Anthrax

Diagnosis

All forms of anthrax disease are diagnosed using a combination of clinical and laboratory findings.

Cutaneous anthrax. The key to diagnosis centers upon the presence of the characteristic painless skin lesion which progresses to a vesicle, ulcer, then eschar, with surrounding edema. While arachnid bites or cutaneous tularemia may appear similar, these lesions are characteristically painful. Known exposure history or risk may also be present. To perform Gram stain and bacterial culture of the lesion, samples should be collected by using two dry Dacron or rayon swabs, ideally with the fluid of an unopened vesicle. If no vesicle is present, use moistened swabs (sterile saline) to swab under an eschar or in the base of an ulcer. Gram stain often demonstrates large gram-positive bacilli if the patient has not yet received antibiotics. If the gram stain and culture are negative, collect a 4-mm punch biopsy (or two if both eschar and vesicle are present) of the leading margin of the lesion for general histology and immunostaining. Blood culture should be collected in all patients suspected of having anthrax.

Gastrointestinal anthrax. History of exposure to or ingestion of the meat of sick animals should be obtained. Clinical suspicion should be elevated for multiple cases of similar disease. Oropharyngeal disease can mimic diphtheria, and vaccination and travel history should be obtained. Gram stain and culture of the oral lesion may often be positive for B. anthracis if collected before initiation of antibiotics. Intestinal anthrax may mimic acute gastroenteritis, acute abdomen with peritonitis (thus focal and rebound tenderness), or dysentery. Abdominal radiographic studies are non-specific, sometimes showing diffuse air-fluid levels, bowel thickening, and peritoneal fluid. Surgical findings may include hemorrhagic mesenteric adenitis, serosanguinous to hemorrhagic ascites, bowel ulceration (usually ileum and cecum), edema, and necrosis. Stool culture is variably positive in intestinal anthrax. Peritoneal fluid should be sent for Gram stain, culture, immunostaining, and PCR. Blood should be collected for culture, serology (paired frozen serum 3-4 weeks apart, -70oC) and PCR (lavender tube, refrigerated) in patients with either form of GI disease. Ascitic fluid can be sent for culture, PCR, and immunostaining.

Inhalational anthrax. Early IA is a non-specific syndrome which may be difficult to distinguish clinically from other illnesses. Notably absent in inhalational anthrax are upper respiratory symptoms (rhinorrhea, coryza, congestion) as one would see with influenza. Pneumonia generally does not occur; therefore, lung exam may be unrevealing and organisms are not typically seen in the sputum. Patients suspected of having IA should have a complete blood count (CBC), blood culture, and serum electrolytes. White blood cell count is typically elevated only slightly at presentation (mean 9,800/microliter in 2001 cases) with a neutrophil predominance. Hemoconcentration may be evidenced by elevated serum sodium and hematocrit. Mildly elevated serum AST and ALT may be present as well as hypoalbuminemia. Bacillus anthracis will be detectable even in the early phase of disease by routine blood culture and may even be seen on Gram stain of blood later in the course of the illness; however, even one or two doses of antibiotics will render blood (and other sites) sterile. In patients with neurologic symptoms, CSF may show evidence of hemorrhagic meningitis with numerous gram-positive bacilli. Pleural effusions may be large and bloody; Gram stain may show organisms. If cultures are sterile, blood and other fluids may be sent for PCR; CSF, pleural fluid, and tissue may be sent for immunostaining; and acute and convalescent serum may be collected for serology. All patients suspected of having IA should have a chest radiograph (CXR) to look for mediastinal adenitis (seen as a widened mediastinum or mediastinal "fullness") and pleural effusions. If the radiograph is normal, then chest CT should be performed. In the attacks of 2001, CXR and/or chest CT were abnormal in all cases.

Differential Diagnosis

The differential diagnosis for anthrax depends upon the clinical syndrome (cutaneous, inhalational, gastrointestinal, or meningeal). Other diagnoses to consider are outlined in the tables below.

Differential Diagnosis for Cutaneous Anthrax

(Note: Two key features that distinguish cutaneous anthrax from other conditions in differential diagnosis are painlessness of the lesion and the relatively large extent of associated edema.)

Diagnosisa-c

Distinguishing Features

Ecthyma gangrenosum

—Usually in neutropenic patients with Pseudomonas aeruginosa bacteremia
—Edema usually not present

Ulceroglandular tularemia (Francisella tularensis)

—Clinical course usually indolent; disease often self-limited
—Systemic toxicity uncommon

Bubonic plague (Yersinia pestis)

—Systemic toxicity common
—Extremely tender regional lymphadenopathy present
—Ulceration and eschar formation usually absent

Staphylococcal or streptococcal cellulitis

—May be history of trauma or preexisting lesion at site of infection
—Eschar formation does not occur
—Usually painful

Necrotizing soft tissue infections (particularly Group A Streptococcus and Clostridium species)

—Severe systemic toxicity often present
—Early in course, pain usually more severe than clinical findings would indicate

Bite of brown recluse spider (Loxosceles reclusa)d

—Brown recluse spiders prefer warm temperatures and are not native to northern half of United States
—Spiders tend to hide in barns, woodpiles, and similar places
—Bite usually causes painful blister that progresses to necrosis (unlike anthrax, which is painless)
—Edema generally absent

Rickettsialpox (Rickettsia akari)

—Initial presentation involves painless papule that forms black eschar
—Generalized maculopapular rash appears 2-3 days later

Scrub typhus (Orientia tsutsugamushi; formerly Rickettsia tsutsugamushi)

—Zoonotic infection from chigger bites; occurs in endemic areas (Asia and Western Pacific)
—Often associated with generalized maculopapular rash

Orf (orf virus, a parapox virus)

—Occurs in farm workers
—Characterized by pustule that progresses to weeping nodule
—Eschar formation does not occur
—Edema usually absent

Necrotic herpes simplex infection

—More likely to occur in immunocompromised host

aSee References: Dixon 1999.
bSee References: Swartz 2001.
cSee References: Bell 2002.
dSee References: Nelson 2002.


Differential Diagnosis for Inhalational Anthrax

(Note: Features that distinguish inhalational anthrax from other conditions in differential diagnosis include presence of widened mediastinum and pleural effusions on chest radiograph or CT scan with minimal evidence of pneumonia.)

Diagnosisa,b

Distinguishing Features

Pneumonic plague (Yersinia pestis)

—Hemoptysis relatively common with pneumonic plague, but rare with inhalational anthrax

Tularemia (Francisella tularensis)

—Clinical course usually indolent, lasting weeks
—Less likely to be fulminant

Community-acquired bacterial pneumonia
—Mycoplasmal pneumonia (Mycoplasma pneumoniae)
—Pneumonia caused by Chlamydia pneumoniae
—Legionnaires' disease (Legionella pneumophila or other Legionella species)
—Psittacosis (Chlamydia psittaci)
—Other bacterial agents (eg, Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, Klebsiella pneumoniae, Moraxella catarrhalis)

—Rarely as fulminant as inhalational anthrax
—Legionellosis and many other bacterial agents (S aureus, S pneumoniae, H influenzae, K pneumoniae, M catarrhalis) usually occur in persons with underlying pulmonary or other disease or in elderly
—Bird exposure with psittacosis
—Gram stain of sputum may be useful
—Community outbreaks caused by other etiologic agents not likely to be as explosive as pneumonic plague outbreak
—Outbreaks of S pneumoniae usually institutional
—Community outbreaks of Legionnaires' disease often involve exposure to cooling towers

Viral pneumonia
—Influenza
—Hantavirus
—RSV
—CMV

—Influenza generally seasonal (October-March in United States) or involves history of recent cruise ship travel or travel to tropics
—Exposure to mice infected with hantavirus or their urine or feces
—RSV usually occurs in children (although may be cause of pneumonia in elderly); tends to be seasonal (winter/spring)
—CMV usually occurs in immunocompromised patients

—Q fever (Coxiella burnetii)

—Exposure to infected parturient cats, cattle, sheep, goats
—Severe pneumonia not prominent feature

Abbreviations: CMV, cytomegalovirus; CT, computed tomography; RSV, respiratory syncytial virus.

aSee References: Dixon 1999.
bSee References: Bell 2002.


Differential Diagnosis for Gastrointestinal Anthrax

Diagnosis

Distinguishing Features

Differential Diagnosis for Gastrointestinal Anthrax

Typhoid fever (Salmonella typhi)

—Ascites usually not present
—Other clinical features may be similar

Intestinal tularemia (Francisella tularensis)

—Illness often less severe than that seen with gastrointestinal anthrax
—Ascites not present
—Less likely to resemble acute abdomen
—Fever may be less prominent

Bacillary dysentery (Shigella dysenteriae)

—Ascites usually not present
—Other clinical features may be similar

Acute bacterial gastroenteritis caused by other agents (eg, Campylobacter jejuni, Shiga toxin–producing Escherichia coli, Yersinia enterocolitica)

—Illness often less severe than that seen with gastrointestinal anthrax
—Ascites not present
—Less likely to resemble acute abdomen
—Fever may be less prominent
—Hemolytic uremic syndrome may occur with infection caused by Shiga toxin–producing E coli

Bacterial peritonitis

—Gastrointestinal symptoms (nausea, vomiting, gastrointestinal bleeding, diarrhea) not prominent features
—Tends to occur in persons with underlying medical conditions (eg, alcoholism, other liver disease)

Acute abdomen (eg, appendicitis)b

—Anthrax generally begins with vague systemic symptoms rather than abdominal pain
—Ascites is relatively common with gastrointestinal anthrax and less common with appendicitis and similar conditions

Oropharyngeal Subtype

Diphtheria (Corynebacterium diphtheriae)

—Primarily occurs in nonimmune children under 15 yr of age
—Pharyngeal membrane is prominent feature; ulcerative or necrotic lesions generally not present
—Removal of pharyngeal membrane often causes bleeding of submucosa

Pharyngeal tularemia (Francisella tularensis)

—Neck swelling usually absent
—Exudative pharyngitis common; ulcerative lesions may occur

Streptococcal pharyngitis (Streptococcus pyogenes)

—Exudative pharyngitis most prominent feature; necrotic ulcers generally absent
—Neck edema usually absent, although cervical lymphadenopathy may be prominent

Infectious mononucleosis

—Most common in young adults
—Splenomegaly commonly occurs
—Neck edema usually absent, although cervical lymphadenopathy may be prominent

Enteroviral vesicular pharyngitis (coxsackievirus)

—Small vesicles noted on soft palate, uvula, or anterior tonsillar pillars
—Generally occurs in children
—Neck edema usually absent

Acute herpetic pharyngitis (herpes simplex virus)

—Vesicles, shallow ulcers may be noted, but lesions usually not necrotic
—Neck edema usually absent, although cervical lymphadenopathy may be prominent

Anaerobic pharyngitis (Vincent's angina)

—Purulent exudate covers posterior pharynx
—Tonsillar abscesses may occur
—Neck edema usually absent

Yersinia enterocolitica pharyngitis

—Exudative pharyngitis most prominent feature
—Neck edema usually absent
—Cervical adenopathy, abdominal pain may occur

aSee References: Dixon 1999.
bSee References: Kanafani 2003.


Differential Diagnosis for Anthrax Meningitis

Diagnosis

Distinguishing Features

Subarachnoid hemorrhage

—Fever not usually prominent feature
—Can be distinguished by CT without contrasta

Bacterial meningitis from other causes

—Meningitis not usually hemorrhagic as seen with anthrax meningitis
—CSF Gram stain may be useful in diagnosis

Aseptic meningitis

—Meningitis not hemorrhagic
—CSF does not show characteristic gram-positive bacilli
—CSF usually demonstrates lymphocytosis

Encephalitis

—CSF findings may be variable, depending on etiology
—CSF Gram stain may be useful in diagnosis

Abbreviations: CSF, cerebrospinal fluid; CT, computed tomography.

aSee References: Dixon 1999.

Staging of Inhalational Anthrax

Historically, inhalational anthrax has been divided into a prodromal phase and a fulminant phase. The table below outlines a proposed staging scheme (see References: Lucey 2005) that adds an intermediate stage in which symptoms are clearly worsening but the illness may still be treated successfully.

Proposed Staging of Inhalational Anthrax

Stage

Comments

1: Asymptomatic

—Usually <1 wk after exposure and rarely >1 mo

2: Early—Prodromal

—Nonspecific malaise, myalgias, low-grade fever, mild headache, nausea, general "flu-like" prodromal illness

3: Intermediate—Progressive

—Blood cultures positive in <24 hr
—Mediastinal lymphadenopathy
—Pleural effusions that are often hemorrhagic and large and require repeated drainage
—Findings may include: high fever, dyspnea, confusion or syncope, increasing nausea/vomiting
—Patients at this stage can still be cured with antibiotics and intensive support

4: Late—Fulminant

—Respiratory failure requiring intubation, sepsis, meningitis, end-organ hypoperfusion (ie, "shock")
—Cure less likely at this stage
—Future therapies for this stage may require inhibitors of both anthrax toxin and systemic inflammatory response, in addition to antibiotics and intensive care

Adapted from Lucey 2005 (see References).

Distinguishing Inhalational Anthrax from Influenza-Like Illness (ILI) and Community-Acquired Pneumonia (CAP)

Early symptoms of inhalational anthrax, ILI, and CAP are similar and include fever, chills, myalgias, fatigue, malaise, and cough. However, several features can be used to distinguish these illnesses. One study of symptomatic patients with possible exposure to anthrax found that the presence of nonheadache neurologic symptoms (eg, dizziness, confusion), dyspnea, and upper gastrointestinal tract symptoms (eg, nausea, vomiting) were more suggestive of anthrax, whereas rhinorrhea and sore throat were far more common in patients with viral illnesses (see References: Hupert 2003).

Another study reviewed the CDC guidelines for inhalational anthrax during the 2001 outbreak and found that the guidelines would have missed 10 of the 11 cases (see References: Mayer 2003). The authors found that the modifications to the CDC guidelines shown below in italics would have led to recognition of 8 of the 11 cases.

  • Fever
  • Sweats
  • Fatigue
  • Cough
  • Chest discomfort, pleuritic pain
  • Nausea, vomiting
  • Headache
  • Dyspnea
  • Myalgias
  • Abdominal pain
  • Confusion
  • Fever (low grade: mean temperature, 38°C)
  • Tachycardia (mean heart rate, 121 beats per minute)
  • Clinical presentation consistent with inhalational anthrax when five or more of the above symptoms are present, in addition to tachycardia and fever

Howell and colleagues have suggested that use of this revised screening protocol may incur lower medical costs than the screening protocol proposed by Hupert and coworkers (outlined in the first paragragh of this section) and may be similar in its sensitivity to detect anthrax cases (although the numbers of anthrax cases in the comparison study were small) (see References: Howell 2004, Hupert 2003, Mayer 2003).

Another study examined the clinical features of the 2001 inhalational anthrax cases and compared them with those of ILI cases seen in an ambulatory clinic and of hospitalized patients with CAP. On the basis of these comparisons, the authors developed scoring systems for distinguishing ILI and CAP from inhalational anthrax (see References: Kuehnert 2003).

  • The scoring system for comparing inhalational anthrax with ILI included the following features. Patients with a score of 4 or more were more likely to have inhalational anthrax (sensitivity, 100%; specificity, 96.1%) than those with lower scores.
    • Low serum albumin (2 points)
    • Tachycardia (2 points)
    • No nasal symptoms (2 points)
    • No myalgias or arthralgias (1 point)
    • Low serum sodium level (1 point)
    • No headache (1 point)
    • High hematocrit or hemoglobin level (1 point)
  • The scoring system for comparing inhalational anthrax with CAP included the following features. Patients with a score of 2 or more were more likely to have inhalational anthrax (sensitivity, 100%; specificity, 48%) than those with lower scores. When the score was increased to 3 or more, the sensitivity dropped to 82% and the specificity increased to 81%.
    • Elevated serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels (1 point)
    • Low serum sodium level (1 point)
    • Normal white blood cell count (1 point)
    • Nausea and vomiting (1 point)
    • Tachycardia (1 point)

A third study, which compared 47 historical anthrax cases (including 11 with bioterrorism-related anthrax) with 376 controls with CAP or ILI, found that the most accurate predictor of anthrax was mediastinal widening or pleural effusion on chest radiograph (see References: Kyriacou 2004).

A report from the CDC included the following table, which compared the clinical features of 10 patients with inhalational anthrax to patients with laboratory-confirmed influenza.

Symptoms and Signs of Inhalational Anthrax, Laboratory-Confirmed Influenza, and Influenza-Like Illness (ILI) from Other Causes

Sign/Symptom

Inhalational Anthraxa (%)

Laboratory-Confirmed Influenza (%)

ILI from Other Causes (%)

Elevated temperature

70

68-77

40-73

Fever or chills

100

83-90

75-89

Fatigue/malaise

100

75-94

62-94

Cough

90

84-93

72-80

Shortness of breath

80

6

6

Chest discomfort/pain

60

35

23

Headache

50

84-91

74-89

Myalgias

50

67-94

73-94

Sore throat

20

64-84

64-84

Rhinorrhea

10

79

68

Nausea or vomiting

80

12

12

Abdominal pain

30

22

22

aN=10.

Adapted from CDC 2001. Considerations for distinguishing influenza-like illness from inhalational anthrax (see References).

A literature review of 42 patients who had atypical anthrax presentations (ie, patients with confirmed anthrax infection who did not have known cutaneous, gastrointestinal, or inhalational ports of entry) revealed that these patients were significantly less likely to have cough, chest pain, or abnormal lung findings, even though they most likely had inhalational anthrax (see References: Holty 2006: Anthrax: a systematic review of atypical presentations).

A 2004 study used a decision-analytic model to assess the best treatment strategy for patients presenting with ILI in settings with varying probabilities for inhalational anthrax (see References: Fine 2004). The authors concluded that, for inhalational anthrax probabilities between 0.1% and 2%, when the sensitivity of blood culture exceeds 95%, the best strategy is to treat with a short course of empiric ciprofloxacin until blood culture results are available. During influenza season, the best strategy involves rapid testing for influenza followed by empiric treatment for anthrax pending blood culture results for those who test negative for influenza.

Pediatric Considerations

Reports in the literature support the following observations about anthrax in children.

  • Inhalational anthrax is uncommon in children. For example, none of the cases in the Sverdlovsk inhalational anthrax outbreak occurred in children (see References: Meselson 1994), and reports of inhalational disease among children are rare.
  • Naturally occurring cutaneous anthrax also is uncommon in children, probably because children have less opportunity for exposure to infected animals.
  • Other modes of transmission (such as person-to-person through skin-to-skin contact or transmission via fomites) may be more common for young children who acquire cutaneous anthrax (see References: Freedman 2002).
  • The skin lesions described for children who have cutaneous anthrax are usually similar to those seen in adults. Progression to severe systemic disease can occur (see References: Freedman 2002).
  • Anthrax meningitis has been reported in children and may be the presenting feature (see References: Rangel 1975, Tabatabaie 1993).
  • A review of 73 cases (5 inhalational, 22 gastrointestinal, 37 cutaneous, 6 primary meningoencephalitis, and 3 atypical) in children from 1900 to 2005 noted that children with inhalational anthrax lacked nonheadache neurologic symptoms, a key distinguishing finding (see References: Bravata 2007).
  • Another review of 62 pediatric cases of anthrax (2 inhalational, 20 gastrointestinal, 37 cutaneous, and 3 atypical) between 1966 and 2005 suggests that infected children may manifest different symptoms than do infected adults and that difficulties in diagnosing the disease in children may lead to delays in care (see References: AHRQ 2006). Children with gastrointestinal anthrax have two distinct clinical presentations, similar to adults; however, children with inhalational anthrax may have atypical presentations, including meningoencephalitis. Clinicians and public health officials must recognize the broad spectrum of potential presentations for timely diagnosis and detection.

Anthrax During Pregnancy

A report summarized two cases of anthrax in pregnant women; the features of these cases are outlined in the table below (see References: Kadanali 2003).

Summary of Clinical Features for Two Pregnant Women with Anthrax

Patient Age

Weeks of Gestation at Illness Onset

Clinical Presentation of Anthrax

Outcome of Pregnancy

33

32

Cutaneous anthrax (treated with penicillin G and prednisone)

—Infant delivered preterm at 35 wk
—No evidence of congenital infection

29

33

Cutaneous anthrax (treated with procaine penicillin)

—Infant delivered preterm at 34 wk
—No evidence of congenital infection

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