1 From the Departments of Radiology (J.P.E., D.C., E.B., B.U.) and Emergency Medicine (C.M., D.P., T.M.), INOVA Fairfax Hospital, Falls Church, Va; Fairfax Radiological Consultants, 2722 Merrilee Dr, Fairfax VA 22031 (J.P.E., D.C., E.B., B.U.); and Departments of Infectious Disease (J.R., N.F., S.B.M.) and Pulmonary Medicine (P.P.W., R.C.), Mid-Atlantic Permanente Medical Group, Kaiser Permanente, Fairfax, Va. Received November 16, 2001; revision requested November 19; revision received November 25; accepted November 27.
The radiographic and computed tomographic (CT) findings in two
patients with documented inhalational anthrax resulting from
bioterrorism exposure are presented. Chest radiographs demonstrated
mediastinal widening, adenopathy, pleural effusions, and air-space
disease. Chest CT images revealed enlarged hyperattenuating
mediastinal and hilar lymph nodes and edema of mediastinal fat.
Chest CT findings are helpful for making the initial diagnosis.
To the authors’ knowledge, the spectrum and follow-up
of CT findings have not been previously described.
Index terms: Anthrax • Lung, CT, 60.12111, 60.12112 • Lung, infection, 60.2019 • Special Reports
Editor’s Note: The two patients described in this article have been recently reported on in the Journal of the American
Medical Association
(JAMA 2001; 286:2549–2553). However, in view of the importance of this information to the imaging community, the more extensive emphasis on the spectrum and follow-up of imaging findings, and the potentially different readership of Radiology
and JAMA, we are publishing this report in Radiology.
—Anthony V. Proto, MD, Editor
Reports of the radiographic findings of inhalational anthrax are limited owing to the rarity of the disease (1–8). Prior to the recent terrorism-related cases, the last documented case of inhalational anthrax in the United States occurred in 1976 (9). Reports of additional cases, including the largest series that followed the unintentional anthrax exposure in Sverdlovsk, Russia, in 1979, gave only limited descriptions of the radiologic findings (2–8). The authors of these prior reports described chest radiographic findings of mediastinal widening, hilar adenopathy, pleural effusions, and peripheral air-space disease.
The cases of inhalation anthrax in this report have been traced to a letter opened by a staff member of U.S. Senator Tom Daschle on October 15, 2001 (10). Subsequent polymerase chain reaction analysis demonstrated that the letter contained spores of Bacillus anthracis. The patients, both postal workers, presented to the emergency department several days after the letter was opened, before postal employees were considered to be at risk for the disease. Clinical and epidemiologic details of these two cases have been previously reported (10,11). Both patients gave written informed consent, and our institutional review board approved publication of the data and images. This report focuses on the radiologic findings both at presentation and during subsequent hospitalizations. We will emphasize the critical role that diagnostic imaging plays in the evaluation and diagnosis of this disease.
Case 1On October 19, a 56-year-old male postal worker presented to
the emergency department complaining of 3 days of low-grade
fever, chills, cough, dyspnea during exertion, and generalized
malaise. On the night of admission, the patient’s cough
became blood tinged and he developed midsternal chest tightness.
Initial vital signs were temperature of 37.5°C, pulse of
110 beats per minute, respiration of 18 breaths per minute,
blood pressure of 157/75 mm Hg (systolic/diastolic), and oxygen
saturation of 98% on room air. Physical examination revealed
a decrease in breath sounds in the left lung base. The white
blood cell count was 7,500 cells per microliter (segmented neutrophils,
76; bands, eight; lymphocytes seven; monocytes, seven). Serum
chemistry results were normal with the exception of creatinine
kinase, which was 207 U/L. Arterial blood gas findings were
pH of 7.45, Pa
CO2 of 27 mm Hg, Pa
O2 of 80.3 mm Hg, and oxygen
saturation of 97% on room air.
Initial posteroanterior and lateral chest radiographs depicted a minimally widened mediastinum with right paratracheal fullness, bilateral hilar enlargement, small bilateral pleural effusions, and subtle left lower lobe air-space disease (Fig 1). On the basis of the patient’s clinical course and abnormal radiographic findings, a nonenhanced chest computed tomographic (CT) image was ordered by the emergency department physicians. This was performed with a multi–detector row helical CT scanner (Lightspeed QX/I; GE Medical Systems, Milwaukee Wis). The protocol used 7.0-mm collimation, 120 kV, 250 mA, and 0.8-second scanning time.
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Figure 1. Case 1. Initial posteroanterior (left) and lateral (right) chest radiographs depict a minimally widened mediastinum with right paratracheal fullness (arrow), bilateral hilar enlargement (arrowheads), small bilateral pleural effusions, and subtle left lower lobe air-space disease. (Reprinted, with permission, from reference 11.)
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CT demonstrated widespread hyperattenuating paratracheal, aorticopulmonary
window, subcarinal, hilar, and azygoesophageal recess adenopathy
(
Fig 2). The nodes had attenuation of 46–62 HU (mean ±
SD, 53 HU ± 8.1). The largest lymph node was in the subcarinal
region and measured 4.2 cm in maximal transverse diameter; hilar
nodes measured 2–3 cm in diameter. In addition, there
was evidence of edema of mediastinal fat. Bilateral moderate-sized
pleural effusions were noted that appeared somewhat larger than
on the chest radiograph. Bibasilar air-space disease and peribronchial
thickening were present. The interpreting radiologist made a
presumptive diagnosis of inhalational anthrax based on these
examination findings and the stated clinical history.
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Figure 2a. Case 1. Initial transverse CT images. (a) Widespread hyperattenuating adenopathy. The largest lymph node (arrow) is in the subcarinal region. (Reprinted, with permission, from reference 11.) (b) There is also edema of mediastinal fat (arrowheads), (c) bilateral moderate-sized pleural effusions, bibasilar air-space disease, and (d) peribronchial thickening (arrows).
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Figure 2b. Case 1. Initial transverse CT images. (a) Widespread hyperattenuating adenopathy. The largest lymph node (arrow) is in the subcarinal region. (Reprinted, with permission, from reference 11.) (b) There is also edema of mediastinal fat (arrowheads), (c) bilateral moderate-sized pleural effusions, bibasilar air-space disease, and (d) peribronchial thickening (arrows).
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Figure 2c. Case 1. Initial transverse CT images. (a) Widespread hyperattenuating adenopathy. The largest lymph node (arrow) is in the subcarinal region. (Reprinted, with permission, from reference 11.) (b) There is also edema of mediastinal fat (arrowheads), (c) bilateral moderate-sized pleural effusions, bibasilar air-space disease, and (d) peribronchial thickening (arrows).
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Figure 2d. Case 1. Initial transverse CT images. (a) Widespread hyperattenuating adenopathy. The largest lymph node (arrow) is in the subcarinal region. (Reprinted, with permission, from reference 11.) (b) There is also edema of mediastinal fat (arrowheads), (c) bilateral moderate-sized pleural effusions, bibasilar air-space disease, and (d) peribronchial thickening (arrows).
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Blood cultures obtained at the time of admission showed prominent
gram-positive rods at 11 hours. Treatment was promptly started
with 400 mg of ciprofloxacin every 8 hours, 300 mg of rifampin
every 12 hours, and 900 mg of clindamycin every 8 hours. The
patient was admitted to the hospital for further therapy. On
October 21, 2001, polymerase chain reaction results from the
Virginia State Health Laboratory and the Centers for Disease
Control and Prevention (CDC) confirmed that
B anthracis was
the etiologic organism.
Serial radiographs were obtained daily and, at times, more frequently (Fig 3). These showed that the effusions and air-space disease increased dramatically over the initial several days. The effusions re-accumulated several times and necessitated repeated thoracentesis.
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Figure 3a. Case 1. Serial frontal radiographs. (a) Effusions and air-space disease increased dramatically over the initial several days. (b) Radiograph obtained on hospital day 19 appears near normal, with the exception of small bilateral effusions.
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Figure 3b. Case 1. Serial frontal radiographs. (a) Effusions and air-space disease increased dramatically over the initial several days. (b) Radiograph obtained on hospital day 19 appears near normal, with the exception of small bilateral effusions.
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Follow-up CT images included a contrast material–enhanced
(150 mL of ioversol, Optiray; Mallinckrodt, St Louis, Mo) study
on hospital day 5 that showed that the effusions were considerably
larger and filled more than 50% of each thoracic cavity (
Fig 4).
The mediastinal nodes increased in size, enlarging from
4.2 to 6.4 cm in the subcarinal region and from 2.6 to 3.5 cm
in the left hilum. This second CT examination was performed
with intravenous administration of contrast material, but the
attenuation of the nodes was lower (36–42 HU; mean ±
SD, 38 HU ± 9.6) in the center than that on the initial
study. Edema of mediastinal fat, air-space disease, and peribronchial
thickening became more severe on the follow-up study. CT images
depicted a hyperattenuating blood clot in the left pleural space
on hospital day 9. The lymph nodes remained enlarged on hospital
day 19 despite substantial clinical improvement.
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Figure 4a. Case 1. Follow-up transverse CT scans. (a) Effusions were considerably larger and filled more than 50% of each thoracic cavity on hospital day 4. (b) Mediastinal nodes also increased in size, and a hyperattenuating blood clot (arrow) in the left pleural space could be seen on hospital day 9. (c) Subcarinal and left hilar nodes remained enlarged on hospital day 19 despite substantial clinical improvement.
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Figure 4b. Case 1. Follow-up transverse CT scans. (a) Effusions were considerably larger and filled more than 50% of each thoracic cavity on hospital day 4. (b) Mediastinal nodes also increased in size, and a hyperattenuating blood clot (arrow) in the left pleural space could be seen on hospital day 9. (c) Subcarinal and left hilar nodes remained enlarged on hospital day 19 despite substantial clinical improvement.
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Figure 4c. Case 1. Follow-up transverse CT scans. (a) Effusions were considerably larger and filled more than 50% of each thoracic cavity on hospital day 4. (b) Mediastinal nodes also increased in size, and a hyperattenuating blood clot (arrow) in the left pleural space could be seen on hospital day 9. (c) Subcarinal and left hilar nodes remained enlarged on hospital day 19 despite substantial clinical improvement.
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The patient was discharged to home in good condition after a
24-day hospitalization.
Case 2
A 56-year-old male postal worker presented to the emergency department with progressively worsening headache of 3 days duration, nausea, chills, and night sweats. He had no respiratory complaints other than a mild sore throat. Initial vital signs were temperature of 37.6°C, pulse of 127 beats per minute, respiration of 20 breaths per minute, blood pressure of 133/87 mm Hg, and oxygen saturation of 94% on room air. Physical examination findings were notable only for diffuse rhonchi and decreased breath sounds in both lung bases. His white blood cell count was 9,700 cells per microliter with a normal differential, and the remainder of laboratory study results were normal. Nonenhanced head CT findings were normal. He underwent lumbar puncture, which showed 20 red blood cells per high-power field, four white blood cells per high-power field, glucose level of 92 mg/dL (5.1 mmol/L), and no organisms at Gram staining. Culture and Gram stain of the cerebrospinal fluid were negative.
A bedside anteroposterior chest radiograph showed a widened mediastinum and low lung volumes (Fig 5). In contradistinction to case 1, the mediastinum was clearly widened, measuring 10.4 cm on the radiograph. A right hilar mass was present, as were a right pleural effusion and right perihilar air-space disease. Initially, the widened mediastinum on the chest radiograph was misinterpreted as a tortuous aorta.
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Figure 5. Case 2. Initial portable anteroposterior chest radiograph shows widened mediastinum, right hilar mass (arrow), right pleural effusion, and right perihilar air-space disease. (Reprinted, with permission, from reference 11.)
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Nonenhanced chest CT was ordered because of the abnormal chest
radiograph and a history of working in the Brentwood Postal
Facility in Washington, DC, the site of presumed anthrax exposure
(
Fig 6). The protocol used was the same as in case 1. CT demonstrated
enlarged hyperattenuating right hilar and azygoesophageal recess
adenopathy. Lymph nodes were fewer in number and smaller than
those in case 1. The largest node measured 3.5 cm in maximal
transverse diameter and was located in the right hilum. Smaller
(0.5–1.5-cm) nodes were seen in the right paratracheal,
aorticopulmonary window, and left hilar regions. The nodes were
hyperattenuating, measuring 47–59 HU (mean ± SD,
55.2 HU ± 7.3). Diffuse edema of mediastinal fat and
bilateral pleural effusions were present. Peribronchial thickening
was more extensive than in case 1. The left lung and hilum appeared
relatively spared compared with the right lung, although a small
left pleural effusion was present. As in case 1, the extent
of involvement appeared much greater on CT images than on the
initial chest radiograph.
fig.ommitted
|
Figure 6a. Case 2. Initial nonenhanced transverse helical chest CT scans. (a) Enlarged hyperattenuating right hilar (lateral arrow) and azygoesophageal recess (medial arrow) adenopathy are shown. (b) Edema of mediastinal fat and bilateral pleural effusions are present. (c) Peribronchial thickening and air-space disease are more severe than in case 1.
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Figure 6b. Case 2. Initial nonenhanced transverse helical chest CT scans. (a) Enlarged hyperattenuating right hilar (lateral arrow) and azygoesophageal recess (medial arrow) adenopathy are shown. (b) Edema of mediastinal fat and bilateral pleural effusions are present. (c) Peribronchial thickening and air-space disease are more severe than in case 1.
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fig.ommitted |
Figure 6c. Case 2. Initial nonenhanced transverse helical chest CT scans. (a) Enlarged hyperattenuating right hilar (lateral arrow) and azygoesophageal recess (medial arrow) adenopathy are shown. (b) Edema of mediastinal fat and bilateral pleural effusions are present. (c) Peribronchial thickening and air-space disease are more severe than in case 1.
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A presumptive diagnosis of inhalational anthrax was rendered
by the interpreting radiologist on the basis of the abnormal
chest radiograph and the strong similarity of the CT study with
that in case 1. Treatment was promptly started with 400 mg of
ciprofloxacin every 8 hours, 300 mg of rifampin every 12 hours,
and 900 mg of clindamycin every 8 hours.
B anthracis was present
in blood cultures at 15 hours and was confirmed with polymerase
chain reaction by the Virginia Department of Health and the
CDC.
Daily serial chest radiographs were obtained during the admission (Fig 7). As in case 1, radiographs showed effusions and air-space disease that worsened dramatically over the initial several days. The pleural fluid re-accumulated several times, necessitating repeated thoracentesis. The mediastinum appeared near normal at chest radiography on hospital day 17.
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Figure 7a. Case 2. Follow-up frontal radiographs. (a) Pleural effusions and air-space disease increased dramatically by hospital day 4. (b) Right lower lobe air-space disease persisted on day 11. (c) The mediastinum appears near normal, but a right pleural effusion and air-space disease remained as of hospital day 17.
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Figure 7b. Case 2. Follow-up frontal radiographs. (a) Pleural effusions and air-space disease increased dramatically by hospital day 4. (b) Right lower lobe air-space disease persisted on day 11. (c) The mediastinum appears near normal, but a right pleural effusion and air-space disease remained as of hospital day 17.
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Figure 7c. Case 2. Follow-up frontal radiographs. (a) Pleural effusions and air-space disease increased dramatically by hospital day 4. (b) Right lower lobe air-space disease persisted on day 11. (c) The mediastinum appears near normal, but a right pleural effusion and air-space disease remained as of hospital day 17.
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Follow-up CT included contrast-enhanced chest CT on hospital
days 4 and 9 and nonenhanced CT on day 15 (
Fig 8). Mediastinal
lymph nodes were lower in attenuation (37–41 HU; mean
± SD, 39 HU ± 14.1) at contrast-enhanced CT performed
on day 4 than they were at admission. As in case 1, the mediastinal
nodes again enlarged on the initial follow-up studies but decreased
slightly in size by day 15. Right pleural hemorrhage was depicted
on day 15.
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Figure 8a. Case 2. Follow-up transverse CT scans. (a) A slightly larger but lower attenuation adenopathy (arrows) was seen by day 4. (b) Right pleural clot (arrow) was depicted on day 15.
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Figure 8b. Case 2. Follow-up transverse CT scans. (a) A slightly larger but lower attenuation adenopathy (arrows) was seen by day 4. (b) Right pleural clot (arrow) was depicted on day 15.
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The patient was discharged to home in good condition after a
20-day hospitalization.
Anthrax is an ancient disease that has unfortunately reemerged
in the 21st century as a biological weapon of terror. It is
described as one of the 10 plagues in ancient Egypt, and both
Homer and Virgil wrote about anthrax epidemics (
12). In 1876,
Robert Koch published a paper confirming the "germ theory" linking
B anthracis as the cause of anthrax (
12). In 1881, Louis Pasteur
successfully immunized sheep with a weakened form of the bacterium
(
12).
B anthracis is a gram-positive, rod-shaped, spore-forming bacterium that most commonly infects livestock. Human infection is normally due to exposure to infected animals or animal products and most commonly occurs in the setting of occupational exposure. Anthrax spores can remain dormant for decades and still retain substantial virulence, a fact that has led to their development as a biological weapon by a number of nations (12,13).
Infection of humans may cause pulmonary, cutaneous, or gastrointestinal disease. Inhalational anthrax is rare but its clinical course has been fairly well described (8,14–18). After deposition of a sufficient number of spores into the alveolar space, the spores are phagocytosed by alveolar macrophages and transported to the mediastinal lymph nodes. Here the spores germinate into B anthracis bacterium within 1 to 6 days, although this occasionally takes up to 60 days (2,18). The bacteria release a lethal exotoxin complex that causes hemorrhagic mediastinitis, edema, and hemorrhagic pleural effusions. Hematogenous spread of the toxin results in shock, severe respiratory distress, and death (8,16–18). Massive hemorrhagic mediastinitis is the most typical manifestation of the inhalational form of the disease (8,16–18).
Inhalational anthrax is characterized as having a two-stage clinical course. Initial symptoms are nonspecific and include fever, myalgia, malaise, and nonproductive cough. The nonspecific clinical course makes diagnosis of the disease difficult in its early stage unless there is a known exposure to anthrax. The first stage lasts for an average of 4 days and is rapidly followed by the second stage. The second (or septic) stage develops suddenly and includes dyspnea, profound respiratory distress, cyanosis, and shock. Up to 86%–97% of patients with inhalational anthrax die within 24 to 48 hours of onset of the second stage (8,16–18). Because of the high mortality and rapid progression of the second stage, antibiotic therapy must be initiated as soon as a presumptive diagnosis of inhalational anthrax is entertained. If treatment is withheld until blood or sputum cultures are positive, the patient is less likely to survive.
Chest radiographs play a critical role in the diagnosis of inhalational anthrax. The presence of a widened or abnormal mediastinum in a previously healthy patient with flulike symptoms is pathognomonic of inhalational anthrax if there is a history of exposure (1,14,16). Other radiographic findings include hilar adenopathy, pleural effusions, and peripheral air-space disease. Radiographs provide critical diagnostic information many hours or even days before blood and sputum cultures can be used to confirm the presence of anthrax. In prior cases, the presence of radiographic signs became apparent only during the second stage of the disease, when the diagnosis is associated with a very poor prognosis (14).
The initial chest radiographs presented here were abnormal. In neither case, however, did the radiographic findings lead to a presumptive diagnosis of inhalational anthrax. Radiographs in case 1 depicted right paratracheal adenopathy, subtle air-space disease, and small bilateral pleural effusions. At the time, however, postal workers were not considered to be at risk, and it was not until chest CT was performed that a diagnosis of anthrax was established. Radiographs in case 2 showed more substantial mediastinal widening, a larger pleural effusion, and peripheral air-space disease. These findings were initially misinterpreted, however, and a history of possible anthrax exposure was not obtained until several hours after admission. Only after CT was performed was a presumptive diagnosis of inhalational anthrax rendered.
Initial CT studies in both cases were markedly abnormal and had an unusual combination of findings that may prove to be useful for diagnosing inhalational anthrax. Findings include the presence of hyperattenuating enlarged mediastinal lymph nodes, diffuse edema of mediastinal fat, peribronchial thickening, and pleural effusions. To our knowledge, prior to the recent series (11), there have been no published reports of the spectrum and follow-up of CT findings of inhalational anthrax and no prior cases of inhalational anthrax with correlative CT imaging accessioned at the Armed Forces Institute of Pathology in Washington, DC (Galvin JR, written communication, October 2001). Although pathologic correlation of adenopathy was not obtained in these cases, on the basis of prior reports the hyperattenuation of the nodes is likely due to hemorrhage (19,20).
According to current recommendations by the CDC, both chest radiographs and CT studies play a key role in the diagnosis of inhalational anthrax (Fig 9) (10). In each of the cases presented here, chest abnormalities appeared more extensive on chest CT images than was suggested by the initial radiographs. Given the differences in the imaging studies, it is conceivable that a patient with earlier stage disease could have a normal or near normal chest radiograph but an abnormal chest CT study. The CDC guidelines imply that this may occur and recommend that chest CT be performed if the chest radiograph is normal and there is a high clinical suspicion of anthrax (10).
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Figure 9. Diagrammatic representation of current recommendations by the CDC for the evaluation of inhalational anthrax. Both chest radiographs and CT studies play a key role in the diagnosis of inhalational anthrax. (Reprinted, with permission, from reference 10.) The fifth bulleted item in the box marked "YES" should read "Consider chest computerized tomography (CT) if CR diagnosis is uncertain" (25).
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The presence of hyperattenuating mediastinal lymph nodes on
CT images may add a degree of certainty over chest radiographs
in the diagnosis of inhalational anthrax. Hyperattenuating nodes
are reported as an uncommon manifestation of lymphoma and breast
and ovarian cancer and in several rare diseases including Merkel
cell carcinoma and malacoplakia of the bladder (
21–
23).
However, these diseases are unlikely to manifest as an acute
febrile respiratory illness. Hyperattenuating mediastinal lymph
nodes and edema of mediastinal fat in the setting of acute respiratory
illness should be considered indicative of possible inhalational
anthrax.
For optimal depiction of the presence of hyperattenuating adenopathy, nonenhanced CT images seem more appropriate than contrast-enhanced images. As an initial screening tool, we now perform nonenhanced CT, rather than contrast-enhanced CT, in patients suspected of having inhalational anthrax. In addition, if the patient is in an early or advanced stage of shock, renal function may be impaired and use of nephrotoxic contrast material may be contraindicated. Nonenhanced CT studies are also faster and less expensive to perform, which is potentially useful if a large population requires screening. To date, our emergency department has screened several hundred patients with possible anthrax exposure, and, of these, more than 50 have undergone chest CT. None of these patients have had positive cultures or developed inhalational anthrax, and none of the CT images depicted enlarged hyperattenuating nodes or edema of mediastinal fat.
After admission, both patients underwent several follow-up CT examinations. These were useful for accurate assessment of the size of the pleural effusions, the change in mediastinal findings, and the presence of hemorrhage into the pleural space in both cases. Radiographs were helpful for clinical management and to help monitor the size of the effusions and extent of peripheral air-space disease.
Currently at our institution, symptomatic patients with known or suspected exposure to anthrax spores undergo chest radiography. If any of the classically described findings of mediastinal widening, hilar adenopathy, pleural effusions, or infiltrates are present, nonenhanced chest CT is performed. Patients with normal radiographs still undergo chest CT if there is high clinical suspicion of inhalational anthrax. We have not yet identified findings of anthrax on chest CT images in patients with normal chest radiographs. However, it is possible that nonenhanced chest CT may be the first imaging test capable of demonstrating the abnormal mediastinal findings of inhalational anthrax.
As of the time of this writing, there have been 10 reported cases of inhalational anthrax associated with the recent events in the United States. Four of the 10 patients have died, and the remaining six have survived (24). This mortality rate is substantially lower than the previously reported 86%–97% (8,16–18). It appears that early diagnosis and rapid initiation of appropriate antibiotic treatment may reduce the previously reported mortality rates (24).
Diagnostic imaging played an important role in helping establish a rapid diagnosis in the two cases of inhalational anthrax presented in this report. Radiologists and other physicians need to be aware of the radiographic and CT findings of inhalational anthrax and should not rule out clinically suspected disease if initial radiographs are normal or near normal.
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作者：
James P. Earls MD Donald Cerva Jr MD Elise Be 2007-5-12