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Radiologic Manifestations of Potential Bioterrorist Agents of Infection

¹ Department of Radiology, University of New Mexico Health Science Center, 915 Camino de Salud N.E., Albuquerque, NM 87131-5336.
² Department of Internal Medicine, Section of Infectious Diseases, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
³ Instituto Nacional de Enfermedades Virales, Humana (INEVH) "J. Maiztegui," Pergamino, Argentina.

Received February 19, 2002; accepted after revision June 11, 2002.

 
Address correspondence to L. Ketai.

Introduction

Top Introduction Anthrax Smallpox Plague Tularemia Q Fever Viral Encephalitides Hemorrhagic Fevers Conclusion References

 
Biologic weapons are not new to warfare. Smallpox-contaminated blankets and other crude biologic weapons have been used intermittently over several hundred years [1]. Unfortunately, the 20th century brought more intense interest in the development of biologic agents as a means of mass destruction. During the 1930s and 1940s, the Japanese military experimented with cholera, plague, and anthrax, resulting in the deaths of thousands of military prisoners and the instigation of plague outbreaks in several Chinese cities [2]. After World War II, the United States and the Soviet Union developed large-scale programs under which multiple organisms were "weaponized." The United States program was halted by executive order from President Nixon in 1969. In 1972, the United States and more than 100 other nations (including the Soviet Union and Iraq) signed a treaty prohibiting the development of biologic weapons. Unfortunately, several nations, including the Soviet Union, continued activities prohibited by the treaty for some years, as attested by the 1979 outbreak of inhalational anthrax at Sverdlovsk (Yekaterinburg) Russia [3, 4]. Few details are known regarding the number and type of biologic weapons currently existing around the world.

Many bacteria and viruses have the potential to serve as biologic weapons. For an organism to be an effective biologic weapon, it must be easily produced in large scale, be stable during storage, and be able to kill or incapacitate its victims at deliverable doses [5]. During World War I and World War II, biologic agents were used to contaminate food and water supplies, and intentional contamination of food with Salmonella and Shigella organisms has occurred during the 1990s in the United States [2, 6]. Most recent development and evaluation of biologic weapons, however, have concentrated on the respiratory delivery of pathogens. To be effectively delivered to the respiratory tract, biologic agents must be capable of being aerosolized to form particles of a size that can readily reach the small airways and alveoli during inhalation [7]. Some bacteria or viruses that enter the body through inhalation produce disease by damaging the lungs; however, several (e.g., the equine encephalitides) use the respiratory system only as a portal.

In this article, we survey the imaging literature on biologic agents that could potentially be used as weapons. Because respiratory delivery is the most likely method of attack, in most cases we have focused on the manifestations of disease that can be seen after inhalation of the infectious organism. Many of the diseases that can serve as biologic weapons currently occur sporadically (plague, tularemia, eastern equine encephalitis) or as epidemics in localized geographic regions (Rift Valley fever) [8]. Other infections are largely prevented by public health measures (e.g., anthrax prevention by animal vaccination). Smallpox has been eradicated and can recur only if purposefully introduced into the human population. Because these diseases are not widespread, imaging information is limited and, in many cases, relies on radiography. Cross-sectional imaging data are limited. Until the fall of 2001, for instance, no cross-sectional imaging of inhalational anthrax had been reported.

Anthrax

Top Introduction Anthrax Smallpox Plague Tularemia Q Fever Viral Encephalitides Hemorrhagic Fevers Conclusion References

 
Anthrax is caused by a sporulating gram-positive bacteria. The organism injures the host by producing a three-component exotoxin consisting of the edema factor, the lethal factor, and a protective antigen [9]. All three components must work in concert to produce toxicity. Although most recent attention has focused on the criminal distribution of anthrax, the spores are endemic in the soil in many areas worldwide, including Texas, Oklahoma, and the lower Mississippi River Valley [10]. Most infections occur in animals; the occurrence is controlled by livestock vaccination.

Human anthrax may present as a cutaneous, a gastrointestinal, or a pulmonary infection. Most naturally occurring anthrax outbreaks, including those in Zimbabwe and central Asia, have been of the cutaneous form [11]. Gastrointestinal anthrax occurs after the ingestion of infected meat and presents as either an oropharyngeal or an abdominal infection. Anthrax from skin or gastrointestinal sources can enter the lymphatic system and, after proliferation within macrophages, can cause septicemia and death. Meningoencephalitis is a rare complication of septicemia, causing parenchymal hemorrhage at the gray-white cortical junction and meningeal enhancement that can be detected by neuroimaging [12].

Inhalational anthrax is rare despite the fact that anthrax spores are of an ideal size (2-6 µm) for deposition in the distal respiratory tract after inhalation. Fortunately, anthrax spores appear to have a tendency to clump, particularly when binding to soil, which creates much larger particles that are not easily aerosolized or inhaled. This tendency probably explains the previous rarity of inhalational anthrax even in areas of heavy soil contamination. The clumping of spores may also explain the failure of the Japanese terrorist group, Aun Shinrikyo, to induce inhalational anthrax in the Japanese public despite multiple attempts [13].

When anthrax spores are inhaled into the lower respiratory tract, they are initially ingested by macrophages. Surviving spores are transported via lymphatics to the mediastinal lymph nodes, where they remain for a variable time until germinating. Usually germination and the onset of symptoms occur within a week, but delays of more than a month have been documented. Radiographic findings during this period of incubation have not been reported and are unlikely to occur.

The subsequent disease develops in two stages. Initially symptoms are nonspecific and include fever, chills, cough, weakness, and abdominal pain. These symptoms last 1-3 days and may or may not be followed by a brief period of improvement. The patient then enters the second stage of the illness, which is characterized by fever, stridor, dyspnea, and shock. Death usually occurs despite treatment with appropriate antibiotics. Victims of the recent terrorist attacks in the United States presented a median of 3.5 days after the onset of symptoms, a point in the course of inhalational anthrax that usually marks the onset of the second stage of the disease [14].

Imaging findings of inhalational anthrax are caused by hemorrhagic lymphadenitis and mediastinitis. Chest radiographs at admission of the victims of the recent terrorist attacks all showed abnormal findings, including radiographs of patients presenting before the onset of fulminant disease [15, 16]. Chest radiographs obtained at presentation of inhalational anthrax show hilar prominence and mediastinal widening, particularly in the right paratracheal area (Figs. 1A, 1B). Pleural effusions are also usually present. Peribronchial opacities may be seen on chest radiographs, but extensive consolidation is absent.

View larger version (122K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 1A. —Middle-aged man with inhalational anthrax. Chest radiograph at admission shows modest widening of right mediastinal contour at level of carina. Note also subtle increase in bronchovascular opacities.

View larger version (132K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 1B. —Middle-aged man with inhalational anthrax. Chest radiograph obtained next day shows marked mediastinal widening (accentuated by rightward rotation), particularly in right paratracheal area. Markedly increased bronchovascular opacities are seen radiating from hila.

Reports of cross-sectional imaging of inhalational anthrax are confined to the victims of recent terrorism-related cases and include a detailed description by Earls et al. [17] of imaging findings in two surviving patients. Chest CT scans have shown the mediastinal adenopathy to be more dramatic than seen on radiography, and CT scans have shown markedly abnormal findings in two patients in whom the chest radiographic findings were initially interpreted as normal. CT images of victims of the terrorists attacks in the fall of 2001 have consistently shown enlarged high-attenuation mediastinal nodes, consistent with intranodal hemorrhage [16, 17] (Fig. 1C). This finding may best be seen on CT scans without IV contrast material. The peribronchial distribution of parenchymal opacities, most likely representing lymphatic involvement, is also accentuated on CT images. However, only a few patients with inhalational anthrax have undergone chest CT. The available images may not accurately represent the spectrum of abnormalities that can be caused by the disease.

View larger version (123K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 1C. —Middle-aged man with inhalational anthrax. CT scan of chest obtained with IV contrast material on same day as radiograph B reveals marked edema of mediastinal fat that obscures margins of lymph nodes in paratracheal area. High-attenuation foci seen in right paratracheal soft tissue (arrowheads) most likely represent hemorrhagic foci in lymph nodes. Superior vena cava is compressed.

Smallpox

Top Introduction Anthrax Smallpox Plague Tularemia Q Fever Viral Encephalitides Hemorrhagic Fevers Conclusion References

 
The last endemic case of smallpox occurred in 1977, and the last laboratory-related case was reported in England in 1978 [18]. Nevertheless, this exclusively human disease is still considered a potential biologic weapon because of its continued existence in government-sanctioned repositories. The disease is caused by variola, a DNA virus in the genus Orthopoxvirus. The genus contains other viruses that can occasionally affect humans, such as monkeypox and camelpox. None, however, manifests the virulence and potential for human-to-human transmission seen with variola infections [19].

After a victim undergoes natural exposure to aerosolized variola, the virus travels to the pulmonary lymph nodes, replicates, and then disseminates to the liver, spleen, bone marrow, and skin. After 3 days of fever, chills, and malaise, the characteristic rash appears beginning on the extremities and face, and spreading to the trunk. Lesions on the mucous membranes of the oropharynx shed organisms and probably account for the spread of infection from respiratory secretions.

Smallpox may have a relatively mild presentation, variola minor, with less systemic toxicity and smaller skin lesions than typical smallpox (variola major). The variola minor manifestation of smallpox carries a 1% mortality rate in unvaccinated hosts. Variola major, the more severe syndrome, has a mortality rate of 3% in vaccinated individuals and 30% in those who are not vaccinated. [3] Two more severe variants of variola major also occur: flat-type smallpox, which causes flat, slowly developing skin lesions and produces systemic toxicity so severe that mortality is approximately 95% in unvaccinated patients; and hemorrhagic-type smallpox, in which mucosal hemorrhage and death usually intervene before the development of typical skin lesions [20]. Fortunately, these two variants combined make up fewer than 10% of all variola major cases.

Respiratory signs and symptoms are not part of the 2-3 day febrile prodrome that occurs before the onset of the smallpox skin rash. Cough commonly occurs in patients in the later stages of the disease, usually after the first week of illness [21]. Although pneumonia has developed in some patients during outbreaks of smallpox, the exact incidence was not well documented, and it is uncertain whether this represented a viral pneumonia or a bacterial superinfection. Pulmonary edema is a common complication of the flat and hemorrhagic smallpox types and possibly represents diffuse alveolar damage.

To our knowledge, no study summarizing the appearance of chest radiographs in variola major patients has been published. More important, because respiratory symptoms usually occur many days after the onset of the characteristic skin rash, chest radiography is unlikely to play a role in the early detection of a smallpox outbreak.

Most descriptions of the radiographic findings of lung disease in smallpox patients have focused on a mild pulmonary form of smallpox unaccompanied by skin lesions that is sometimes termed "smallpox handler's lung." This disease has been reported in vaccinated individuals who are exposed to patients with active disease [22, 23]. The best-documented cases occurred during the South Wales smallpox outbreak of 1962 in affected health care workers who had previously been immunized to smallpox [24, 25, 26]. Patients with smallpox handler's lung developed a febrile illness 9-12 days after exposure. Chest radiographs showed illdefined nodular opacities in the upper lung field, some of which remained evident on chest radiographs for several months (Fig. 2A, 2B). Long-term follow-up has shown that these nodules may slowly calcify over several years (Fig. 3A, 3B).

View larger version (130K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 2A. —Previously vaccinated middle-aged female health care worker exposed to smallpox during epidemic. (Reprinted with permission from [25]) Frontal chest radiograph taken during acute illness shows multiple ill-defined patchy opacities in lung parenchyma.

View larger version (82K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 2B. —Previously vaccinated middle-aged female health care worker exposed to smallpox during epidemic. (Reprinted with permission from [25]) Detail of right upper lobe shows these findings more clearly.

View larger version (119K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 3A. —Middle-aged woman with "smallpox handler's lung." (Reprinted with permission from [25]) Frontal chest radiograph during acute illness shows multiple small, ill-defined bilateral nodules.

View larger version (119K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 3B. —Middle-aged woman with "smallpox handler's lung." (Reprinted with permission from [25]) Frontal chest radiograph taken several years after A shows interval calcification of numerous nodules. Large calcification in right upper lobe was tuberculous in origin.

In a minority of cases (<1%), variola can affect the bones and joints. Involvement is usually symmetric, presents as severe periostitis, and usually affects the diaphyses of long bones [27]. This disease also causes patchy destruction of the metaphyses and may involve the joints, with a predilection for the elbow (Fig. 4).

View larger version (183K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 4. —2-year-old girl with smallpox. Bilateral radiograph of forearms shows extensive periosteal reaction caused by smallpox. Arrow indicates small area of radiolucency in distal ulnar metaphysis. (Reprinted with permission from [27])

Plague

Top Introduction Anthrax Smallpox Plague Tularemia Q Fever Viral Encephalitides Hemorrhagic Fevers Conclusion References

 
Plague is caused by Yersinia pestis and is a zoonotic infection usually transmitted to humans by the bites of infected fleas. In the aftermath of several pandemics, multiple endemic foci now exist, including one in the Southwestern United States. During World War II, initial Japanese military attempts to develop aerosolized plague were unsuccessful and led to the development and testing of biologic weapons that dispersed plague-infected fleas. Although a plague weapon could still use fleas as a vector, both the United States and the former Soviet Union have developed the capability to effectively aerosolize plague bacteria, and a modern weapon would most likely use this technology. Once aerosolized, plague bacteria remain viable for approximately an hour and may travel several kilometers [28].

Naturally occurring plague infections may have several clinical manifestations, of which bubonic plague is the most common. In this presentation, the development of suppurative lymphadenopathy closely follows symptoms of acute fever, chills, and prostration. Secondary pneumonia occurs in approximately 10% of patients.

Septicemic plague may occur primarily (without bubo formation) or as a complication of bubonic plague. In patients with septicemic plague, the presentation is essentially that of gram-negative bacteremic shock, and the mortality rate is significantly greater than in the bubonic form. Bilateral pulmonary infiltrates frequently are present but may be caused by either secondary plague pneumonia or diffuse alveolar damage related to sepsis.

Pneumonic plague may be caused by hematogenous dissemination or may be acquired directly from inhalation of plague bacteria (primary plague pneumonia). After exposure to aerosolized plague, patients develop cough, dyspnea, and, frequently, hemoptysis within 2-4 days. The course of the pneumonia is fulminant and, if untreated, rapidly fatal.

During the last two decades, several cases of human primary plague pneumonia in the United States were acquired from infected cats [28, 29, 30]. Fortunately, the incidence of respiratory transmission of plague pneumonia from person to person has been extremely low in this country, the last case occurring in 1924 [31]. In 1997, however, a single individual with secondary pneumonic plague in Madagascar transmitted the infection to 18 other patients, eight of whom died [32]. Pneumonic plague would be the most likely clinical presentation of plague infections resulting from terrorist use of an aerosolized weapon.

The radiographic manifestations of secondary plague are variable but most commonly include bilateral parenchymal infiltrates that may initially have a nodular appearance [33] (Fig. 5A, 5B). Cavitation may occur but is uncommon (Fig. 6) [34]. Once the disease becomes extensive, the bilateral opacities caused by primary or secondary plague pneumonia are indistinguishable from acute respiratory distress syndrome on chest radiographs. Mediastinal, cervical, and hilar adenopathy can be present in both bubonic plague and secondary pneumonic plague but are not a consistent finding (Fig. 7). Individual case reports of primary plague pneumonia have described chest radiographs showing multilobar air-space disease without the presence of extensive hilar or mediastinal adenopathy [28, 29, 30].

View larger version (155K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 5A. —14-year-old boy with secondary pneumonic plague. (Reprinted with permission from [33]) Frontal chest radiograph shows bilateral nodular opacities.

View larger version (145K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 5B. —14-year-old boy with secondary pneumonic plague. (Reprinted with permission from [33]) Within 24 hr, these nodular opacities progressed to diffuse air-space disease. Plague pneumonia was confirmed at autopsy.

View larger version (124K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 6. —30-year-old woman with secondary plague pneumonia. Frontal chest radiograph shows left lower lobe air-space disease with formation of large cavity. Cavitation occurred after 2 weeks of illness and is an uncommon manifestation of plague.

View larger version (141K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 7. —3-year-old boy with bubonic plague. Chest radiograph shows extensive mediastinal adenopathy. Bubo can also been seen in left axilla (arrow).

Tularemia

Top Introduction Anthrax Smallpox Plague Tularemia Q Fever Viral Encephalitides Hemorrhagic Fevers Conclusion References

 
Tularemia is caused by Francisella tularensis, a small gram-negative intracellular bacteria. Both A and B types of F. tularensis exist, type A being significantly more virulent. Although tularemia causes granulomatous inflammation, it presents as an acute rather than a chronic febrile illness and is usually accompanied by pneumonia. Pathologic changes in the lung include necrotizing bronchopneumonia and caseous necrosis. In the 1960s, the United States armed forces exposed volunteers to aerosolized tularemia and developed biologic weapons containing the organism [35].

Naturally occurring tularemia may be acquired from contaminated ticks, the consumption of contaminated water or food, or via inhalation [36]. These endemic cases of tularemia usually present as an ulceroglandular or typhoidal form. The former is most common, causing fever, chills, and a characteristic cutaneous ulcer with accompanying regional adenopathy. The typhoidal form is usually acquired by ingestion of contaminated food and has a mortality rate of 30% if untreated. Pneumonia occurs in most patients with the typhoidal form and in approximately 30% of patients with ulceroglandular disease. The presence of pneumonia is associated with increased mortality from tularemia and is probably related to the higher mortality of the typhoidal form. Primary pneumonic tularemia occurs occasionally and has been associated with inhalation of organisms while cutting hay [37]. A recent outbreak of tularemia occurred on Martha's Vineyard, MA, in 2000, probably associated with aerosolization of bacteria during lawn mowing and brush cutting [38].

Early clinical articles suggested that the typhoidal form usually involved the lungs primarily, whereas the ulceroglandular form of disease initially affected the mediastinal lymph nodes with later retrograde spread into the lung parenchyma. More recent work has not confirmed these observations and instead suggests that the radiographic manifestation of ulceroglandular and typhoidal forms are indistinguishable. Overall, three quarters of patients with naturally occurring tularemia present with bronchopneumonia that is usually bilateral and may cavitate. Lymphadenopathy and pleural effusions occur in approximately one third of patients [39] (Fig. 8A, 8B). Complications of the adenopathy include airway obstruction and extension of the infection into the pericardium. Insufficient (unclassified) data exist to determine whether pneumonic tularemia (such as that acquired from an aerosol weapon) might produce a radiographic pattern different from the ulceroglandular or typhoidal types of tularemia. During the aerosolized tularemia outbreak on Martha's Vineyard, initial chest radiographic findings were occasionally normal. Within 1-2 days after the onset of infectious symptoms, however, multifocal segmental or lobar infiltrates developed (personal communication, Miller SW). Mediastinal adenopathy was not seen; however, hilar adenopathy subsequently developed in some cases (Fig. 9).

View larger version (137K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 8A. —51-year-old woman with tularemia. (Courtesy of Rubin S, Galveston, TX) Chest radiograph shows patchy segmental opacities and right hilar adenopathy.

View larger version (136K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 8B. —51-year-old woman with tularemia. (Courtesy of Rubin S, Galveston, TX) Follow-up radiograph several days later shows some areas have cavitated and right pleural effusion has developed.

View larger version (141K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 9. —40-year-old man with tularemia acquired from aerosol exposure. Chest radiograph taken 2 weeks after initial appearance of left lung infiltrate shows cavitary air-space disease in mid and upper left lung. Note moderate left hilar adenopathy (arrow). (Courtesy of Miller SW, Boston, MA)

Q Fever

Top Introduction Anthrax Smallpox Plague Tularemia Q Fever Viral Encephalitides Hemorrhagic Fevers Conclusion References

 
Q fever is caused by Coxiella burnetii, an obligate intracellular Rickettsia-like organism. It is a zoonosis with a worldwide distribution and has caused epidemics in Eastern Europe during the 1990s [40]. The organism is so infectious that an inoculum of more than five organisms is likely to produce a symptomatic infection. This characteristic, and the ability of C. burnetii to produce a sporelike form resistant to heat and drying, help make the organisms attractive as a biologic weapon. Fortunately, the mortality rate of Q fever pneumonia is probably less than 1%, even if untreated. Malaise and fatigue, however, may last for months. The rare fatal cases may be related to the development of myocarditis.

Q fever infections can present as pneumonia, meningoencephalitis, or granulomatous hepatitis. Hepatitis tends to occur in younger patients. In most series, pneumonia is the most common clinical presentation, occurring in more than half the patients with the disease [41]. Q fever pneumonia has a nonspecific appearance on chest radiographs (Fig. 10) and on chest CT. On either imaging modality, the infection may appear to have segmental, patchy, or lobar consolidation with or without a small pleural effusion. CT may detect mild lymph node enlargement that is not evident on radiography, a finding that is not specific for Q fever [42] (Fig. 11).

View larger version (146K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 10. —37-year-old man with Q fever pneumonia. Posteroanterior chest radiograph shows consolidation of medial segment of right middle lobe. (Courtesy of Gikas A and Tritou I, Heraklion, Crete, Greece)

View larger version (73K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 11. —46-year-old man with Q fever pneumonia. CT scan shows multiple patchy, nodular areas of consolidation located peripherally in both right and left lungs. Some of these opacities appear to have feeding vessel and halo of ground-glass opacification, appearance similar to CT images of septic emboli. (Courtesy of Gikas A and Tritou I, Heraklion, Crete, Greece)

Viral Encephalitides

Top Introduction Anthrax Smallpox Plague Tularemia Q Fever Viral Encephalitides Hemorrhagic Fevers Conclusion References

 
Viral encephalitis has also been explored as a biologic weapon [3]. Most research has concerned the American equine encephalitides, which include Venezuelan equine encephalitis, western equine encephalitis, and eastern equine encephalitis. Although naturally occurring infections are transmitted by mosquitoes, the viruses are also highly infectious when dispersed in aerosol, a characteristic that has led to more than 100 laboratory infections. The organisms are also stable during storage and can be grown in large quantities.

Almost all Venezuelan equine infections are symptomatic, producing high fever, chills, and malaise. The development of clinical encephalitis, however, is much less common. Clinical encephalitis occurs in fewer than 1% of adults but has a case fatality rate of 10%. Among children, the incidence of encephalitis is 4% and the resulting mortality, 30%. Western equine encephalitis has a similar clinical presentation to Venezuelan equine encephalitis and produces encephalitis of a similar severity. The incidence of symptomatic infection with eastern equine encephalitis is probably lower than with Venezuelan equine encephalitis; however, the development of encephalitis is more frequent, occurring in approximately 5% of infections. When encephalitis does occur, it is more severe than in Venezuelan or western equine encephalitis and carries a case fatality rate of 50-75%.

Imaging findings have been best studied in eastern equine encephalitis. MR imaging is more sensitive than CT, but both studies show abnormalities in the area of the basal ganglia and thalamus [43] (Figs. 12A, 12B and 13). MR imaging with T2-weighted sequences shows foci of increased signal intensity in the basal ganglia that most likely represent inflammation, ischemia, and edema rather than necrosis (Fig. 14). Accordingly, imaging abnormalities often regress if clinical improvement occurs. Meningeal enhancement occasionally occurs, as do cortical lesions. The predominance of basal ganglia rather than temporal lobe lesions is distinctly different from herpes encephalitis (Fig. 15), which can have a clinical presentation similar to that of eastern equine encephalitis.

View larger version (116K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 12A. —14-year-old boy with eastern equine encephalitis that occurred as a sporadic case in 2001. (Courtesy of Quint D, Ann Arbor, MI) CT scans show low-attenuation in area of left basal ganglia and internal capsule (arrowheads, A) with obliteration of left anterior temporal horn of lateral ventricle.

View larger version (121K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 12B. —14-year-old boy with eastern equine encephalitis that occurred as a sporadic case in 2001. (Courtesy of Quint D, Ann Arbor, MI) CT scans show low-attenuation in area of left basal ganglia and internal capsule (arrowheads, A) with obliteration of left anterior temporal horn of lateral ventricle.

View larger version (121K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 13. —Another 14-year-old boy with eastern equine encephalitis. CT scan shows low attenuation (arrowheads) in area of basal ganglia and thalamus that appears similar to that in Figure 12A,12B. (Reprinted with permission from [43])

View larger version (141K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 14. —Yet another 14-year-old boy with eastern equine encephalitis. T2-weighted MR image shows high signal intensity (arrowheads) in area of left basal ganglia. (Reprinted with permission from [43])

View larger version (140K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 15. —65-year-old man with herpes encephalitis. T2-weighted MR image shows diffuse high signal intensity in left temporal lobe (arrow). Focal area of low signal intensity in medial aspect of lobe is consistent with hemorrhage (arrowhead). Although herpes simplex may also cause fulminant encephalitis, predilection for involvement of temporal lobes is markedly different from distribution of eastern equine encephalitis seen in Figure 14.

Hemorrhagic Fevers

Top Introduction Anthrax Smallpox Plague Tularemia Q Fever Viral Encephalitides Hemorrhagic Fevers Conclusion References

 
Viral hemorrhagic fevers are illnesses characterized by fever, prostration, increased vascular permeability, and abnormalities of coagulation. All these agents are RNA viruses and are members of four virus families: Arenaviridae (Lassa fever virus, Argentine hemorrhagic fever virus), Bunyaviridae (Rift Valley fever virus, Crimean-Congo hemorrhagic fever virus, hantaviruses), Filoviridae (Ebola and Marburg viruses), and Flaviviridae (dengue hemorrhagic fever virus). Most of these viruses are transmitted to humans from animal reservoirs or from arthropods, but they are also highly infectious as aerosols and therefore have potential as a biologic weapon. Person-to-person airborne transmission of viral hemorrhagic fevers is rare but has probably occurred in a few cases.

Most viral hemorrhagic fever viruses can reach concentrations in cell cultures that are adequate to construct a small biologic weapon that would be harmful if released in a small space such as an office building [44]. Thus far, hantaviruses have not been found to replicate well in cell culture. These technical difficulties may be overcome in the future. Furthermore, Andes virus, a South American hantavirus, has shown evidence of person-to-person transmission [45], which increases the potential risk that specific hantaviruses pose if developed as biologic weapons [46].

The vasculature is the target tissue for viral hemorrhagic fevers. Infection causes increased blood vessel permeability, which leads to hypovolemia and shock and, in advanced cases, generalized bleeding. The pattern of organ involvement differs among the different virus species. The South American arenaviruses, the Ebola and Marburg viruses, and the Crimean-Congo hemorrhagic fever virus frequently cause hemorrhagic manifestations, whereas Rift Valley and yellow fever viruses are hepatotropic and can cause hepatic dysfunction and jaundice [46]. Neurologic manifestations can be caused by the South American hemorrhagic fever virus and several other viruses. Deafness has been a frequent sequel of severe Lassa fever, and retinitis is a characteristic complication of Rift Valley fever [47, 48, 49]. Although any of the hemorrhagic fever viruses may cause renal failure from hypovolemia and hypotension, Asian and European hantaviruses specifically target the kidneys. The American hantaviruses (Sin Nombre virus, Andes virus, and others) are unique in their predilection for the lung vasculature, resulting in noncardiogenic pulmonary edema and respiratory failure termed "hantavirus pulmonary syndrome" [50, 51]. Although patients with hantavirus pulmonary syndrome develop thrombocytopenia, bleeding diatheses do not occur, leading some authors to categorize this illness separately from viral hemorrhagic fevers [46, 52].

Few reports exist of the radiologic manifestation of viral hemorrhagic fevers. Only the American hantaviruses cause extensive changes on chest radiographs. Chest radiographs early in the course of the hantavirus pulmonary syndrome show marked interstitial edema with prominent Kerley B lines and sub-pleural edema despite profound hypovolemia. Patients with limited disease do not progress past the interstitial edema stage on chest radiographs [53]. Patients with more severe disease show progression to bilateral alveolar filling within 48 hr (Fig. 16A, 16B). The mortality rate of these patients exceeds 50%.

View larger version (124K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 16A. —50-year-old man with hantavirus pulmonary syndrome. Chest radiograph early in course of disease shows marked interstitial edema.

View larger version (118K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 16B. —50-year-old man with hantavirus pulmonary syndrome. Chest radiograph taken 48 hr later shows interval development of extensive air-space disease.

Chest radiographic abnormalities are not as common or as severe in illnesses caused by other viral hemorrhagic fevers. For instance, chest radiographic findings in patients with Argentine hemorrhagic fever are often normal. Lobar opacities develop only late in the course of the disease in the 20% of patients who develop a bacterial superinfection. Physical examination of the chest in patients with Ebola, Marburg, and Lassa fevers often shows scattered rales, but florid pulmonary edema is rare unless it is preceded by vigorous fluid volume resuscitation (Fig. 17). In these diseases, extensive pulmonary edema is more likely to represent the effects of fluid therapy than viral damage to the lung (personal communication, Bausch D).

View larger version (122K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 17. —Middle-aged man with Lassa fever. Chest radiograph shows mild interstitial edema, which later worsened (not shown) after aggressive fluid volume resuscitation. (Courtesy of Bausch D, Atlanta, GA)

Reports of cross-sectional imaging in viral hemorrhagic fevers are rare; most describe neuroimaging findings. Recently, CT was performed on a patient with persistent neurologic symptoms after encephalitis from Rift Valley fever. Imaging showed evidence of multiple cortical infarcts that were most prominent in the occipital cortex (Fig. 18A, 18B). Although Rift Valley fever may cause retinitis, these findings raise the possibility that central lesions could also be responsible for visual symptoms.

View larger version (130K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 18A. —18-year-old woman with Rift Valley fever. Patient with visual symptoms and encephalitis was confirmed to have positive serology findings for acute Rift Valley fever infection during recent outbreak in Saudi Arabia. Initial CT of brain had normal findings (not shown). Neurologic symptoms of lethargy, confusion, and paralysis persisted. Repeated CT scans without (A) and with (B) IV contrast material. Both images show multiple areas of low attenuation in cerebral cortex, most prominently in occipital lobes (arrows). Although similar appearance can be caused by microvascular damage to occipital white matter as a result of hypertensive encephalopathy, patient had no history of hypertension.

View larger version (128K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 18B. —18-year-old woman with Rift Valley fever. Patient with visual symptoms and encephalitis was confirmed to have positive serology findings for acute Rift Valley fever infection during recent outbreak in Saudi Arabia. Initial CT of brain had normal findings (not shown). Neurologic symptoms of lethargy, confusion, and paralysis persisted. Repeated CT scans without (A) and with (B) IV contrast material. Both images show multiple areas of low attenuation in cerebral cortex, most prominently in occipital lobes (arrows). Although similar appearance can be caused by microvascular damage to occipital white matter as a result of hypertensive encephalopathy, patient had no history of hypertension.

Neurologic complications are quite common in Argentine hemorrhagic fever, occurring more frequently than even hemorrhagic complications. Severe cases manifest seizures and coma with a high mortality rate. Patients with Argentine hemorrhagic fever are treated with immune plasma, and approximately 10% of these individuals develop a late neurologic syndrome that manifests cerebellar signs (personal communication, Enria D). Although a form of leukoencephalopathy had been suspected clinically, MR imaging in these patients did not show evidence of white matter disease.

Conclusion

Top Introduction Anthrax Smallpox Plague Tularemia Q Fever Viral Encephalitides Hemorrhagic Fevers Conclusion References

 
More than a dozen organisms have already been tested as potential biologic weapons or used in biologic warfare. Despite an international treaty, the world community may not be protected from further illness and death resulting from the release of these agents in the future by terrorists or warring nations. Many of these diseases are most effectively transmitted as aerosols. Most available imaging data describe findings on chest radiography (Table 1).

Some illnesses that could be caused by biologic weapons, such as inhalational anthrax, have characteristic radiologic appearances. The radiologic appearance of other infections, such as the basal ganglia lesions caused by eastern equine encephalitis, may suggest the correct diagnosis when combined with clinical findings. The remaining infectious diseases, such as smallpox and the viral hemorrhagic fevers, have striking clinical presentations. In these diseases, radiology will prove helpful only when the disease presentation is atypical (e.g., smallpox handler's lung) or when specific complications occur.

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Top Introduction Anthrax Smallpox Plague Tularemia Q Fever Viral Encephalitides Hemorrhagic Fevers Conclusion References

 

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