AJR 2003; 181:1071-1078
© American Roentgen Ray Society
Inhalational Anthrax: Radiologic and Pathologic Findings in Two Cases
Bradford J. Wood1,
Bryan DeFranco2,
Mary Ripple3,
Martin Topiel4,
Carlos Chiriboga5,
Venkat Mani6,
Kevin Barry7,
Dave Fowler3,
Henry Masur8 and
Luciana Borio9
1 Diagnostic Radiology Department, National Institutes of Health, Rm. 1C 660,
Bldg. 10, 10 Center Dr., Bethesda, MD 20892.
2 Department of Radiology, Southern Maryland Hospital Center, 7503 Surratts Rd.,
Clinton, MD 20735.
3 Office of the Chief Medical Examiner, State of Maryland, 111 Penn St.,
Baltimore, MD 21201.
4 Infectious Disease Physicians, PA, Ste. 250, 1001 Briggs Rd., Mt. Laurel, NJ
08054.
5 Intensive Care Unit, Southern Maryland Hospital Center, 7503 Surratts Rd.,
Clinton, MD 20753.
6 Infectious Disease Associates of Southern Maryland, Heritage Medical Park,
Ste. 503, 8926 Woodyard Rd., Clinton, MD 20735.
7 Radiology Associates Burlington County, 1295 Rte. 38 West, P.O. Box 479,
Hainesport, NJ 08036-0479.
8 Critical Care Medicine Department, Warren G. Magnuson Clinical Center,
National Institutes of Health, Rm. 7D 43, Bldg. 10, Bethesda, MD 20892.
9 Johns Hopkins Center for Civilian Biodefense, Critical Care Medicine
Department, NIH, Ste. 830, 111 Market Pl., Baltimore, MD 21202.
Received December 11, 2002;
accepted after revision March 3, 2003.
Address correspondence to B. J. Wood
(bwood{at}nih.gov).
Introduction
The occurrence of 11 cases of inhalational anthrax associated with letters
containing Bacillus anthracis powder sent through the United States
Postal Service in Florida, New York, New Jersey, and in Washington, DC, in
September and October 2001 has emphasized the necessity for health care
practitioners to be familiar with the manifestations of inhalational anthrax.
A wide variety of health care practitioners, including radiologists and
pathologists, have the potential to alert other physicians to the possibility
of inhalational anthrax because the clinical manifestations of early disease
are nonspecific, consisting of flulike symptoms, fever, sweats, malaise, and
myalgias. In the absence of known exposure to B. anthracis, the
appropriate cultures may not be obtained, and potentially life-saving therapy
may not be instituted in a timely manner. The predicted case fatality of
inhalational anthrax from historical data was approximately 90%
[1]. The United States outbreak
showed that with early diagnosis and institution of antimicrobial therapy,
mortality can be substantially reduced
[2]. In addition, timely
identification of inhalational anthrax cases is important so that appropriate
public health and law enforcement officials can be notified and can take
necessary measures to limit morbidity and mortality. Such notification allows
other patients and clinicians to be alerted about the potential for new
exposure and allows evidence about the perpetrator to be collected
expeditiously.
The clinical histories of the 11 cases of bioterrorism-related inhalational
anthrax in the United States have been described in detail in several recent
publications
[27].
Here we describe the clinical course of two of the affected patients, with
emphasis on imaging findings, in an effort to increase clinician awareness
about this disease. We also provide correlation with the postmortem
examination of the fatal case.
Case Report 1
On October 16, 2001, a 47-year-old male postal worker developed progressive
nausea, abdominal pain, and flulike symptoms that prompted him to seek
emergency medical care 5 days later (October 21). Chest radiographs obtained
on his presentation to the emergency department revealed a subtle parenchymal
lung infiltrate limited to the right suprahilar region
[5]
(Fig. 1A). The patient was sent
home with a presumptive diagnosis of gastroenteritis. He continued to
deteriorate and on the following day was taken to the hospital by ambulance.
When he arrived, signs of shock were already present. Sequential chest
radiographs at 26, 30, and 32 hr after the initial chest radiograph showed
rapid progression of air-space disease, perihilar infiltrates, pleural
effusions, and mediastinal widening (Figs.
1B,
1C,
1D)
[5]. He was pronounced dead a
few hours later, on October 22, despite aggressive medical therapy. Blood
cultures grew B. anthracis within 6 hr of incubation.

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Fig. 1A. 47-year-old man with inhalational anthrax and
gastrointestinal anthrax. Chest radiograph on presentation shows subtle right
suprahilar infiltrate (arrow). (Reprinted with permission from
[5])
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Fig. 1B. 47-year-old man with inhalational anthrax and
gastrointestinal anthrax. Sequential chest radiographs between 26 and 32 hr
later show rapid progression of patchy hilar and peribronchial infiltrates
(arrow, C), blurring of mediastinal borders, and eventual
opacification of right hemithorax (D). (Reprinted with permission from
[5])
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Fig. 1C. 47-year-old man with inhalational anthrax and
gastrointestinal anthrax. Sequential chest radiographs between 26 and 32 hr
later show rapid progression of patchy hilar and peribronchial infiltrates
(arrow, C), blurring of mediastinal borders, and eventual
opacification of right hemithorax (D). (Reprinted with permission from
[5])
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Fig. 1D. 47-year-old man with inhalational anthrax and
gastrointestinal anthrax. Sequential chest radiographs between 26 and 32 hr
later show rapid progression of patchy hilar and peribronchial infiltrates
(arrow, C), blurring of mediastinal borders, and eventual
opacification of right hemithorax (D). (Reprinted with permission from
[5])
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Contrast-enhanced CT scans of the chest (obtained on day 7 of illness,
shortly before death) revealed perihilar parenchymal infiltrates that cause
widening of the central silhouette (Fig.
1E). This may be a CT correlate of the traditional
preCT-era description of inhalational anthrax as wide mediastinum on
radiography. Compared with radiography, CT better defines the mediastinal
borders (Fig. 1F); hilar
adenopathy; pleural effusions, peribronchial thickening and encasement;
interstitial infiltrates; and patchy air-space disease, most prominent on the
right (Fig. 1F). Postmortem
examination showed hilar soft-tissue perivascular and peribronchial hemorrhage
(Fig. 1G) and necrosis
(Fig. 1H). Special stains
confirmed the presence of abundant gram-positive bacilli
(Fig. 1I) consistent with
B. anthracis.

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Fig. 1E. 47-year-old man with inhalational anthrax and
gastrointestinal anthrax. Contrast-enhanced chest CT scans reveal perihilar
parenchymal lung disease (arrow, E) widening central
silhouette, hilar adenopathy, pleural effusions, and peribronchial infiltrates
as well as patchy peribronchial air-space disease, especially on right
(arrow, F).
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Fig. 1F. 47-year-old man with inhalational anthrax and
gastrointestinal anthrax. Contrast-enhanced chest CT scans reveal perihilar
parenchymal lung disease (arrow, E) widening central
silhouette, hilar adenopathy, pleural effusions, and peribronchial infiltrates
as well as patchy peribronchial air-space disease, especially on right
(arrow, F).
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Fig. 1G. 47-year-old man with inhalational anthrax and
gastrointestinal anthrax. Photomicrograph of histopathologic specimen shows
hilar soft tissue with perivascular and peribronchial hemorrhage
(arrow). (H and E, x10)
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Fig. 1H. 47-year-old man with inhalational anthrax and
gastrointestinal anthrax. Photomicrograph of histopathologic specimen of hilar
soft tissue shows hemorrhage and necrosis (arrow). (H and E,
x20)
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Fig. 1I. 47-year-old man with inhalational anthrax and
gastrointestinal anthrax. Photomicrograph of histopathologic specimen of hilar
soft tissue shows abundant gram-positive bacilli (arrow).
(BrownBrenn, x100)
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CT scans obtained with mediastinal window settings showed high-attenuation
subcarinal lymph nodes (Fig.
1J), consistent with hemorrhagic lymphadenitis, and mediastinal
blood (Fig. 1K), consistent
with hemorrhagic mediastinitis. Postmortem examination confirmed mediastinal
soft-tissue hemorrhage (Fig.
1L) and hilar hemorrhagic necrotizing lymphadenitis
(Fig. 1M). Special stains
revealed abundant gram-positive bacilli in the hilar lymph nodes
(Fig. 1N).

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Fig. 1J. 47-year-old man with inhalational anthrax and
gastrointestinal anthrax. Contrast-enhanced CT scans with mediastinal window
settings show high-attenuation subcarinal lymph node (arrow,
J), signifying hemorrhagic lymphadenitis, and mediastinal blood
(arrow, K), signifying hemorrhagic mediastinitis. Well-defined
high attenuation in node differentiates this from free blood in mediastinum,
seen as thin wisps of high attenuation with ill-defined borders. (K
reprinted with permission from
[5])
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Fig. 1K. 47-year-old man with inhalational anthrax and
gastrointestinal anthrax. Contrast-enhanced CT scans with mediastinal window
settings show high-attenuation subcarinal lymph node (arrow,
J), signifying hemorrhagic lymphadenitis, and mediastinal blood
(arrow, K), signifying hemorrhagic mediastinitis. Well-defined
high attenuation in node differentiates this from free blood in mediastinum,
seen as thin wisps of high attenuation with ill-defined borders. (K
reprinted with permission from
[5])
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Fig. 1L. 47-year-old man with inhalational anthrax and
gastrointestinal anthrax. Photomicrograph of histopathologic specimen of
mediastinal soft tissue shows hemorrhage (arrow). (H and E,
x20)
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Fig. 1M. 47-year-old man with inhalational anthrax and
gastrointestinal anthrax. Photomicrograph of histopathologic specimen of hilar
lymph node shows hemorrhagic necrotizing lymphadenitis (arrow). (H
and E, x20)
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Fig. 1N. 47-year-old man with inhalational anthrax and
gastrointestinal anthrax. Photomicrograph of histopathologic specimen of hilar
lymph node shows abundant gram-positive bacilli (arrow).
(BrownBrenn, x64)
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Abdominal CT scan (obtained concomitantly with the chest CT scan on day 7
of illness) showed ascites, mesenteric inflammation and edema, bowel wall
edema, small-bowel distention with pneumatosis
(Fig. 1O), and portal venous
gas (Fig. 1P). On postmortem
examination, an area of affected small bowel confirmed the presence of
necrotizing infection with abundant neutrophils
(Fig. 1Q) and gram-positive
bacilli (Fig. 1R) extending to
the lamina propria.

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Fig. 1O. 47-year-old man with inhalational anthrax and
gastrointestinal anthrax. Abdominal CT scans show ascites (black
arrow, O), mesenteric inflammation and edema (arrowhead,
O), small-bowel distention and wall thickening with pneumatosis
(white arrows, O), and portal venous gas (arrow,
P). (O reprinted with permission from
[5])
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Fig. 1P. 47-year-old man with inhalational anthrax and
gastrointestinal anthrax. Abdominal CT scans show ascites (black
arrow, O), mesenteric inflammation and edema (arrowhead,
O), small-bowel distention and wall thickening with pneumatosis
(white arrows, O), and portal venous gas (arrow,
P). (O reprinted with permission from
[5])
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Fig. 1Q. 47-year-old man with inhalational anthrax and
gastrointestinal anthrax. Photomicrograph of histopathologic specimen of
segment of affected small bowel shows necrotizing infection with abundant
neutrophils (arrow) extending to lamina propria. (H and E,
x64)
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Fig. 1R. 47-year-old man with inhalational anthrax and
gastrointestinal anthrax. Photomicrograph of histopathologic specimen of
segment of affected small bowel shows abundant gram-positive bacilli
(arrow) extending to lamina propria. (BrownBrenn,
x64)
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Case Report 2
A 56-year-old woman, who worked at a mail sorting facility, developed
vomiting and diarrhea on October 14, 2001. As her symptoms progressed, she
developed headaches, fever, chills, mild dyspnea, and pleuritic substernal
chest pain. She sought medical care 5 days later (October 19) and on arrival
was in respiratory distress. A working diagnosis of inhalational anthrax was
established, and she was treated with combination antimicrobial therapy. She
developed large bilateral pleural effusions, which were noted to be
hemorrhagic when drained. The pleural fluid was tested by the Centers for
Disease Control and Prevention (CDC) and was positive for B.
anthracis capsule and cell wall antigens.
A chest CT scan obtained on day 8 (October 22) of illness showed
mediastinal and cervical lymphadenopathy
(Fig. 2A), bibasilar
infiltrates, and large pleural effusions. CT performed on day 13 (October 27)
showed interval development of bibasilar parenchymal lung infiltrates
(Fig. 2B) and continued
pleural effusions (Fig. 2C). The imaging decompensation coincided with clinical improvement. This could be
explained by a delay in the imaging evolution of findings or a second process
that occurred simultaneously to resolving inhalational anthrax. Comparison of
contrast-enhanced CT scans obtained on days 8 and 13 shows interval loss of
enhancement within subcarinal lymph node (Figs.
2D and
2E); however, the contrast
bolus timing differed between studies. Slight shrinkage with possible loss of
enhancement was noted in an axillary node (Figs.
2F and
2G) after 5 days of supportive
and antimicrobial therapy; however, the change could simply represent
differences in contrast bolus pharmacokinetics. An enhancing adjacent axillary
node apparently disappeared by day 13 (Figs.
2H and
2I); however, differing arm
positions could have accounted for this change.

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Fig. 2B. 56-year-old woman with inhalational anthrax.
Contrast-enhanced CT scans show bibasilar parenchymal lung infiltrates with
air bronchograms (arrow, B) and pleural effusions, developing
between day 8 and day 13.
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Fig. 2C. 56-year-old woman with inhalational anthrax.
Contrast-enhanced CT scans show bibasilar parenchymal lung infiltrates with
air bronchograms (arrow, B) and pleural effusions, developing
between day 8 and day 13.
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Fig. 2D. 56-year-old woman with inhalational anthrax.
Contrast-enhanced CT scans show interval loss of enhancement within subcarinal
lymph node (arrows), measuring 116 H on day 8 and 46 H on day 13,
after 5 days of antimicrobial and supportive therapy.
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Fig. 2E. 56-year-old woman with inhalational anthrax.
Contrast-enhanced CT scans show interval loss of enhancement within subcarinal
lymph node (arrows), measuring 116 H on day 8 and 46 H on day 13,
after 5 days of antimicrobial and supportive therapy.
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Fig. 2F. 56-year-old woman with inhalational anthrax.
Contrast-enhanced CT scans show interval shrinkage and possible loss of
enhancement within axillary lymph node (arrows), after 5 days of
antimicrobial and supportive therapy. Pleural effusions have resolved after
placement of chest tubes.
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Fig. 2G. 56-year-old woman with inhalational anthrax.
Contrast-enhanced CT scans show interval shrinkage and possible loss of
enhancement within axillary lymph node (arrows), after 5 days of
antimicrobial and supportive therapy. Pleural effusions have resolved after
placement of chest tubes.
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Fig. 2H. 56-year-old woman with inhalational anthrax.
Contrast-enhanced CT scans of chest show interval apparent disappearance of
enhancing adjacent node (arrow, H) after 5 days of
antimicrobial and supportive therapy.
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Fig. 2I. 56-year-old woman with inhalational anthrax.
Contrast-enhanced CT scans of chest show interval apparent disappearance of
enhancing adjacent node (arrow, H) after 5 days of
antimicrobial and supportive therapy.
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Discussion
Typically, the initial presentation of inhalational anthrax is nonspecific;
lasts several days; and includes symptoms of fever, myalgias, and malaise.
Often, unless there is a known exposure to anthrax spores, patients may not
seek medical attention at this stage. If they do seek medical care, the
diagnosis would not usually be entertained in the absence of known exposure
because of the lack of distinguishing clinical signs and symptoms. As the
disease gradually progresses into a second stage, more ominous findings of
dyspnea, respiratory distress, high fever, shaking chills, and hypotension may
ensue. If patients are not treated appropriately at this stage, death occurs
2472 hr after presentation.
The limited number of reports on inhalational anthrax in the medical
literature describe disease manifestations as pleural effusions, mediastinal
widening, and rarely pneumonia
[8-11].
Mediastinal widening has been reported to be the earliest radiographic sign
[9]. In the second patient,
enhancing nodes occurred in the absence of mediastinal widening or hemorrhagic
mediastinitis. Nodal enhancement may be an early sign of infection, occurring
even before mediastinal widening. Radiographic appearance of consolidation and
air-space disease were also presenting features of inhalational anthrax in
these cases. However, infectious pneumonia is found only rarely in postmortem
tissue examinations. In our first patient, the infiltrates were identified as
peribronchial hemorrhage because the postmortem examination did not show any
evidence of infectious pneumonia. In a series of 42 autopsies from the
Sverdlovsk experience in 1979, 11 cases had focal, hemorrhagic, necrotizing
pneumonic lesions without a bronchoalveolar pneumonic process
[1,
10,
11].
The first 10 patients from this recent bioterrorism-related outbreak had
abnormal findings on chest radiographs at presentation. Eight had pleural
effusions, seven had a wide mediastinum, and seven had lung infiltrates
[12]. Thus, in the correct
epidemiologic setting, radiologists and clinicians need to consider
inhalational anthrax in the differential diagnosis of patchy air-space disease
as well as widened mediastinum or bloody pleural effusions. Imaging methods,
of course, may not differentiate pneumonia from hemorrhage.
Most published experience with inhalational anthrax occurred before
widespread availability of CT. Mediastinal widening with high-attenuation
mediastinal and hilar lymph nodes on CT in the absence of trauma, dissection,
or bleeding diathesis is suspicious. In fact, this constellation of imaging
features in a patient with possible exposure is almost pathognomonic for
inhalational anthrax.
The loss of nodal enhancement or the disappearance of adenopathy on CT may
be surrogate markers for clinical improvement. Nodal permeability may be the
underlying cellular process altered by acute inhalational anthrax. The
temporalspatial factors that may influence nodal enhancement are not
well understood; however, they may be related to timing of the imaging,
severity of disease, and contrast pharmacokinetics (injection rate, hydration
status, hemodynamics, washout into extracellular space). Nodal enhancement in
our second patient was seen on day 8. Nodal enhancement without internal
necrosis or hemorrhage could potentially represent improving or less severe
infection. Decreased nodal enhancement has been previously reported during
treatment for inhalation anthrax
[13]. However, adenopathy did
not resolve in days, as it may have in one node presented here. CT of
enhancing nodes associated with inhalational anthrax may show differing
degrees of edema and enhancement
[13,
14]. Ill-defined ringlike
nodal enhancement has been described on 20-min delayed CT
[14]. This has been postulated
to be the result of nodal hemodynamics, with rapid nodal enlargement and
vascular compromise.
Pneumatosis and portal venous gas have not been previously reported in
association with inhalational anthrax. Bowel wall pneumatosis with portal
venous gas can signify bowel ischemia or infarction and may constitute a
surgical emergency in certain clinical settings
[15,
16]. The abdominal features of
pneumatosis, portal venous gas, ascites, and bowel wall thickening in patients
with possible exposure should also alert clinicians to the possibility of
inhalational anthrax. Both of these patients initially presented with
gastrointestinal symptoms, and gram-positive bacilli were found in the small
bowel on postmortem examination of our first patient. Abdominal CT scan may be
helpful in the evaluation of this unusual presentation, but clinicians should
think of ischemia before inhalational anthrax as a cause of portal venous gas,
bowel wall thickening, and pneumatosis.
Gastrointestinal anthrax is considered a rare disease. It may present with
nausea, vomiting, malaise, bloody diarrhea, and it may progress to acute
abdominal sepsis and shock. It predominantly affects the terminal ileum or
cecum [1,
11]. Both of our patients
presented with gastrointestinal symptoms. However, postmortem examination
(available for our first patient) did not reveal primary gastrointestinal
anthrax, because no mucosal lesions or regional lymphadenitis was found. This
patient's gastrointestinal disease was most likely related to direct infection
after hematogenous spread; however, bowel ischemia from sepsis, hypovolemia,
or distention itself may have also been a contributing factor.
Although chest radiography may be the most cost-effective screening tool,
chest CT is surely the most sensitive and specific imaging test capable of
depicting the abnormal thoracic and abdominal findings of inhalational
anthrax. In addition, CT may play a yet-unidentified role in the follow-up of
clinical response or in the detection of gastrointestinal manifestations of
inhalational anthrax. The sequence and natural history of clinical and imaging
findings of inhalational anthrax have not yet been well defined. However, the
CDC recommends that chest CT should be considered if findings on chest
radiography are normal or uncertain and there is high clinical suspicion
[1719].
The unfortunate opportunity to document the diverse radiologic and
pathologic features of inhalational anthrax has revealed a wide variety of
manifestations [20]. Patient
survival and outbreak control may depend on an informed and suspicious health
care team, so the appropriate diagnostic tests and treatment are begun quickly
and relevant public health and legal authorities can be notified.
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[Abstract]
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A. M. Firoved, G. F. Miller, M. Moayeri, R. Kakkar, Y. Shen, J. F. Wiggins, E. M. McNally, W.-J. Tang, and S. H. Leppla
Bacillus anthracis Edema Toxin Causes Extensive Tissue Lesions and Rapid Lethality in Mice
Am. J. Pathol.,
November 1, 2005;
167(5):
1309 - 1320.
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