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Biological diseases and the agents that might be used for terrorism have been divided into three categories by the US Centers for Disease Control and Prevention (the CDC):
These agents/diseases include: Coxiella burnetti (Q fever), Brucella species (
brucellosis), Burkholderia mallei (glanders
), ricin toxin from Ricinus communis (castor beans), the epsilon toxin of Clostridium perfringens
, and Staphylococcus
enterotoxin B.
Category C Biological Disease:
-- Third highest priority agents include emerging pathogens that could be engineered for mass dissemination in the future because of
- availability;
- ease of production and dissemination; and
- potential for high morbidity and mortality and major health impact.
These agents/diseases include: Nipah virus, the hantaviruses, the tickborne hemorrhagic fever viruses, the tickborne encephalitis viruses, yellow fever, and
multidrug-resistant tuberculosis.
Biological Warfare Agents by Daniel J Dire, MD, FACEP, COL, MC, USAR, USAWC Senior Service Fellow, Center for Strategic Analysis, University of Texas at Austin
HISTORIC ASPECTS OF BIOLOGICAL WARFARE AGENTS
Biological agents are easy to
acquire, synthesize, and use. The small amount of agents necessary to kill hundreds of thousands of people in a metropolitan area make the concealment, transportation, and dissemination of biological agents relatively
easy. In addition, BW agents are difficult to detect or protect against; they are invisible, odorless, tasteless, and their dispersal can be performed silently. Dissemination of BW agents may occur by aerosol sprays, explosives (artillery, missiles, detonated bombs), or food or water contamination. Variables that can alter the
effectiveness of a delivery system include particle size of the agent, stability of the agent under desiccating conditions, UV light, wind speed, wind direction, and atmospheric stability.The use of an explosive
device to deliver and disseminate biological agents is not very effective, since such agents tend to be inactivated by the blast. Contamination of municipal water supplies requires an unrealistically large amount of
agent and introduction into the water after it passes through a regional treatment facility. To be an effective biological weapon, airborne pathogens must be dispersed as fine particles less than 5
mm in size. Infection with an aerosolized agent usually requires deep inspiration of an infectious dose. Advanced weapons
systems (eg, warheads, missiles) are not required for the aerosolized delivery of biological agents. Low-technology aerosolization methods including agricultural crop-dusters; aerosol generators on small boats, trucks,
or cars; backpack sprayers; and even purse-size perfume atomizers suffice. Aerosolized dispersal of biological agents is the mode most likely to be used by terrorists and military groups.Detection of biological
agents involves either finding the agent in the environment or medical diagnosis of the agent's effect on human or animal victims. Early detection of a biological agent in the environment allows for early specific
treatment and time during which prophylaxis would be effective. Unfortunately, currently no reliable detection systems exist for BW agents. The US Department of Defense has placed a high priority on research and
development of a detector system. Methods are being developed and tested to detect a biological aerosol cloud using an airborne pulsed laser system to scan the lower altitudes upwind from a possible target area. A
detection system mounted on a vehicle also is being developed. This system will analyze air samples to provide a plot of particle sizes, detect and classify bacterial cells, and measure DNA content, ATP content, and
identify agents using immunoassays. A BW agent attack is likely to be covert. Thus, detection of such an attack requires recognition of the clinical syndromes associated with various BW agents. Physicians must be
able to identify early victims and recognize patterns of disease. This requires integrated epidemiologic surveillance systems performing real-time monitoring with information shared at many levels of the health care
system (eg, ED to ED or ED to public health officials). Preliminary criteria for suspicious outbreaks of disease that could provide indications of a possible biological weapons event include the following: · Disease (or strain) not endemic · Unusual antibiotic resistance patterns ·
Atypical clinical presentation · Case distribution geographically and/or temporally
inconsistent (eg, compressed time course) · Other inconstant elements (eg, number of cases,
mortality and morbidity rates, deviations from disease occurrence baseline) Indications of possible BW agent attack include the following:
- Disease entity that is unusual or that does not occur naturally in a given geographical area or combinations of unusual disease entities in the same patient population
- Multiple disease entities in the same patients, indicating that mixed agents have been used in the attack
- Large numbers of both military and civilian casualties when such populations inhabit the same area
- Data suggesting a massive point-source outbreak
- Apparent aerosol route of infection
- High morbidity and mortality relative to the number of personnel at risk
- Illness limited to fairly localized or circumscribed geographic areas
- Low attack rates in personnel who work in areas with filtered air supplies or closed ventilation systems
- Sentinel dead animals of multiple species
- Absence of a competent natural vector in the area of outbreak (for a biological agent that is vector-borne in nature)
PROTECTIVE MEASURES
Protective measures can be taken against BW agents. These should be implemented early (if warning is received) or later (once suspicion of BW agent use is made).
Currently, available masks such as the military gas mask or high-efficiency particulate air (HEPA) filter masks used for tuberculosis (TB) exposure filter out most BW particles delivered by aerosol. Multilayered HEPA
masks can filter 99.9% of 1-5 mm particles, but face-seal leaks may reduce the efficacy by as much as 10-20%.
Individual face-fit testing is required to correct seal leak problems.Most aerosolized biological agents do not penetrate unbroken skin, and few organisms adhere to skin or clothing. After an aerosol attack, simple
removal of clothing eliminates a great majority of surface contamination. Thorough showering with soap and water removes 99.99% of the few organisms left on the victim's skin after disrobing. The use of sodium
hypochlorite is not recommended over soap and water. The use of special suits by health care providers is not necessary. Normal clothing provides a reasonable degree of protection against dermal exposure. Latex gloves
and universal precautions provide sufficient protection when treating most infected patients. Place patients in a private negative-pressure room and practice proper sanitation with universal precautions. Proper disposal
of corpses is essential. In the case of anthrax spores, this should be performed by incineration. Of the potential BW agents, only plague, smallpox, and viral hemorrhagic fevers are spread readily person to person by
aerosol and require more than standard infection control precautions (gown, mask with eye shield, gloves). Regardless, place all potential victims of BW agents in isolation. Medical personnel caring for these patients
should wear a HEPA mask in addition to standard precautions pending the results of a more complete evaluation. Broad-spectrum intravenous antibiotic coverage is recommended initially for victims when a BW agent is
suspected. Institute this even prior to the identification of the specific BW agent. Vaccinations currently are available for anthrax, botulinum toxin, tularemia, plague, Q fever, and smallpox. The widespread
immunization of nonmilitary personnel has not been recommended by any governmental agency. Immune protection against ricin and staphylococcal toxins may be feasible in the near future. ANTHRAX INTRODUCTION
Bacillus anthracis
is a large, aerobic, gram-positive, spore forming, nonmotile bacillus. The bacterium ordinarily produces a zoonotic disease in domesticated and wild animals such as goats, sheep, cattle, horses, and swine. Humans become infected by contact with infected animals or contaminated animal products. Infection occurs predominantly through the cutaneous route and only rarely via the respiratory or gastrointestinal (GI) route.
Anthrax occurs worldwide. The organism exists in the soil as a spore. The form of the organism in infected animals is the bacillus. Sporulation occurs only when the organism in the carcass is exposed to air. The
true incidence of human anthrax is unknown. Reporting of illness has been unreliable. In 1958, an estimated 20,000-100,000 cases occurred worldwide. In the US, the annual incidence of human anthrax has declined steadily
from approximately 127 cases in the early years of this century to approximately 1 per year for the past 10 years. PATHOPHYSIOLOGY - ANTHRAX
B anthracis
possesses 3 known virulence factors, an antiphagocytic capsule and 2 protein exotoxins (lethal and edema toxin). The role of the capsule in pathogenesis was demonstrated in the early 1900s when anthrax strains, lacking a capsule, were demonstrated to be virulent. In more recent years, the genes encoding synthesis of the capsule were found to be encoded on a 110-kilobase plasmid. The capsule is composed of a polymer of poly-D-glutamic acid, which confers resistance to phagocytosis and may contribute to the resistance of anthrax to lysis by serum cationic proteins.
The anthrax toxins, like many bacterial and plant toxins, possess the following 2 components: a cell binding B-domain and an active A-domain. The A-domain confers enzymatic activity and toxicity. Edema toxin, which
consists of the same protective antigen together with a third protein, edema factor, causes edema when injected into the skin of experimental animals. Infection begins when the spores are inoculated through skin or
mucosa. It is believed that spores are ingested locally by tissue macrophages. Subsequently, spores germinate within macrophages to the vegetative bacilli, which produce capsules and toxins. Bacteria proliferate at
these tissue sites and produce the edema and lethal toxins that impair host leukocyte function and lead to the following distinctive and pathologic findings: edema, hemorrhage, tissue necrosis, and a relative lack of
leukocytes. In inhalation anthrax, the spores are ingested by alveolar macrophages, which transport them to the regional tracheobronchial lymph nodes, where germination occurs. Once in the tracheobronchial lymph
nodes, the local production of toxins by extracellular bacilli gives rise to the characteristic pathologic picture of massive hemorrhagic, edematous, and necrotizing lymphadenitis and mediastinitis. The bacillus then
can spread to the blood, leading to septicemia and frequently causing hemorrhagic meningitis. Death results from respiratory failure, overwhelming bacteremia, septic shock, and meningitis.
CLINICAL FEATURES - ANTHRAX
Cutaneous: More than 95% of cases of anthrax are cutaneous. After inoculation, the incubation period is 1-5 days. The disease first appears as a small papule that progresses
over 1-2 days to a vesicle containing serosanguinous fluid with many organisms and a paucity of leukocytes. This often has been referred to as a malignant pustule; however, this is a misnomer because no pustular lesions
are found in anthrax patients. The vesicle ruptures, leaving a necrotic ulcer. The lesion usually is painless, and varying degrees of edema may be present around it. The edema occasionally may be massive, encompassing
the entire face or limb, and is described as malignant edema. Patients generally experience fever, malaise, and headache, which may be severe in those with extensive edema. Local lymphadenitis also may be present. The
ulcerbase develops a characteristic 1-5 cm black eschar. (The black appearance of the eschar gives anthrax its name [Greek anthrakos
= coal].) After a period of 2-3 weeks, the eschar separates, often leaving a scar. Septicemia is rare. Mortality should be less than 1% with adequate treatment. Inhalation: Also known as woolsorter's disease, inhalation anthrax has a typical incubation period of 1-6 days, but a latent period as long as 60 days has been described.
Initial manifestations are nonspecific and include headache, malaise, fatigue, myalgia, and fever. Associated nonproductive cough and mild chest discomfort may occur. These symptoms usually persist for 2-3 days, and in
some patients a short period of improvement may occur. This is followed by the sudden onset of increasing respiratory distress with dyspnea, stridor, cyanosis, increased chest pain, and diaphoresis. Associated edema of
the chest and neck may be present. Chest x-ray usually shows the characteristic widening of the mediastinum and often, pleural effusion. Pneumonia is an uncommon finding. The onset of respiratory distress is followed by
the rapid onset of shock and death within 24-36 hours. Mortality is nearly 100% despite appropriate treatment. Inhalation anthrax is the most likely form of disease to follow military or terrorist attack. Such an attack
likely will involve the aerosolized delivery of anthrax spores. Oropharyngeal and gastrointestinal: These result
from the ingestion of infected meat that has not been cooked sufficiently. After an incubation period of 2-5 days, patients with oropharyngeal disease present with severe sore throat or a local oral or tonsillar ulcer,
usually associated with fever, toxicity, and swelling of the neck due to cervical or submandibular lymphadenitis or edema. Dysphagia and respiratory distress also may be present. GI anthrax begins with nonspecific
symptoms of nausea, vomiting, and fever. These are followed in most patients by severe abdominal pain. The presenting sign may be an acute abdomen, which may be associated with hematemesis, massive ascites, and
diarrhea. Mortality in both forms may be as high as 50%, especially in the GI form.Meningitis: This may occur following bacteremia as a complication of any of the other clinical forms. Meningitis
also may occur, rarely, without any of the other clinical forms of the disease. It often is hemorrhagic and almost invariably fatal. DIAGNOSIS - ANTHRAX
The most critical aspect in making a
diagnosis is a high index of suspicion associated with a compatible history of exposure. Consider cutaneous anthrax following the development of a painless, pruritic papule, vesicle, or ulcer. This area often is
associated with surrounding edema that develops into a black eschar. With extensive or massive edema, such a lesion is almost pathognomonic. Gram stain or culture of the lesion confirms the diagnosis. The differential
diagnosis should include tularemia and staphylococcal or streptococcal species. The diagnosis of inhalation anthrax is extremely difficult, but suspect the disease with a history of exposure to a
B anthracis-containing aerosol. Early symptoms are entirely nonspecific. The development of respiratory distress in association with radiographic evidence of a widened mediastinum due to hemorrhagic mediastinitis
and the presence of hemorrhagic pleural effusions or hemorrhagic meningitis should suggest the diagnosis. Sputum Gram stain and culture usually are not helpful, since pneumonia is an uncommon feature of illness. Gram
stain of peripheral blood may be positive for gram-positive bacilli and should be performed. GI anthrax also is exceedingly difficult to diagnose because of the rarity of the disease and nonspecific symptoms.
Diagnosis usually is confirmed only with a history of ingesting contaminated meat in the setting of an outbreak. Once again, cultures generally are not helpful in making the diagnosis. Meningitis from anthrax is
clinically indistinguishable from meningitis due to other etiologies. A distinguishing feature is that the spinal fluid is hemorrhagic in as many as 50% of patients. The diagnosis can be confirmed by identifying the
organism in the spinal fluid by microscopy, culture, or both. Serology can be used to make a retrospective diagnosis. Antibody develops in 68-93% of reported cases of cutaneous anthrax and 67-94% of reported cases of
oropharyngeal anthrax. A positive skin test to anthracin also has been used to make a retrospective diagnosis of anthrax. The most useful microbiologic test is the standard blood culture, which is almost
always positive in patients with systemic illness. Blood cultures should show growth in 6-24 hours. If the laboratory has been alerted to the possibility of anthrax, biochemical testing and review of colonial morphology
should provide a preliminary diagnosis 12-24 hours later. However, if the laboratory has not been alerted to the possibility of anthrax, B anthracis may not be identified correctly.
New rapid diagnostic tests for B anthracis
and its proteins include polymerase chain reaction (PCR), enzyme-linked immunoassay (ELISA), and direct fluorescent antibody (DFA) testing. Currently, these tests are only available at national reference laboratories.
TREATMENT - ANTHRAX A number of possible therapeutic strategies have yet to be fully explored experimentally or submitted for approval to the Food and Drug Administration (FDA). The
recommendations provided do not represent uses currently approved by the FDA but are a consensus based on best available information of recent studies. Given the fulminant course of inhalation anthrax, early
antibiotic administration is essential to maximize patient survival. Given the difficulty in achieving timely microbiologic diagnosis of anthrax, all persons with fever or evidence of systemic disease in an area where
anthrax cases are occurring should be treated empirically for anthrax until the disease is excluded. No clinical studies exist of the treatment of inhalation anthrax in humans. Most naturally occurring strains of
anthrax are sensitive to penicillin, and penicillin historically has been the preferred therapy for the treatment of anthrax. Penicillin and doxycycline are FDA-approved antibiotics for anthrax. Doxycycline is the
preferred option from the tetracycline class of antibiotics because of its proven efficacy in monkey studies. Experts currently recommend initiation of ciprofloxacin or other fluoroquinolones in adults with presumed
inhalation anthrax infection. Following a terrorist attack, assume resistance to penicillin and tetracycline class antibiotics until laboratory testing demonstrates otherwise. In a contained casualty setting (a
situation in which a modest number of patients require therapy), initiate intravenous antibiotics for symptomatic patients. In adults, ciprofloxacin 400 mg IV q12h is recommended. Traditionally, ciprofloxacin and other
fluoroquinolones are not recommended for use in children younger than 16-18 years because of a link to permanent arthropathy in adolescent animals and transient arthropathy in a small number of children.
Balancing these small risks against the real risk of death and resistant strains of B anthracis, experts recommend that ciprofloxacin be given to a pediatric population for initial therapy or postexposure
prophylaxis following anthrax attack. In children, ciprofloxacin at 20-30 mg/kg/d IV in 2 daily doses (not to exceed 10 g/d) is recommended. If antibiotic susceptibility testing allows, substitute intravenous penicillin
for the fluoroquinolones. For adults and children older than 12 years, penicillin G at 4 million U IV q4h is recommended for 60 days. Doxycycline at 100 mg IV q12h for 60 days is an acceptable alternative for adults.
For children younger than 12 years, penicillin G is dosed 50,000 U/kg IV q6h for 60 days. In experimental models, antibiotic therapy during anthrax infection has prevented development of an immune response. This
suggests that even if the antibiotic-treated patient survives anthrax infection, risk of recurrence remains for at least 60 days. Oral therapy should replace intravenous therapy as soon as a patient's clinical condition
improves. Historically, the treatment of cutaneous anthrax has been oral penicillin. Recent recommendations suggest that oral fluoroquinolones or tetracycline antibiotics, as well as amoxicillin, are suitable
alternatives if antibiotic susceptibility is proven. Although previous guidelines have suggested treating cutaneous anthrax with 7-10 days of therapy, recent recommendations suggest treatment for 60 days in the setting
of bioterrorism, given the presumed exposure to the primary aerosol. Treatment of cutaneous anthrax generally prevents progression to systemic disease, although it does not prevent the formation and evolution of the
eschar. Other antibiotics effective against B anthracis
in vitro include chloramphenicol, erythromycin, clindamycin, extended spectrum penicillins, macrolides, aminoglycosides, vancomycin, cefazolin, and other first-generation cephalosporins. In pregnant women, experts
recommend that ciprofloxacin be given for therapy and postexposure prophylaxis following anthrax attack. Substitute intravenous penicillin for the fluoroquinolones if microbiologic testing confirms penicillin
susceptibility. PREVENTION/PROPHYLAXIS-ANTHRAX No FDA-approved chemoprophylactic regimens are available following exposure to an anthrax aerosol. For postexposure prophylaxis,
experts recommend the same oral regimen as that recommended for treatment of mass casualties. For adults, administer ciprofloxacin 500 mg PO bid for 60 days. Ciprofloxacin may be changed to amoxicillin at 500 mg PO tid
or doxycycline 100 mg PO bid for 60 days if microbiologic testing confirms such antibiotic susceptibility. In children, administer ciprofloxacin at 20-30 mg/kg/d PO taken twice daily (not to exceed 1 g/d) for 60 days.
If the strain is susceptible to penicillins and patient weight is greater than 20 kg, amoxicillin may be given at 500 mg PO tid. For a child who weighs less than 20 kg, amoxicillin is administered at 40 mg/kg/d divided
tid for 60 days. A licensed vaccine, an aluminum hydroxide-absorbed preparation, is derived from culture fluid supernatant taken from an attenuated strain. The vaccination series consists of 6 subcutaneous doses at 0,
2, and 4 weeks, then at 6, 12, and 18 months, followed by annual boosters. Insufficient data are available regarding efficacy against inhalation anthrax in humans, although studies in rhesus monkeys indicate that it is
protective. If information indicates that a BW attack is imminent or may have occurred, prophylaxis of unimmunized individuals with ciprofloxacin (500 mg PO bid) or doxycycline (100 mg PO bid) is recommended. Initiate
the vaccination series for unimmunized individuals. Should an anthrax attack be confirmed, continue chemoprophylaxis for at least 4 weeks and until all those exposed receive 3 doses of vaccine (at 0, 2, and 4 wk). PLAGUE INTRODUCTION
Plague is a zoonotic infection caused by Yersinia pestis, a gram-negative coccobacillus, which has been the cause of 3 great human
pandemics in the Common Era, in the 6th, 14th, and 20th centuries. Throughout history, the oriental rat flea (Xenopsylla cheopis) has been largely responsible for spreading bubonic plague. After the flea ingests
a blood meal on a bacteremic animal, bacilli can multiply and essentially block the flea's foregut with a fibrinoid mass of bacteria. When an infected flea with a blocked foregut attempts to feed again, it regurgitates
clotted blood and bacteria into the victim's blood stream and so passes the infection onto the next victim, whether rat or human. As many as 24,000 organisms may be inoculated into the host.
Although the largest outbreaks of plague have been associated with X cheopis, all fleas should be considered dangerous in plague-endemic areas. The most important vector in the US is Diamanus montanus, the
most common flea of rock squirrels and California ground squirrels. The black rat, Rattus rattus, has been most responsible worldwide for the persistence and spread of plague in urban epidemics. Plague is
characterized by the abrupt onset of high fevers, painful lymphadenopathy, and bacteremia. Septicemic plague sometimes can ensue from untreated bubonic plague or, de novo, after a flea bite. Patients with the bubonic
form of the disease may develop secondary pneumonic plague. This complication can lead to human-to-human spread by the respiratory route and cause primary pneumonic plague. Pneumonic plague is the most severe form of
disease and, untreated, has a mortality rate approaching 100%. Mortality from endemic plague continues at low rates throughout the world despite the availability of effective antibiotics. People continue to die of
plague, not because the bacilli have become resistant but, most often, because physicians do not include plague in their differential diagnosis, and treatment is delayed. PATHOPHYSIOLOGY - PLAGUE
Y pestis is a gram-negative, nonacid-fast, nonmotile, nonsporulating coccobacillus. Its bipolar appearance is best appreciated when Wright-Giemsa, Wayson, or Gram stains are used. Y pestis
grows optimally at 28 °C. Biochemically, the plague bacillus produces no hemolysins; is positive for catalase;
and is negative for hydrogen sulfide, oxidase, and urease.The known virulence factors of Y pestis
are encoded on the chromosomes of its 3 plasmids. The pH6 antigen, a protein located on the surface of the bacterium, is necessary for complete virulence. It is induced in vivo at sites of inflammation and cellular necrosis and within phagocytic cells. The low calcium response (LCR) plasmid, which is homologous in
Y pestis and the other 2 Yersinia pathogens, Yersinia pseudotuberculosis and Yersinia enterocolitica, codes for several secreted proteins and is also necessary for virulence.
As few as 1-10 organisms of Y pestis are sufficient to infect rodents and primates via the oral, intradermal, subcutaneous, or intravenous routes. After
being introduced into the mammalian host by a flea, the organism is thought to be susceptible initially to phagocytosis and killing by neutrophils. However, some of the bacteria
may grow and proliferate within tissue macrophages. Within the human host, several environmental signals (temperature of 37°C, contact with eukaryotic cells, location within mononuclear cells, pH) are thought to induce the synthesis and activity of a multitude of factors that contribute to virulence.
Bacteria become resistant to phagocytosis and proliferate unimpeded extracellularly. During the incubation phase, the bacilli most commonly spread to
regional lymph nodes, where supportive lymphadenitis develops, producing the characteristic bubo. Dissemination from the local site is thought to be related to the action of both plasminogen activator and Yop M.
Infection progresses if untreated; septicemia develops, and the infection spreads to other organs. The endotoxin probably contributes to the development of septic shock, which is similar to the shock states observed
with other causes of gram-negative sepsis. Tissues most commonly infected include the spleen, liver, lungs, skin, and mucous membranes. Late infection of the meninges also occurs, especially if suboptimal antibiotic
therapy has been administered. Primary pneumonic plague, the most severe form of the disease, arises from inhalation of an infectious aerosol. Primary pneumonic plague is more rapidly fatal than the secondary form,
because the inhaled droplets already contain phagocytosis-resistant bacilli, which have arisen from their growth in the vertebrate host. Primary septicemia plague can arise from direct inoculation of bacilli into the
bloodstream, bypassing initial multiplication in the lymph nodes. CLINICAL FEATURES - PLAGUE In the US, most patients (85-90%) with human plague present clinically with the
bubonic form, 10-15% with the primary septicemia form, and 1% with the pneumonic form. Secondary septicemic plague occurs in 23% of patients who present with bubonic plague, and secondary pneumonic plague occurs in 9%.
If Y pestis
were used as a BW agent, it most likely would be inhaled as an infectious aerosol and result in primary pneumonic plague (epidemic pneumonia). If fleas were used as carriers of disease, bubonic or septicemic plague would result.
Bubonic plague:
Buboes manifest after a 1- to 8-day incubation period. Their appearance is associated with the onset of sudden fever, chills, and headache, which often are followed by nausea and vomiting several hours later. Presenting symptoms include severe malaise (75%), headache (20-85%), vomiting (25-49%), chills (40%), altered mentation (26-38%), cough (25%), abdominal pain (19%), and chest pain (13%). Buboes occur in the groin (90% femoral, more frequent femoral than inguinal), axillary, or cervical regions, depending on the site of inoculation, 6-8 hours after the onset of symptoms. Buboes become visible within 24 hours and are characterized by severe pain. Untreated, septicemia develops in 2-6 days. Approximately 5-15% of bubonic plague patients develop secondary pneumonic plague and thus the ability to spread illness from person to person by respiratory droplets.
Septicemia plague:
Septicemia plague may occur primarily or secondarily as a result of hematogenous dissemination of bubonic plague. Presenting signs and symptoms of primary septicemic plague are essentially the same as those for any gram-negative septicemia and include fever, chills, nausea, vomiting, and diarrhea; later, purpura, disseminated intravascular coagulation (DIC), and acrocyanosis and necrosis occur.
Pneumonic plague:
Pneumonic plague may occur primarily from inhalation of aerosols or secondarily from hematogenous dissemination. Patients typically have a productive cough with blood-tinged sputum within 24 hours of symptom onset. The findings on chest x-ray are variable, but bilateral alveolar infiltrates appear to be the most common findings in pneumonic plague.
Plague meningitis:
This is observed in 6-7% of patients. The condition manifests itself most often in children after 9-14 days of ineffective treatment. Symptoms are similar to those of other forms of acute bacterial meningitis. DIAGNOSIS - PLAGUE The diagnosis of bubonic plague should be made readily on clinical grounds if a patient presents with a painful bubo, fever, prostration, and history of exposure
to rodents or fleas in an endemic area. However, if the patient presents in a nonendemic area or without a bubo, then the diagnosis can be difficult to make. When a bubo is present, the differential diagnosis should
include tularemia, cat scratch disease, lymphogranuloma venereum, chancroid, TB, streptococcal adenitis, and scrub typhus. The differential diagnosis of septicemic plague also includes meningococcemia,
gram-negative sepsis, and rickettsioses. A presentation of systemic toxicity, a productive cough, and bloody sputum suggests a large differential diagnosis. However, demonstration of gram-negative coccobacilli in the
sputum readily should suggest the correct diagnosis, because Y pestis
is perhaps the only gram-negative bacterium that can cause extensive, fulminant pneumonia with bloody sputum in an otherwise healthy, immunocompetent host. In addition, Y pestis
has unique bipolar, safety-pin morphology. In patients with lymphadenopathy, perform a bubo aspiration. Air-dry the aspirate on a slide for Gram, Wright-Giemsa, or Wayson stain. If available, obtain a DFA
stain of the aspirate for the presence of Y pestis capsular antigen. A positive DFA is more specific for Y pestis than the other stains listed. Perform cultures of blood, bubo aspirate, sputum, and
cerebrospinal fluid (CSF). Tiny 1- to 3-mm beaten copper colonies appear on blood agar in 48 hours. It is important to remember that colonies may be negative at 24 hours. Complete blood counts (CBCs) often reveal
leukocytosis with a left shift. Platelet counts may be normal or low, and activated partial thromboplastin times (aPTTs) may be increased. When DIC is present, fibrin degradation products are elevated. Because of liver
involvement, alanine aminotransferase, aspartate aminotransferase, and bilirubin levels may be increased. Most naturally occurring strains of Y pestis
produce an F1-antigen in vivo, which can be detected in serum samples by immunoassay. Because fractional antigen and antibody do not occur early in the infection, perform titers for both on several sequential blood specimens. A four-fold rise in antibody titer in patient serum is retrospectively diagnostic.
TREATMENT - PLAGUE Isolate patients with plague for the first 48 hours after treatment initiation. If pneumonic plague is present, continue isolation for 4 days. Since l948,
streptomycin has been the treatment of choice for bubonic, septicemic, and pneumonic plague. Administer it in a dose of 30 mg/kg/d IM divided bid. In patients with meningitis or hemodynamic instability, add intravenous
chloramphenicol (50-75 mg/kg/d) divided qid. Gentamicin has had much less clinical usage but can be used as an alternative to streptomycin. Continue treatment for a minimum of 10 days or 3-4 days after clinical
recovery. In patients with very mild bubonic plague who are not septic, tetracycline can be used orally at a dose of 2 g/d divided qid for 10 days. Doxycycline, ofloxacin, and ceftriaxone have been demonstrated to be
effective in animal models. In pregnant women, use streptomycin or gentamicin unless chloramphenicol specifically is indicated. Streptomycin is also the treatment of choice for newborns. If treated with antibiotics,
buboes typically recede in 10-14 days and do not require drainage. Patients are unlikely to survive primary pneumonic plague if antibiotic therapy is not initiated within 18 hours of symptom onset. Without treatment,
mortality is 60% for bubonic plague and 100% for the pneumonic and septicemic forms. PREVENTION/PROPHYLAXIS - PLAGUE All plague control measures must include insecticide use,
public education, and reduction of rodent populations with chemicals such as cholecalciferol. Fleas always must be targeted before rodents, because killing rodents may release massive amounts of infected fleas. Treat
contacts of patients with pneumonic plague and individuals who have been exposed to aerosols with tetracycline 15-30 mg/kg/d divided qid for 6 days. If tetracycline is not available, doxycycline 100 mg bid is an
effective alternative. Pregnant women and children younger than 8 years should receive trimethoprim/sulfamethoxazole (40 mg sulfa/kg/d) divided bid for 6 days. Contacts of patients with bubonic plague do not require
prophylactic therapy. However, administer prophylaxis to people who were in the same environment and potentially exposed to the same source of infection. In addition, previously vaccinated individuals should receive
prophylactic antibiotics if they have been exposed to a plague aerosol. Only individuals at high risk for plague should be immunized with a licensed, killed, whole cell vaccine. Vaccinate military troops
and personnel working in endemic areas, lab personnel working with Y pestis, and people who reside in enzootic or epidemic areas. While epidemiologic evidence supports the efficacy of the current vaccine against
bubonic plague, its efficacy against aerosolized Y pestis is believed to be poor. CHOLERA
INTRODUCTIONCholera is an acute and potentially severe GI disease caused by Vibrio cholerae. V cholerae
is a short, curved, motile, gram-negative, nonsporulating rod. Two serogroups (01, 0139) have been associated with cholera in humans. The 01 serotype exists as 2 biotypes, classical and El Tor. The organisms are strongly anaerobic, preferring alkaline and high-salt environments. They do not invade the intestinal mucosa but rather adhere to it. Cholera is the prototype toxigenic diarrhea, which is secretory in nature.
This agent has been investigated in the past as a biological weapon. Cholera does not spread easily from human to human; therefore, it appears that major drinking water supplies would have to be contaminated heavily
for this agent to be effective as a biological weapon. The rate of symptomatic-to-asymptomatic cases during exposures is 1:400. PATHOPHYSIOLOGY- CHOLERA All strains of
V cholerae
elaborate the same enterotoxin, a protein molecule with a molecular weight of 84,000 daltons. The entire clinical syndrome is caused by the action of the toxin on the intestinal epithelial cell. Cholera toxin causes active secretion of chloride and blocks sodium absorption in the small intestine, with the colon relatively insensitive to the toxin. The large volume of fluid produced in the upper intestine overwhelms the capacity of the lower intestine to absorb. The diarrhea is classically thin, grayish brown, and mucoid and may reach a rate of 1 L/h.
Transmission is made through direct or indirect fecal contamination of water or foods and by heavily soiled hands or utensils. All populations are susceptible, while natural resistance to infection varies. Drying easily kills the organism. It is not viable in pure water but survives up to 24 hours in sewage and as long as 6 weeks in certain types of relatively impure water containing organic matter. It can
withstand freezing for 3-4 days. It is killed readily by dry heat at 117 °C, steam and boiling, short-term
exposure to ordinary disinfectants, and chlorination of water.CLINICAL FEATURES - CHOLERA Infection generally occurs within a week of exposure and is classically of abrupt onset
following a brief nonspecific prodrome. Fever is rare. The syndrome is characterized by sudden onset of nausea and vomiting and profuse diarrhea with a classic rice water appearance. If untreated, the disease generally
lasts 1-7 days. The clinical manifestations of cholera are related to the profound fluid and electrolyte depletion that occurs. Acute treatment consists of rapid, aggressive fluid resuscitation with isotonic solutions
and potassium. Children may experience seizures caused by hypoglycemia and hypernatremia and may have potassium depletion severe enough to cause an arrhythmia. The rapid loss of body fluids often leads to toxemia and
frequent cardiovascular collapse. Mortality can range as high as 50% in untreated cases. DIAGNOSIS- CHOLERA The incubation period ranges from 12-72 hours and depends on the dose
of ingested organisms. Onset of illness usually is sudden. Initially, the disease presents with intestinal cramping and painless diarrhea. Vomiting, malaise, and headache often accompany the diarrhea, especially early
in the illness. On microscopic examination of the stool, few or no red cells, white cells, and almost no protein are found. The absence of inflammatory cells and erythrocytes reflects the noninvasive
character of V cholerae infection of the intestinal lumen. The organism can be identified in liquid stool or enrichment broths by darkfield or phase contrast microscopy and by identifying darting motile Vibrio
species. Bacteriologic diagnosis is not necessary for treatment, as it can be diagnosed clinically. TREATMENT - CHOLERA Treatment depends on replacement of fluids and
electrolyte losses. This is best accomplished using oral rehydration therapy, but intravenous fluid replacement is occasionally necessary for persistent vomiting or high rates of stool loss (10 mL/kg/h). Antibiotics
shorten the duration of diarrhea and reduce fluid losses. Tetracycline (500 mg q6h for 3 d) or doxycycline (300 mg once or 100 mg bid for 3 d) is an acceptable alternative. However, due to resistance, ciprofloxacin (500
mg q6h for 3 d) or erythromycin (40 mg/kg/d divided qid for 3 d) also has been accepted. PREVENTION/PROPHYLAXIS - CHOLERA A licensed, killed vaccine is available for use in those
considered to be at risk for exposure. The vaccine is protective for only approximately 50% of those immunized, and protection lasts for no more than 6 months. The vaccination schedule is an initial dose followed by
another dose 4 weeks later, with booster doses every 6 months. An inactivated oral vaccine (WC/rBs) is safe and provides rapid short-term protection. WC/rBs requires 2 doses and has approximately 85% efficacy lasting
2-3 years for both El Tor and classic biotypes. TULAREMIA INTRODUCTION Tularemia is a zoonosis caused by the gram-negative, facultative intracellular bacterium
Francisella tularensis. The disease is characterized by fever, localized skin or mucous membrane ulceration, regional lymphadenopathy, and occasionally pneumonia. GW McCay discovered the disease in Tulare County,
California, in 1911. The first confirmed case of human disease was reported in 1914. Edward Francis, who described transmission by deer flies via infected blood, coined the term tularemia in 1921. F tularensis
has been considered an important BW agent because of its high infectivity after aerosolization. F tularensis is a nonmotile, obligate aerobic, gram-negative coccobacillus with 2 subspecies.
F tularensis subsp tularensis is the most common in the US. F tularensis subsp palearctica
is more common outside the US. The subspecies are indistinguishable serologically, although they may be distinguished by 169 ribosomal ribonucleic acid (rRNA) analysis. A capsule has been reported to contribute to virulence. No known toxins are produced.
The principal reservoir in North America is the tick. In North America, the rabbit is the most common vertebrate associated with transmission of tularemia. In other areas of the world, tularemia is maintained in
water rats and other aquatic animals. PATHOPHYSIOLOGY - TULAREMIA F tularensis
usually is introduced into the host through breaks in the skin or through the mucous membranes of the eye, respiratory tract, or GI tract. Ten virulent organisms injected subcutaneously and 10-50 organisms given by aerosol can cause infection in humans. After inoculation,
F tularensis is ingested by and multiplies within macrophages. The host defense against F tularensis
is mediated by a T cell-independent mechanism, which appears early after infection (<3d), and a T cell-dependent mechanism, which appears later(>3 d) after infection. The role of humoral-medicated immunity and neutrophils in the host defense against
F tularensis remains unclear. CLINICAL FEATURES - TULAREMIA Tularemia can be divided into the ulceroglandular (75% of patients) and typhoidal (25% of patients) forms based
on clinical findings. Patients with ulceroglandular tularemia have lesions of the skin or mucous membranes, lymph nodes greater than 1 cm in diameter, or both. Patients with typhoidal tularemia present with lymph nodes
less than 1 cm in diameter and without skin or mucous membrane lesions. After an incubation period of 3-6 days, patients with the ulceroglandular form of the disease develop a constellation of symptoms consisting of
fever (85%), chills (57%), headache (45%), cough (38%), and myalgia (31%). Patients also may complain of chest pain, vomiting, arthralgia, sore throat, abdominal pain, diarrhea, dyspnea, back pain, or neck stiffness.
A cutaneous chancrelike ulcer occurs in approximately 60% of patients and is the most common sign of tularemia. Ulcers are generally single lesions with heaped up borders 0.4-3 cm in diameter. Lesions associated with
infection acquired from mammalian vectors usually are located on the upper extremities, whereas lesions associated with infection from arthropod vectors usually are located on the lower extremities. Enlarged lymph
nodes are seen in approximately 85% of patients and may be the initial or the only sign of infection. Although enlarged lymph nodes usually occur as single lesions, they may appear in groups. The appearance of enlarged
lymph nodes in upper or lower extremities and the correlation with the vector is the same as for ulcerative lesions. Enlarged lymph nodes may become fluctuant, drain spontaneously, or persist for as long as 3 years.
When fluctuant, they may be confused with buboes of bubonic plague. A minority of patients with typhoidal disease develop a morbilliform eruption. Pharyngitis may occur in up to 25% of patients with tularemia. On
occasion, patients with pharyngitis also may develop a retropharyngeal abscess or suppuration of regional lymph nodes. Pharyngeal ulcers may be found in patients with aerosol-induced disease. The lower respiratory
tract is involved in 47-94% of patients. Approximately 30% of patients with ulceroglandular and 80% of patients with typhoidal tularemia have pneumonia. Patients present with productive or nonproductive cough and less
commonly with pleuritic chest pain, shortness of breath, or hemoptysis. Fifty percent of patients have radiographic evidence of pneumonia, and 1% or fewer have hilar adenopathy. Pleural effusions are seen in 15% of
patients with pneumonia. DIAGNOSIS - TULAREMIA Tularemia can be diagnosed by recovery of F tularensis
in culture. Although difficult to culture, it can be recovered from blood, ulcers, sputum, conjunctival exudate, pharyngeal exudates, and gastric washings. On media containing cysteine, F tularensis
appears as small, smooth, opaque colonies after 24-48 hours of incubation at 37 °C. Identification of the
organism is made on the basis of its growth characteristics and bacterial agglutination or fluorescent stain using antiserum specific for F tularensis.Most diagnoses of tularemia are made serologically using
bacterial agglutination or ELISA. The serologic response may be blunted by the use of antibiotics and may not appear for more than 2 weeks. Patients usually do not have abnormalities in the hemoglobin, hematocrit, or
platelet count. The peripheral white blood cell count usually is elevated only mildly and often shows a lymphocytosis late in the disease. Patients may have microscopic pyuria, which may lead to erroneous diagnosis of
urinary tract infection. Some patients show mild elevations in lactic dehydrogenase, serum transaminases, and alkaline phosphatase. CSF is usually normal. TREATMENT - TULAREMIA
Patients with tularemia who do not receive appropriate antibiotic therapy may have a prolonged illness characterized by malaise, weakness, and weight loss. With appropriate therapy, tularemia has a mortality of only
1-2.5%. Streptomycin (30 mg/kg/d IM divided bid for 10-14 d) is the drug of choice for tularemia. Gentamicin (3-5 mg/kg/d parenterally for 10-14 d) is also effective. Tetracycline and chloramphenicol are effective as
well but have been associated with significant relapse rates. Although laboratory-related infections with this organism are common, human-to-human spread is unusual, and respiratory isolation is not required. PROPHYLAXIS/PREVENTION - TULAREMIA Antibiotic prophylaxis after exposure to tularemia is difficult, because the ideal drug, streptomycin, must be administered parenterally.
Tetracycline is effective after exposure to an aerosol of tularemia if administered within 24 hours of the exposure at an oral dose of 2 g/d for 14 days. A live attenuated vaccine has been developed and
used in humans since 1940. In the 1960s, a further purified derivative was introduced and called live vaccine strain (LVS). Extensive studies have demonstrated that the LVS vaccine protected humans against an aerosol
challenge with virulent F tularensis. Evidence indicates that immunization with the LVS vaccine prevents the typhoidal and ameliorates the ulceroglandular forms of tularemia. BRUCELLOSIS
INTRODUCTIONBrucellosis is a zoonotic infection of domesticated and wild animals caused by an organism of the genus Brucella. The organism infects mainly cattle, sheep,
goats, and other ruminants, causing abortion, fetal death, and genital infection. Humans, who usually are infected incidentally by contact with infected animals, may develop numerous symptoms in addition to the usual
ones of fever, malaise, and muscle pain. The disease often becomes chronic and may relapse, even with appropriate treatment. The ease of transmission by aerosol suggests that Brucella
species may be useful as a BW agent. PATHOPHYSIOLOGY - BRUCELLOSIS Brucella
species are small, nonmotile, nonsporulating, aerobic, gram-negative coccobacilli that may represent a single species. However, they are classified into 6 species. Each species has a characteristic predilection to infect certain animal species. Only
Brucella melitensis, Brucella suis, Brucella abortus, and Brucella canis cause disease in man. Infection of humans with Brucella ovis and Brucella neotomae
has not been described. Animals may transmit Brucella organisms during septic abortion, at the time of slaughter, and in their milk. Brucellosis is rarely, if ever, transmitted from human to human.
Brucella
species can enter mammalian hosts through skin abrasions or cuts, the conjunctiva, the respiratory tract, and the GI tract. Organisms are ingested rapidly by polymorphonuclear leukocytes, which generally fail to kill them. Organisms also are phagocytized by macrophages, which traffic to lymphoid tissue and eventually localize in lymph nodes, liver, spleen, joints, kidneys, and bone marrow.
Brucellosis also can replicate extracellularly in host tissue. The host cellular response may range from abscess formation to granuloma formation with caseous necrosis.
CLINICAL FEATURES - BRUCELLOSIS Clinical manifestations of brucellosis are diverse, and the course of the disease varies. Patients may present with an acute, systemic, febrile illness; an insidious
chronic infection; or a localized inflammatory process. The disease may be abrupt or insidious in onset, with an incubation period of 3 days to several weeks. Patients usually have nonspecific symptoms such as fever,
sweats, fatigue, anorexia, and muscle or joint aches. Neuropsychiatric symptoms such as depression, headache, and irritability occur frequently. In addition, focal infection of bones, joints, or the genitourinary tract
may cause local pain. Cough and pleuritic chest pain also may be noted. Symptoms often last 3-6 months and occasionally for longer than a year. Brucellosis usually does not cause leukocytosis, and patients
may be neutropenic. B melitensis tends to cause more severe, systemic illness than the other Brucella species. B suis is more likely to cause localized, suppurative disease.
Infection with B melitensis
leads to bone or joint disease in approximately 30% of patients. Sacroiliitis develops in 6-15%, particularly in young adults. Arthritis of large joints occurs with about the same frequency as sacroiliitis. In contrast to septic arthritis caused by pyogenic organisms, joint inflammation observed with
B melitensis
is mild, and erythema of overlying skin is uncommon. Synovial fluid is exudative, with cell counts in the low thousands, predominantly mononuclear. In both sacroiliitis and peripheral joint infections, destruction of bone is unusual. Organisms can be cultured from fluid in approximately 20% of patients. Spondylitis tends to affect middle-aged or elderly patients, causing back (usually lumbar) pain, local tenderness, and occasionally radicular symptoms.
Radiographic findings, similar to those of tuberculous infection, include disk space narrowing and epiphysitis. Paravertebral abscesses occur rarely. In contrast to frequent infection of the axial skeleton,
osteomyelitis of long bones is rare. Infection of the genitourinary tract, an important target in ruminant animals, also may lead to signs and symptoms of disease in humans. Pyelonephritis, cystitis, and, in males,
epididymo-orchitis may occur. Both diseases may mimic their tuberculous counterparts with sterile pyuria on routine bacteriologic cultures. Lung infections also have been described. Although up to 25% of patients may
complain of respiratory symptoms (mostly cough, dyspnea, or pleuritic pain), chest radiographic examinations usually are normal. Diffuse or focal infiltrates, pleural effusions, abscesses, and granulomas may be seen.
Hepatitis and, rarely, liver abscess also occur. Mild elevations of serum lactase dehydrogenate and alkaline phosphatase are common. Biopsy may show well-formed granulomas or nonspecific hepatitis with collections of
mononuclear cells. Other sites of infection include the heart, central nervous system (CNS), and skin. Brucella
endocarditis, a rare but feared complication, accounts for 80% of deaths from brucellosis. CNS infection usually manifests itself as chronic meningoencephalitis, but subarachnoid hemorrhage and myelitis also occur. Cases of skin abscess also have been reported.
DIAGNOSIS - BRUCELLOSIS A thorough history eliciting details of appropriate exposures (animals, animal products, environmental exposures) is the most important diagnostic tool.
Strongly consider brucellosis in the differential diagnosis when military troops exposed to a biological attack have febrile illnesses. PCR and antibody-based antigen detection systems may demonstrate the presence of
organisms in environmental samples collected from attack areas. When the disease is considered, diagnosis usually is made by serology. The tube agglutination test remains the criterion standard. This test
reflects the presence of anti-O-polysaccharide antibody. Most patients already have high titers at the time of clinical presentation. Serum testing always should include dilution to at least 1:320. The tube
agglutination test does not detect antibodies to B canis, because this organism does not have O-polysaccharide on its surface. In addition to serologic testing, pursue diagnosis by microbiologic
cultures of blood or body fluid samples. Hold cultures for at least 2 months. The reported frequency of isolation from blood varies widely, from less than 10% to 90%. B melitensis
is said to be cultured more readily than B abortus. Culture of bone marrow may increase the yield.
TREATMENT - BRUCELLOSIS Therapy with a single drug has resulted in a high relapse rate, so use combined antibiotic regimens whenever
possible. A 6-week regimen of doxycycline 200 mg/d PO with the addition of streptomycin 1 g/d IM for the first 2 weeks is effective in most adults with most forms of brucellosis. Patients with spondylitis may require
longer treatment. A 6-week oral regimen with both rifampin 900 mg/d and doxycycline 200 mg/d is effective. Several studies have demonstrated that treatment with a combination of streptomycin and doxycycline may result
in less frequent relapse than treatment with the combination of rifampin and doxycycline.Endocarditis likely is best treated with a combination of rifampin, streptomycin, and doxycycline for 6 weeks. Replace infected
valves early. CNS disease responds to a combination of rifampin and trimethoprim/sulfamethoxazole but may need prolonged therapy. The latter combination is also effective for children younger than 8 years. Rifampin is
recommended for pregnant women. PREVENTION/PROPHYLAXIS - BRUCELLOSIS Animal handlers should wear appropriate protective clothing when working with infected animals. Meat should be
well cooked and milk should be pasteurized. Laboratory workers should culture the organism only with appropriate Biosafety level 2 or 3. In the event of a biological attack, the standard gas mask should
protect personnel adequately from airborne Brucella species. No commercially available vaccine exists for humans. Q FEVER INTRODUCTION
Q fever is a zoonotic disease caused by Coxiella burnetii, a rickettsialike organism of low virulence but remarkable infectivity. A single organism may initiate infection. In addition, despite the fact that
C burnetii is unable to grow or replicate outside host cells, a sporelike form of the organism is extremely resistant to heat, pressure, and many antiseptic compounds. This allows C burnetii
to persist in the environment for long periods under harsh conditions. In contrast to this high degree of inherent resilience and transmissibility, the acute clinical disease associated with Q fever is usually a benign, although temporarily incapacitating, illness in humans. Even without treatment, most patients recover.
The primary reservoir for natural human infection is livestock, particularly parturient females, and the distribution is worldwide. Humans who work in animal husbandry, especially those who assist during parturition,
are at risk for acquiring Q fever. The potential of C burnetii as a BW agent is related directly to its infectivity. It has been estimated that 50 kg of dried C burnetii
would produce casualties at a rate equal to that of similar amounts of anthrax or tularemia organisms. The causative agent of Q fever was designated Coxiella burnetii
to recognize the outstanding contribution of both Harold Cox and MacFarlane Burnet in the isolation and characterization of the pathogen. The disease now has been identified in at least 51 countries and on 5 continents.
PATHOPHYSIOLOGY - Q FEVER The genus Coxiella has only 1 species. C burnetii
is extremely infectious. Under experimental conditions, a single organism is capable of producing infection and disease in humans. The host range of C burnetii
is diverse and includes a large number of mammalian species and arthropods. Among these, man is the only host identified that experiences an illness as a result of infection. A number of different strains of
C burnetii have been identified worldwide, and different clinical manifestations and complications may be associated with the various strains. Humans have been infected most commonly by contact with
domestic livestock, particularly goats, cattle, and sheep. The risk of infection is increased substantially if humans are exposed to these animals at parturition. During gestation, the proliferation of C burnetii
in the placenta facilitates aerosolization of large numbers of the pathogen during parturition. Survival of the organism on inanimate surfaces, such as straw, hay, or clothing, allows for transmission to individuals who are not in direct contact with infected animals.
Human infection with C burnetii
is usually the result of inhalation of infected aerosols. Following this, host cells phagocytize the organisms. After phagocytosis by host cells, dissemination of the pathogen occurs as a result of circulation of organism free in the plasma, on the surface of the cells, and carried by circulatory macrophages.
Little host reaction occurs at the initial portal of entry, either in the lung following inhalation of aerosol or in the skin following a tick bite. Q fever develops without formation of a primary
infectious focus in the area of the tick bite, and the organism does not infect the vascular endothelium, as do other rickettsial pathogens. The presence of a lipopolysaccharide on the cell surface of C burnetii
protects the pathogen from host microbicidal activity. CLINICAL FEATURES - Q FEVER Humans are the only hosts that commonly develop an illness as a result of the infection.
Incubation varies from 10-40 days. The duration of the incubation period is correlated inversely with the magnitude of the inoculum. A higher inoculum also increases the severity of the disease. Q fever in humans may be
manifested by asymptomatic seroconversion, acute illness, or chronic disease. The frequency of chronic disease (usually endocarditis) is probably less than 1% of the total infected population. No characteristic
illness is described for acute Q fever, and manifestations may vary considerably between locations where the disease is acquired. The onset of symptomatic Q fever may be abrupt or insidious. Fever, chills, and headache
are the most common signs and symptoms. Diaphoresis, malaise, myalgias, fatigue, and anorexia are also common. Arthralgias are relatively uncommon. Cough often occurs later in the illness. Chest pain occurs in a
minority of patients. Although nonspecific, evanescent skin eruptions have been reported. No characteristic rash results. Most patients appear mildly to moderately ill. The temperature tends to fluctuate,
with peaks at 39-40 °C, and is biphasic in approximately 25% of patients. The fever generally lasts less than 13
days but has been reported to last longer in older adults.Encephalopathic symptoms, headache, hallucinations (visual, auditory), expressive dysphasia, facial pain resembling trigeminal neuralgia, diplopia, and
dysarthria have been reported. Physical findings in acute Q fever are as nonspecific as the clinical symptomatology. Rales are probably the most commonly observed physical finding; evidence of pleural effusion and
consolidation also may be noted but not in most infections. Reports of abnormalities on chest radiographic examination vary with locale, but abnormalities probably are seen 50-60% of the time. The most common
abnormality reported is a unilateral, homogenous infiltrate involving 1 or 2 lobes. Rounded opacities and hilar adenopathy are not uncommon. Consider the diagnosis of Q fever when these abnormalities are observed in the
setting of acute pneumonia. Patients with acute Q fever may present with a clinical picture of acute hepatitis with elevations of aminotransferases that are 2- to 3-fold higher than the upper limit of
normal. The total bilirubin can be expected to be elevated in 10-15% of patients with
acute Q fever. The white blood cell count is usually normal. The erythrocyte sedimentation rate is elevated in 33% of patients. Mild anemia or thrombocytopenia also may be observed. Chronic infection with C burnetii
usually is manifested by infective endocarditis, which also is the most severe complication of Q fever. In addition, hepatitis, infected vascular prostheses, aneurysms, osteomyelitis, pulmonary infection, cutaneous infection, and an asymptomatic form have been reported.
In Q fever endocarditis, fever has been recorded in 85% of patients, along with other systemic symptoms (eg, chills, headache, myalgias, weight loss). Other frequently reported clinical features of Q fever
endocarditis include heart failure, splenomegaly, hepatomegaly, clubbing, and cutaneous signs. Routine blood cultures in Q fever endocarditis are negative, and Q fever should be considered when culture-negative
endocarditis is encountered. The diagnosis of infective endocarditis secondary to Q fever is confirmed by serologic testing. DIAGNOSIS- Q FEVER Diagnosis of Q fever usually is
accomplished by serologic testing; the most common methods are complement fixation, indirect fluorescent antibody, and ELISA. Significant antibody titers usually are not identifiable until 2-3 weeks into the illness.
Of the methods currently used for the diagnosis of Q fever, ELISA is the most sensitive and easiest to perform. This assay can establish a diagnosis of Q fever from a single serum specimen with a sensitivity of 80-84%
in early convalescence and 100% in intermediate and late convalescence. TREATMENT – Q FEVER Tetracycline has been the mainstay of therapy since the 1950s. When initiated within
the first few days of the illness, treatment significantly shortens its course. Macrolide antibiotics, such as erythromycin and azithromycin, are also effective. When chronic Q fever infection is manifested by
infective endocarditis, the mortality is 24% even when patients receive appropriate treatment. At least 2 years of therapy are required, usually with a tetracycline combined with rifampin or aquinolone, although
trimethoprim-sulfamethoxazole also has been used. PREVENTION/PROPHYLAXIS - Q FEVER Although an effective vaccine (Q-vax) is licensed in Australia, all Q fever vaccines used in the
US are investigational. Q fever can be prevented by immunization. SMALLPOX
INTRODUCTIONVariola, the causative agent of smallpox, is the most notorious of the poxviruses (family Poxviridae). Smallpox was an important cause of morbidity and mortality in the developing world until recent times.
In 1980, the World Health Organization (WHO) declared endemic smallpox eradicated, with the last occurrence in Somalia in 1977. Variola represents a significant threat as a BW agent. Variola is highly infectious and
is associated with high mortality and secondary spread. Currently, the majority of the US population has no immunity, little vaccine is readily available, and no effective treatment exists for the disease. Currently, 2
WHO-approved and inspected repositories remain: the CDC in the US and Vector Laboratories in Russia; however, clandestine stockpiles may exist. PATHOPHYSIOLOGY - SMALLPOX Variola
virus is highly infectious by aerosol, environmentally stable, and can retain infectivity for long periods. Infection through contaminated fomites is infrequent. After exposure to aerosolized virus, the virus multiplies
locally in the respiratory tract. After an incubation period of 7-17 days, variola is spread hematogenously (primary viremia) to regional lymph nodes, where additional replication occurs. Subsequently, variola is spread
hematogenously (secondary viremia) to small dermal blood vessels, where skin inflammatory changes (pox) occur. Two types of smallpox generally are recognized. Variola major, the most severe form, has a fatality rate of
30% in unvaccinated individuals and 3% in those previously vaccinated. Variola minor, a more mild form of smallpox, produces lethality in only 1% of unvaccinated individuals.
CLINICAL MANIFESTATIONS - SMALLPOX After a 7- to 17-day incubation period, symptoms begin acutely with high fever, headache, rigors, malaise, myalgias, vomiting, and abdominal and back pain. During
the initial phase, 15% of patients develop delirium, and 10% of light-skinned patients may develop a fleeting erythematous exanthem. After 2-3 days, an exanthem develops on the face, hands, and forearms and extends
gradually to the trunk and lower extremities. The lesions progress synchronously from macules to papules to vesicles to pustules that often are umbilicated, such as in molluscum contagiosum. Centrifugal distribution of
the rash is an important diagnostic feature, with a greater number of lesions on the face and extremities compared to the trunk. Patients are most infectious on days 3-6 after the onset of fever. Virus is shed from
oropharyngeal and respiratory secretions. The above described manifestations are known as variola major. In variola minor (ie, alastrim), cutaneous lesions are similar but smaller and fewer in number. Patients are not
as ill as those who have variola major are. Small numbers (3%) of patients develop hemorrhagic lesions, and these patients typically die of disease before papules develop. Flat smallpox with macular, soft, velvety
lesions develop in 4% of patients and forebodes a poor prognosis. Modified smallpox occurs in those who have been vaccinated and develop a mild prodrome with rapid development of lesions and crusting by day 7.
Frequently patients with modified disease form no pustules. DIAGNOSIS - SMALLPOX The most difficult aspect of diagnosing smallpox is the current lack of familiarity with the
disease for most physicians. Other viral exanthems, such as chicken pox, erythema multiforme with bullae, or allergic contact dermatitis, can look similar. Smallpox is distinguished from chicken pox by the centrifugal
distribution of its rash and the presence of lesions at the same stage of development everywhere on the body. The failure to recognize mild cases of smallpox in persons with partial immunity permits rapid
person-to-person transmission. Exposed people may shed virus from the oropharynx without ever manifesting disease. The usual method of diagnosis is demonstration of characteristic virions on electron microscopy of
vesicular scrapings. Gispen modified silver stain is rapid but relatively insensitive. When microscopy is unavailable, the gel diffusion test, in which vesicular fluid antigen from a pus lesion is incubated with vaccine
hyperimmune serum, may be used. However, none of the above tests differentiate smallpox from monkeypox or cowpox. PCR techniques have been developed and may provide for more accurate diagnosis in the near future. TREATMENT - SMALLPOX It is critical for medical personnel to recognize a vesicular exanthem in possible terrorist areas or warfare theaters as possible smallpox. Immediate
reporting of all possible cases must be made to public health au |
