Lesser Known Biological Agents and Potential Threats
Teriggi J. Ciccone
Seric S. Cusick
TULAREMIA
Tularemia is a bacterial zoonosis caused by Francisella tularensis, a facultative intracellular aerobic gram-negative coccobacilli. Several other names have been used to describe this disease, including rabbit fever, deerfly fever, market men’s disease, or Francis disease. First described in rodents during the early 20th century in Tulare County, California, tularemia results in multiple clinical manifestations in infected humans (1). Clinical disease is caused by two isolates, known as Biovars Jellison Type A and B. This organism is found throughout most of the world with predominance in the Northern Hemisphere. Tularemia is endemic in the United States, northern Europe, Scandinavia, and the former Soviet Union. Cases have been reported in all of the continental United States, predominantly in southern and western states. From 1990 to 2000, 1,368 cases of tularemia were reported in the United States, with more than half of the cases occurring in Missouri, Arkansas, South Dakota, and Oklahoma (2).
THEORETICAL AND SCIENTIFIC BACKGROUND
Human tularemia infection occurs after exposure to the causative agent via insect bite or contact with contaminated substances. Arthropod vectors include ticks, deerflies, and mosquitoes. The natural reservoir for F. tularensis includes rabbits, rats, mice, squirrels, beavers, and deer. Infection can be introduced cutaneously or through mucous membranes after insect or animal bite, handling infected animal carcasses, or exposure to contaminated water. Respiratory exposure to tularemia occurs via inhalation of contaminated soil, dust, or other particles. Disease can also occur after ingestion of contaminated animal products or water. Human-to-human transmission of tularemia has not been reported. Tularemia has been recognized as a possible bioweapon since the 1940s. The United States produced and maintained offensive tularemia during the 1950s and 1960s (3,4). A startling World Health Organization report from 1970 predicted that 50 kg of tularemia disseminated within a population of 5 million persons would result in 250,000 injuries and 19,000 deaths (5,6).
Tularemia is classified as a category A agent by the Centers for Disease Control and Prevention (CDC) (7) and represents a threat for several reasons. The Jellison Type A isolate is highly virulent, causing disease in humans with exposure to fewer than 10 bacteria when inhaled (8,9,10). This agent could be aerosolized and potentially spread over a large area causing pulmonary tularemia. Additionally, tularemia is a highly morbid disease, imposing a significant burden of disease on the victims, and untreated tularemia carries a mortality of upward of 33% (11). In addition to being highly virulent and morbid, F. tularensis can survive for prolonged periods of time in freezing conditions, making its storage and potential shipment relatively simple. Infected frozen rabbit meat has been shown to remain infective for greater than 3 years (12).
SIGNS AND SYMPTOMS
Tularemia causes multiple disease syndromes in infected humans depending on the site and amount of inoculum. Incubation periods after exposure generally range between 3 and 6 days. Initial symptoms are nonspecific and can mimic flulike or upper respiratory infections. Abrupt onset of fever with chills, myalgias, cough, fatigue, and sore throat are the earliest symptoms. Pulse-temperature disassociation has been noted in a large number of patients (11). Beyond this initial period, more readily identifiable syndromes develop.
Ulceroglandular tularemia is the most frequent naturally occurring form of the disease. Lesions on the skin or mucous
membranes accompanied by regional lymphadenopathy characterize this form (13). Infection occurs after inoculation of skin or mucous membranes. A tender, erythematous papule develops a few days after inoculation. The lesion soon begins to ulcerate within a few days with the onset of systemic symptoms, with a granulomatous base and indurated, raised borders. Lesions range in size between 0.5 and 10 cm. As the disease process progresses, an eschar may form over the ulcer. Ulcers and lymphadenopathy may persist for months after onset if left untreated, with lymph nodes draining out onto the skin (13,14). Glandular tularemia is a syndrome in which regional lymphadenopathy occurs without a frank ulcer. Oculoglandular tularemia results from inoculation of the eye. Purulent, painful conjunctivitis, chemosis, and lymphadenitis are predominant features.
membranes accompanied by regional lymphadenopathy characterize this form (13). Infection occurs after inoculation of skin or mucous membranes. A tender, erythematous papule develops a few days after inoculation. The lesion soon begins to ulcerate within a few days with the onset of systemic symptoms, with a granulomatous base and indurated, raised borders. Lesions range in size between 0.5 and 10 cm. As the disease process progresses, an eschar may form over the ulcer. Ulcers and lymphadenopathy may persist for months after onset if left untreated, with lymph nodes draining out onto the skin (13,14). Glandular tularemia is a syndrome in which regional lymphadenopathy occurs without a frank ulcer. Oculoglandular tularemia results from inoculation of the eye. Purulent, painful conjunctivitis, chemosis, and lymphadenitis are predominant features.
Tularemic pneumonia caused by inhalation of infectious particles produces a different symptom complex and occurs in approximately half of all cases of tularemia. This syndrome would be the one most likely occurring during bioterrorist attacks via airborne dispersion of infective particles. Patients become ill 3 to 5 days after exposure. Early constitutional symptoms are often noted before more specific pulmonary manifestations. After 3 to 6 days, sore throat, cough, dyspnea, pleuritic chest pain, and hemoptysis develop. In a majority of cases, patchy bilateral infiltrates or lobar consolidation with or without pleural effusions may make this disease indistinguishable from other pneumonias. More advanced cases of tularemic pneumonia cause pleuropneumonitis accompanied with hilar lymphadenopathy; however, these radiographic signs may be nonspecific or absent. Left untreated, tularemic pneumonia can lead to worsening respiratory failure and acute respiratory distress syndrome requiring assisted ventilation (12,13,14).
Oropharyngeal tularemia occurs after ingestion of contaminated water, plant, or animal products. This syndrome is characterized by pharyngitis, stomatitis, and prominent cervical lymphadenopathy, mimicking acute streptococcal pharyngitis (15,16). Ulcerations may form on the oropharyngeal mucosa. Abdominal pain, nausea, vomiting, and diarrhea may also occur.
Typhoidal tularemia occurs when systemic illness presents without a clear localizing source of inoculation. Tularemic sepsis is the most severe form of disease. The patient may present febrile, obtunded, and hypotensive and ultimately may develop multiorgan failure including disseminated intravascular coagulation, acute renal failure, and meningitis (14,15). Left untreated, this syndrome may result in a fatality rate up to 60% (8,12,13).
MEDICAL MANAGEMENT
The diagnosis of tularemia is challenging for a number of reasons. It is a relatively rare naturally occurring disease and thus not initially suspected by physicians. No specific rapid diagnostic test is readily available in most settings (8,13). From a laboratory perspective, the extremely high virulence of tularemia limits the number of laboratories that can safely work with this bacterium. Additionally, routine Gram stains and cultures from various sources are unreliable. Serological testing using latex agglutination or enzyme-linked immunosorbent assays are available; however, the utility of these studies in an acute outbreak is questionable because the serum antibodies required for serological testing do not develop for days to weeks after infection (13). More rapid diagnostic tests include direct fluorescence antibody and immunohistochemical studies. The use of these modalities is limited by the lack of appropriate equipment and personnel in many hospital laboratories. Most often these studies require samples to be sent to a reference laboratory, adding further delay to the diagnosis.
Given the nonspecific presentations of tularemia and the lack of rapid diagnostic testing, the physician’s clinical suspicion becomes critically important. Tularemia should be suspected in cases where a large number of patients within a specific geographical area develop symptoms of severe respiratory and systemic infections. A cluster of atypical pneumonia with hilar lymphadenopathy in otherwise healthy patients should raise suspicion for possible bioterrorist attack and prompt further actions. Hospital infectious disease authorities should be notified, and a report should be made to local and regional health departments. Clusters of tularemic pneumonia should also be reported to local law enforcement agencies and the Federal Bureau of Investigation.
Routine laboratory data is nonspecific but may reveal a mild leukocytosis with a lymphocytosis (11,13,15,17). Chest roentgenograms should be obtained on all patients with nonspecific pulmonary symptoms searching for pleuropneumonitis and hilar lymphadenopathy. Cultures from blood, sputum, conjunctival, and oropharyngeal secretions should be collected and sent to appropriate laboratories for culture on glucose cysteine blood agar or thioglycollate broth (8,13).
Aminoglycoside antibiotics, specifically streptomycin, are considered the drugs of choice for the treatment of tularemia (8,12,13,15). Streptomycin is dosed as 1g intramuscularly (IM) twice daily for adults, and 15 mg/kg IM twice daily for children. Where streptomycin is unavailable or contraindicated, gentamicin at 5 mg/kg intravenously (IV) daily can be used for adults; 2.5 mg/kg IV three times a day can be used in children. Treatment should continue for 10 days. Alternative choices include doxycycline, chloramphenicol, and ciprofloxacin.
A bioterrorist attack has the potential to cause massive outbreaks of tularemia. Under such circumstances, the use of IV antibiotics on a large scale may not be feasible. The Working Group on Civil Biodefense recommends the use of oral antibiotics in mass casualty events (8). Both doxycycline and ciprofloxacin are recommended for both adults and children. Doxycycline dosing is 100 mg orally twice daily for adults and 2.2 mg/kg orally twice daily for children under 45 kg. Ciprofloxacin dosing is 500 mg orally twice daily for adults and 15 mg/kg orally twice a day for children. Treatment should continue for 14 days.
Methods of postexposure prophylaxis have been recommended for large-scale tularemia attacks. A study in the 1960s found human volunteers treated with tetracycline for 24 hours prior to aerosolized tularemia exposure were protected from disease (18). In the event of a known tularemia attack before the mass outbreak of symptoms, postexposure prophylaxis with doxycycline or ciprofloxacin should be administered to potential victims. In the event of an attack that is not apparent until patients begin manifesting signs and
symptoms of tularemia, asymptomatic patients within the attack area should begin a fever watch and begin postexposure prophylaxis if fever develops (8).
symptoms of tularemia, asymptomatic patients within the attack area should begin a fever watch and begin postexposure prophylaxis if fever develops (8).
TRIAGE CONSIDERATIONS
Because there has never been a reported case of tularemia spread between humans, no specific isolation is required for patients in whom this diagnosis is suspected. In the event of a mass casualty event, priority should be given to those patients with more severe respiratory signs and symptoms such as hypoxia, tachypnea, and respiratory failure. These patients may require immediate advanced airway interventions. The larger remainder of ambulatory patients with symptoms of pneumonia should be triaged based on acuity and comorbid factors. Children and the elderly may develop disease in a more rapid and severe fashion.
PERSONAL PROTECTION
Universal precautions should be observed for patients with suspected tularemia. A 0.5% hypochlorite solution can be used to sanitize bedding and surfaces contacted by patients with tularemia (19). Although no human-to-human transmission has been reported, the high virulence of tularemia in culture requires extreme caution for laboratory workers. Highly trained personnel should perform cultures in a specially equipped reference laboratory. Laboratory workers should wear impervious face masks, gloves, and gowns under negative-pressure microbiological cabinets (12).
Vaccination against tularemia was initiated in the 1930s in the former Soviet Union in endemic areas (20). A live attenuated vaccine has been used in a limited setting among high-risk personnel such as laboratory technicians in the United States. Use of this vaccine is currently under review by the Food and Drug Administration. The Department of Defense maintains this vaccine as an investigational new drug at the U.S. Army Medical Research and Material Command at Fort Detrick, Maryland (13).
SUMMARY
Tularemia is an effective bioweapon due to its virulence, high morbidity and mortality, and ease of storage, transport, and dispersion by aerosol.
Although tularemia causes multiple clinical syndromes, a primarily respiratory disease would result from a bioterrorist attack via aerosolized particles.
Aminoglycosides, specifically streptomycin, are the treatments of choice for tularemia. In mass casualty events, oral doxycycline and ciprofloxacin should be used.
Q FEVER
Q fever is a febrile illness originally described in 1935 as Query fever prior to the discovery of the infectious agent Coxiella burnetii. This obligate intracellular, gram-negative coccobacillus has a worldwide zoonotic reservoir. The organism is located within the acidified phagolysosomes of eukaryotic cells and may sporulate in the presence of unfavorable environmental conditions.
THEORETICAL AND SCIENTIFIC BACKGROUND
An illness initially discovered during an outbreak among abattoir workers in Australia, Q fever remains a disease found primarily among persons in contact with infected livestock. Its zoonotic reservoir is broad, infecting mammals, birds, and arthropods. Arthropod carriage is thought to be an important source for enzoonotic transmission but not human infection (19). Cattle, sheep, and goats are the most common sources of human infection. The bacteria are concentrated in the placenta of mammals and may be shed in milk, urine, and feces. Inhalation of a single aerosolized bacterium may be sufficient to cause human infection. This respiratory route is the primary mode of transmission. Due to high concentration of organisms in birth products, persons in contact with parturient animals are at particularly high risk for contracting the disease. C. burnetii has a marked ability to resist heat and desiccation, and locations at which parturition occur may contain infective particles for weeks. Although less common, infection may also occur through ingestion of raw milk products, requiring a significantly larger inoculum (21). Human-to-human transmission is regarded as rare but has been reported in cases of blood transfusion, transplacental congenital infection, upon autopsy of infected cadavers, and by a case report of an obstetrician becoming infected while performing a therapeutic abortion on an infected woman (21). Sexual transmission has been demonstrated in the murine model and was recently reported in the case of an occupationally exposed man potentially transmitting the bacterium to his wife (22). The organism’s potential infectivity is furthered by the ability to travel long distances windborne or upon contaminated fomites. Downwind reach of C. burnetii in a hypothetical biological attack is estimated to be 20 km (4).
Once infected, most often via the aerosol route, the organism replicates during a 1- to 6-week incubation period (19,21,23). Late in this phase, a transient bacteremia ensues, providing the opportunity for hematogenous seeding of multiple organ systems. Infection with C. burnetii may be asymptomatic in over 50% of cases (19,21). Acute Q fever is typically a self-limited, febrile illness. However it may also present as atypical pneumonia, hepatitis, myocarditis, pericarditis, or encephalitis. Mortality rates of untreated acute Q fever are 1% to 2% with mortality rates in treated patients being less than 1% (21). A
chronic form of Q fever may ensue and is most commonly characterized by endocarditis and/or chronic granulomatous hepatitis. Persons with underlying cardiac valvular abnormalities and various immunodeficiencies are most susceptible to developing chronic Q fever.
chronic form of Q fever may ensue and is most commonly characterized by endocarditis and/or chronic granulomatous hepatitis. Persons with underlying cardiac valvular abnormalities and various immunodeficiencies are most susceptible to developing chronic Q fever.
The prevalence of acute Q fever is difficult to assess and varies dramatically worldwide. It is unclear whether this reflects actual difference in the number of cases, discrepancy in the level of physician awareness, a lack of diagnostic capabilities, or a combination of these factors. Annual incidence in the United States is reported as 20, with an unknown incidence worldwide (19).
C. burnetii has long been recognized as a potential biological agent, as evident by testing that began in the 1950s at Fort Detrick by the U.S. War Reserve Service (4). This microbe was maintained in the U.S. biological arsenal prior to the destruction of such materials in the early 1970s. More recently, the Japanese cult responsible for the March 1995 sarin attack of a Tokyo subway was found to be experimenting with several biological agents, including C. burnetii. This agent’s utility in bioterrorist attacks is enhanced by high infectivity, expansive windborne reach, and its ability to resist unfavorable conditions. However, it is limited as a biological agent due to its prolonged and varied incubation period, the relatively low morbidity and mortality, and the near absence of person-to-person transmission.
SIGNS AND SYMPTOMS
Acute Q fever most commonly presents as a nonspecific febrile illness characterized by an acute onset of headache, fatigue, myalgias, fever, and chills. Another common and often misdiagnosed presentation is atypical pneumonia, which can range from an incidental finding on chest radiograph to, rarely, acute respiratory distress. Clinically evident hepatitis occurs in up to one-third of patients with acute Q fever and may be accompanied by nausea and vomiting, but it is rarely associated with abdominal pain, jaundice, or marked hepatic dysfunction (19,24). Additionally, it has become increasingly recognized that Q fever may be associated with various exanthems, including pink macules and purpura. Physical examination is often unrevealing but may be notable for inspiratory crackles, hepatomegaly, or splenomegaly, in addition to fever and cutaneous findings. The combination of fever, pneumonia, and acute hepatitis should alert the physician to the possibility of acute Q fever.
MEDICAL MANAGEMENT
Often the presentation of acute Q fever resembles that of other pneumonias or viral syndromes. Initial diagnostic evaluations may yield nonspecific results. A normal white blood cell count is found in the majority of patients. However, increased transaminase levels and an elevated erythrocyte sedimentation rate are present in over half of those presenting with acute Q fever (21,23,24). Thrombocytopenia and increased serum creatinine are present in a small fraction of patients. Chest radiographs may be consistent with atypical pneumonia, with increased reticular markings, multiple opacities, atelectasis, or pleural effusion. C. burnetii remains difficult to culture, and diagnosis requires serological tests with subsequent comparison between acute and convalescent phase sera. The diagnostic examinations of choice are indirect immunofluorescence (IFA) and enzyme-linked immunosorbent assay (ELISA).
Diagnosis of Q fever resulting from a bioterrorist attack may prove challenging for physicians. The prolonged incubation time and diverse, often nonspecific, symptoms contribute to the potential difficulty in diagnosis. An increasing number of otherwise healthy persons with a similar constellation of symptoms may allow the physician to consider a common exposure to C. burnetii.
Acute Q fever is often a self-limited disease that resolves without the administration of antimicrobial agents. However, a 5- to 7-day course of tetracycline (500 mg orally every 6 hours) or doxycycline (100 mg orally every 12 hours) is recommended as first-line therapy in order to reduce the rate of complications and the duration of illness. Fluoroquinilones may serve as an alternative in the case of meningoencephalitic disease or tetracycline intolerance (19,21).
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