagnosis:[2]
The gold standard test for diagnosis is culturing Bacillus anthracis from clinical specimens.
Real-time polymerase chain reaction (RT-PCR): detection of B anthracis or anthrax toxin genes by RT-PCR and/or sequencing in clinical specimens collected from a normally sterile site such as blood or cerebrospinal fluid (CSF) or lesion of other affected tissue.
Serology: evidence of a four-fold rise in antibodies to protective antigen between acute and convalescent sera, or a four-fold change in antibodies to protective antigen in paired convalescent sera using quantitative anti-PA immunoglobulin G (IgG) enzyme-linked immunosorbent assay (ELISA) testing in an unvaccinated person.
Detection of anthrax lethal factor (LF) toxin in serum or plasma specimens by LF mass spectrometry.
Immunohistochemistry (IHC): detection ofB anthracis antigens in tissues by immunohistochemical staining using both B anthracis cell wall and capsule monoclonal antibodies.
Specimens should be sent to a laboratory that deals with high-risk pathogens. A confirmed case meets clinical criteria and has confirmed laboratory test results.[2]
Clinical specimens including skin lesion exudates, blood, pleural fluid, CSF, ascites fluid, tissue from a biopsy, or a rectal swab are all considered suitable; however, the specimen collected depends on the clinical presentation.[50] Lumbar puncture should be performed in all paediatric patients with systemic manifestations, unless clinical contraindications exist, given the high rate of meningoencephalitis.[48]
Cutaneous anthrax
Lesion swabs: culture and RT-PCR of fluid carefully expressed from a vesicular lesion, eschar, or ulcer may yield a diagnosis, but manipulation of the lesion can lead to dissemination, so great care must be taken in obtaining the sample.[51] A sample is obtained by unroofing a vesicle with a dry swab, or with a moistened swab at the base of an ulcer or underneath the eschar.[52] Culture of vesicular fluid in cutaneous anthrax is considered the best diagnostic test, but sensitivity is limited (60% to 65%).[53]
Biopsy: punch biopsy of a papule or vesicle for histopathology and IHC is an alternative test when cutaneous anthrax is suspected and wound cultures are negative or cannot be obtained due to a paucity of fluid. Biopsy reveals necrosis of the dermis and epidermis, oedema, and mild inflammatory infiltrate on haematoxylin and eosin stain.[37][54]
Serum/plasma: an acute serum sample (i.e., ≤7 days after symptom onset or as soon as possible after a known exposure) should be taken for serology and to test for anthrax LF toxin. Convalescent serum samples (i.e., 14-35 days after symptom onset) are recommended. Plasma is the preferred specimen for anthrax LF toxin testing.
Blood: only required for culture and RT-PCR in patients with signs of systemic infection (e.g., fever, tachycardia, tachypnoea, hypotension).
CSF: only required for culture and RT-PCR in patients with signs of meningitis (e.g., severe headache, meningeal signs, altered mental status, seizures).
Inhalation anthrax
Blood: blood cultures are recommended for culture and RT-PCR prior to initiation of antimicrobial drugs.
Serum/plasma: an acute serum sample should be taken for serology and to test for anthrax LF toxin. Convalescent serum samples are recommended. Plasma is the preferred specimen for anthrax LF toxin testing.
Pleural fluid: should be tested for culture and RT-PCR, as well as anthrax LF toxin. Thoracentesis may be performed in suspected cases of inhalation anthrax if pleural effusions are present and the blood cultures are negative. Inhalation anthrax does not result in a pneumonic process; therefore, cultures of sputum samples are not helpful in the diagnosis.
Biopsy: pleural and/or bronchial biopsies may be collected for IHC.
CSF: only required for culture and RT-PCR in patients with signs of meningitis (e.g., severe headache, meningeal signs, altered mental status, seizures).
Ingestion anthrax
Blood: blood cultures are recommended for culture and RT-PCR.
Oropharyngeal lesion swabs: should be tested for culture and RT-PCR in patients who have oropharyngeal lesions.
Rectal swabs: should be tested for culture and RT-PCR in patients with gastrointestinal anthrax.
Serum/plasma: an acute serum sample should be taken for serology and to test for anthrax LF toxin. Convalescent serum samples are recommended. Plasma is the preferred specimen for anthrax LF toxin testing.
Ascites fluid: should be tested for culture and RT-PCR, as well as anthrax LF toxin.
CSF: only required for culture and RT-PCR in patients with signs of meningitis (e.g., severe headache, meningeal signs, altered mental status, seizures).
Injection anthrax
Blood: blood cultures are recommended for culture and RT-PCR.
Serum/plasma: an acute serum sample should be taken for serology and to test for anthrax LF toxin. Convalescent serum samples are recommended. Plasma is the preferred specimen for anthrax LF toxin testing.
Biopsy: tissue biopsy from localised lesion tissue debridement.
CSF: only required for culture and RT-PCR in patients with signs of meningitis (e.g., severe headache, meningeal signs, altered mental status, seizures).
If anthrax is suspected, clinical specimens should be collected before starting antibiotic therapy. Full details of specimen collection, processing, and submission are available from the CDC:
Other investigations
A FBC and chest x-ray should also be ordered in patients with inhalation anthrax. The x-ray classically reveals a widened mediastinum.[55] If suspicion for anthrax is high, and x-ray results are negative, a computed tomography (CT) scan of the chest should be ordered. CT may reveal enlarged, hyperdense hilar and mediastinal lymph nodes; mediastinal oedema; and large pleural effusions.[56][57][58] These findings in a previously healthy patient should raise suspicion of inhalation anthrax. Treatment is often started in these patients if the white blood cell count is elevated, or the imaging is abnormal.
Radiographic imaging is not specific in ingestion anthrax and is therefore of limited diagnostic utility in such cases.[59]
Screening tools for anthrax meningitis
In the setting of a mass casualty event, conventional standards for diagnosis of meningitis might be limited or unavailable. Therefore, a screening tool has been developed to identify patients with anthrax meningitis for these situations.
Patients are likely to have anthrax meningitis if they meet either of the following criteria.[1]
≥2 of the following signs or symptoms: severe headache, altered mental status, meningeal signs, or other neurological deficits; or
≥1 of the following signs or symptoms: severe headache, altered mental status, meningeal signs, or other neurological deficits; AND ≥1 of the following signs or symptoms: nausea/vomiting, abdominal pain, or fever (either subjective or measured) or chills.
Patients are unlikely to have meningitis if they do not have severe headache, altered mental status, meningeal signs, and other neurological deficits. This screening tool had a sensitivity of 86% and a specificity of 92%, with 2.5% of adults requiring further testing.
Patients who have sepsis, obesity, hypertension, COPD, and current/former smokers appear to be at increased risk for meningitis.
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