Bayannur – China : high alert after a suspected case of Bubonic Plague

Bayannur, a city in northern China, was on high alert after a suspected case of Bubonic plague was reported Saturday.

According to state-run People’s Daily Online, authorities in the Inner Mongolia Autonomous Region announced a level III warning of plague prevention and control.

Local authorities announced that the warning period will continue until the end of 2020 since the plague ran the risk of spreading.

“At present, there is a risk of a human plague epidemic spreading in this city. The public should improve its self-protection awareness and ability, and report abnormal health conditions promptly,” authorities announced.

Xinhua news agency, another state-run agency, reported on 1 July that two suspected cases of the Bubonic plague, which were recorded in Khovd province in Western Mongolia, were confirmed by labs.

The confirmed cases were of a 27-year-old resident and his 17-year-old brother who had eaten marmot meat. After their cases came to light, health officials urged people to not eat the meat. So far, 146 people who had been in contact with them have been isolated and are being treated.

Key facts

• Plague is caused by the bacteria Yersinia pestis, a zoonotic bacteria usually found in small mammals and their fleas.
• People infected with Y. pestis often develop symptoms after an incubation period of one to seven days.
• There are two main clinical forms of plague infection: bubonic and pneumonic. Bubonic plague is the most common form and is characterized by painful swollen lymph nodes or ‘buboes’.
• Plague is transmitted between animals and humans by the bite of infected fleas, direct contact with infected tissues, and inhalation of infected respiratory droplets.
• Plague can be a very severe disease in people, with a case-fatality ratio of 30% to 60% for the bubonic type, and is always fatal for the pneumonic kind when left untreated.
• Antibiotic treatment is effective against plague bacteria, so early diagnosis and early treatment can save lives.
• From 2010 to 2015 there were 3248 cases reported worldwide, including 584 deaths.
• Currently, the three most endemic countries are the Democratic Republic of the Congo, Madagascar, and Peru.

Plague is an infectious disease caused by the bacteria Yersinia pestis, a zoonotic bacteria, usually found in small mammals and their fleas. It is transmitted between animals through fleas. Humans can be infected through:

• the bite of infected vector fleas
• unprotected contact with infectious bodily fluids or contaminated materials
• the inhalation of respiratory droplets/small particles from a patient with pneumonic plague.

Plague is a very severe disease in people, particularly in its septicaemic (systemic infection caused by circulating bacteria in bloodstream) and pneumonic forms, with a case-fatality ratio of 30% to 100% if left untreated.

The pneumonic form is invariably fatal unless treated early. It is especially contagious and can trigger severe epidemics through person-to-person contact via droplets in the air.

From 2010 to 2015, there were 3248 cases reported worldwide, including 584 deaths.

Historically, plague was responsible for widespread pandemics with high mortality. It was known as the “Black Death” during the fourteenth century, causing more than 50 million deaths in Europe. Nowadays, plague is easily treated with antibiotics and the use of standard precautions to prevent acquiring infection.

Signs and symptoms

People infected with plague usually develop acute febrile disease with other non-specific systemic symptoms after an incubation period of one to seven days, such as sudden onset of fever, chills, head and body aches, and weakness, vomiting and nausea.

There are two main forms of plague infection, depending on the route of infection: bubonic and pneumonic.

• Bubonic plague is the most common form of plague and is caused by the bite of an infected flea. Plague bacillus, Y. pestis, enters at the bite and travels through the lymphatic system to the nearest lymph node where it replicates itself. The lymph node then becomes inflamed, tense and painful, and is called a ‘bubo’. At advanced stages of the infection the inflamed lymph nodes can turn into open sores filled with pus. Human to human transmission of bubonic plague is rare. Bubonic plague can advance and spread to the lungs, which is the more severe type of plague called pneumonic plague.
• Pneumonic plague, or lung-based plague, is the most virulent form of plague. Incubation can be as short as 24 hours. Any person with pneumonic plague may transmit the disease via droplets to other humans. Untreated pneumonic plague, if not diagnosed and treated early, can be fatal. However, recovery rates are high if detected and treated in time (within 24 hours of onset of symptoms).

History of Plague and its Potential as A Weapon of Bioterrorism

Pandemic History and Epidemic Potential

Three well-documented plague pandemics have occurred in the past two millennia, resulting in more than 200 million deaths and great social and economic chaos (Perry and Fetherston, 1997; Pollitzer, 1954).

The Justinian pandemic arose in northern Africa in the mid-6th century, and by the 7th century had spread throughout the Mediterranean and near-eastern regions—severely impacting both the Roman and Byzantine empires.

The second pandemic, the Black Death or great pestilence, originated in Central Asia, was carried to Sicily in 1347 via ships from the Crimea, and rapidly swept through medieval Europe.

By 1352, it had killed 30% or more of afflicted populations, slowly playing itself out in successive epidemics, including the Great Plague of London in 1665 (Perry and Fetherston, 1997).

The third (Modern) pandemic began in southwestern China in the mid-19th, struck Hong Kong in 1894, and was soon carried by rat-infested steamships to port cities on all inhabited continents, including several in the United States (US) (Link, 1955; Pollitzer, 1954).

By 1930, the third pandemic had caused more than 26 million cases and 12 million deaths. Plague in these three pandemics was predominantly the bubonic form, emanating from Yersinia pestis-infected rats and fleas, although terrifying outbreaks of the more virulent person-to-person spreading pneumonic form were recorded during the course of each.

The explosive contagiousness and severity of pneumonic plague was most completely documented in Manchurian epidemics in the early 20th century, which involved tens of thousands of cases, virtually all of them fatal (Wu, 1926).

Improved sanitation, hygiene, and modern disease control methods have, since the early 20th century, steadily diminished the impact of plague on public health, to the point that an average of 2,500 cases is now reported annually (World Health Organization, 2003).

The plague bacillus is, however, entrenched in rodent populations in scattered foci on all inhabited continents except Australia (Gage, 1998; Gratz, 1999b), and eliminating these natural transmission cycles is unfeasible.

Furthermore, although treatment with antimicrobials has reduced the case fatality ratio of bubonic plague to 10% or less, the fatality ratio for pneumonic plague remains high. A review of 420 reported plague cases in the US in the period 1949–2000 identified a total of 55 cases of plague pneumonia, of which 22 (40.0%) were fatal (Centers for Disease Control and Prevention, unpublished data); of 7 primary pneumonic cases, the fatality ratio was 57.1% (Centers for Disease Control and Prevention, 1997).

Although pandemics are unlikely to recur, plague—including the pneumonic form —holds considerable outbreak potential (Boisier et al., 2002; Campbell and Hughes, 1995; Chanteau et al., 1998, 2000; Gabastou et al., 2000; Ratsitorahina, 2000a). This potential could be exploited for purposes of terrorism or warfare.

Plague as a Weapon of Biological Warfare

The idea of using plague as a weapon is not new.

Anecdotal reports describe catapulting of plague cadavers into enemy fortifications in 14th and 18th century warfare (Derbes, 1996; Gasquet, 1908; Marty, 2001).

In World War II, the Japanese military experimented with plague in human subjects at their clandestine biological research facilities in Manchuria, and on several occasions dropped Y. pestis-infested fleas from low-flying planes on Chinese civilian populations, causing limited outbreaks of bubonic plague and initiating cycles of infection in rats (Bellamy and Freedman, 2001; Harris, 1992; Kahn, 2002).

Biological warfare research programs begun by the Soviet Union (USSR) and the US during the Second World War intensified during the Cold War, and in the 1960s both nations had active programs to “weaponize” Y. pestis. 

In 1970, a World Health Organization (WHO) expert committee on biological warfare warned of the dangers of plague as a weapon, noting that the causative agent was highly infective, that it could be easily grown in large quantities and stored for later use, and that it could be dispersed in a form relatively resistant to desiccation and other adverse environmental conditions (World Health Organization, 1970).

Models developed by this expert committee predicted that the intentional release of 50 kg of aerosolized Y. pestis over a city of 5 million would, in its primary effects, cause 150,000 cases of pneumonic plague and 36,000 deaths.

It was further postulated that, without adequate precautions, an initial outbreak of pneumonic plague involving 50% of a population could result in infection of 90% of the rest of the population in 20–30 days and could cause a case fatality ratio of 60–70%.

The work of this committee provided a basis for the 1972 international Biological Weapons and Toxins Convention prohibiting biological weapons development and maintenance, and that went into effect in 1975 (Marty et al., 2001).

It is now known that, despite signing this accord, the USSR continued an aggressive clandestine program of research and development that had begun decades earlier, stockpiling battle-ready plague weapons (Alibek, 1999).

The Soviets prepared Y. pestis in liquid and dry forms as aerosols to be released by bomblets, and plague was considered by them as one of the most important strategic weapons in their arsenal.

They also developed virulent fraction 1 (F1) capsular antigen-deficient and antimicrobial-resistant strains of Y. pestis and performed experiments to create an agent that could evade vaccine-induced immunity, be unresponsive to standard antibiotic treatment, and be difficult to identify.

Moreover, the USSR was capable through a number of industrial plants to manufacture a plague weapon in hundreds of tons (Alibek, 1999).The US military biowarfare program also recognized that aerosolized Y. pestis had the basic attributes suitable for a large-scale attack (Martin and Marty, 2001; Marty, 2001), but US military scientists failed in their attempts to weaponize plague, apparently because they were unable to produce sufficient quantities of Y. pestis in stable form.

Offensive biological weapons research was halted by the US in 1970, but Soviet efforts continued at least until 1990. Although Russia converted its civilian biological weapons to legitimate ends, it is unclear whether their military program has ceased development work and eliminated all of its stores (Alibek, 1999).

Many nations maintain biological weapons defense programs that adhere to the ban on the development of offensive weapons; however, there is an obvious potential offensive value of studies to better understand candidate agents, and their possible modes of delivery, dispersal, and effectiveness under varying conditions.

The goal or function of a terrorist is to create mass hysteria. Health professionals must learn to mitigate this effect by being able to recognize an attack and treat and calm victims.

Terrorist acts can be either covert or overt. In a covert attack, the terrorists are attempting to take advantage of the element of surprise. Health professionals must be diligent in evaluating the possibility of a covert attack when multiple patients arrive with similar signs and symptoms.

In this setting, the healthcare system may be quickly overloaded unless the institution and staff have prepared and have systems in place to handle a large influx of patient volume.

The sooner an event is recognized as an attack; the sooner additional resources can be activated to assist providers. Unless the system prepares in advance, the number of victims triaged may quickly overwhelm the system and result in the terrorist’s goal of creating mass panic.

In an overt attack, terrorists rely heavily on mass hysteria and panic as an impact multiplier. They may announce responsibility immediately for a large-scale event. The number of victims quickly overwhelms even prepared systems that have a well-defined emergency response plan. In either a covert or overt terrorist attack, the system may be flooded with victims.

Weapons of Mass Destruction

Weapons of mass destruction include biological, chemical, or nuclear weapons potentially causing mass casualties. The mnemonic CBRNE assists in remembering weapons of mass destruction:

• Chemical
• Biological
• Radiological
• Nuclear
• Explosives

Issues of Concern

Biological Weapons

Biological warfare agents are bacteria and viruses that infect humans, animals, and crops resulting in an incapacitating or fatal disease or crop destruction. Symptoms may not appear for days to weeks. Often the bacteria or virus is weaponized, and the changes will affect a broader segment of humans, animals, or crops than the normal pathogen.

In a biological warfare terror event, healthcare providers must deal with uncommon pathogens that rarely affect humans. Healthcare facilities will be inundated with victims. The arrival of one or more victims with an odd presentation may be the initial indication that an act of terrorism has occurred.

Biologic agents may be dispersed by several techniques including contaminated water and aerosol sprays. They can also infect individuals and place them on airplanes, buses, or large events that will disperse the virus quickly.

Surveillance

All healthcare providers should have the knowledge to identify and initiate a local response to an act of bioterrorism. The starting point is the status quo or their normal patient population. If there is a significant deviation from the norm, the provider should consider the fact that they may be on the cusp of an endemic deliberately perpetrated on society.

Providers must be aware of clinical features including:

• A cluster of persons with similar symptoms from a common geographical area
• A rapid increase in patients presenting with similar signs and symptoms
• An increase in patients who expire within 72 hours after hospitalization
• An unusual clinical presentation
• Increased dead animals
• Signs and symptoms of biologic warfare agents
• Sudden increases in calls or visits
• Sudden increases in the use of over-the-counter drug purchases

These factors reflect changes from the status quo in the community. An astute clinician with a sense of the community’s general normal health can make a significant difference in how soon a response to the threat begins. If the person admits to no foreign travel in endemic areas of rare viruses, and the suspicion is high, contacting the local health department or CDC is in order.

Classification of Bioweapon Diseases

The Center for Disease Control has identified 30 organisms that might be weaponized and has grouped them into three categories. Classification is based on ease of dissemination, morbidity and mortality, panic potential, and level of public health requirements.

• Category A: Highest priority diseases that pose a risk to national security, are easily transmitted, have high morbidity and mortality, would have a major public health impact and cause panic, and require special public health preparedness. 
• Category B: Moderate priority diseases with lower morbidity and mortality and more difficult to disseminate.
• Category C: High priority diseases that have the potential to cause significant morbidity and mortality and are emerging pathogens that could be engineered for mass dispersion.

Biologic Agents

Category A: High Risk

ANTHRAX: CUTANEOUS, GASTROINTESTINAL, AND INHALATIONAL

Bacillus anthracis is found in the soil and is normally transmitted by handling contaminated animals and animal products. It is a spore-forming organism. Anthrax spores are highly permeable to the porous skin.

An anthrax vaccine does exist but requires many injections to be effective. Anthrax is one of the few biological agents for which federal employees receive vaccination. It may be diagnosed with Gram stain (gram + rod shaped)[3].

• Signs/Symptoms: (Cutaneous) Pruritic macule or papule, ulceration, and eschar; edema; lymphangitis and lymphadenopathy. (Gastrointestinal) abdominal pain, nausea and vomiting, hematemesis, and bowel perforation which may occur after eating contaminated food. (Inhalational) Cough, chest pain, dyspnea, fever, sepsis, hemorrhagic mediastinitis, ending in hemodynamic and respiratory failure.  Symptoms begin within 1 to 60 days of exposure
• Treatment: large early doses of intravenous and oral antibiotics for 60 days may be life-saving, such as ciprofloxacin, doxycycline, erythromycin, penicillin, or vancomycin. FDA-approved agents include ciprofloxacin, doxycycline, and penicillin.
• Biologic Warfare: Contact precautions if copious drainage. Hand hygiene with soap and water or 2% chlorhexidine gluconate for 60 seconds. Over 2000 cases annually worldwide. Fatality > 20% untreated, 1% if treated. Standard precautions as no person-to-person transmission. High risk for use as a biologic weapon.

BOTULISM [4]

Botulism is a neurologic disorder that causes life-threatening neuroparalysis as a result of a neurotoxin produced by Clostridium botulinum. The three main clinical presentations of botulism are as follows: Infant botulism, Foodborne botulism, and Wound botulism.

• Signs/Symptoms: In infants and children constipation, diminished gag reflex, weak neck muscles, lethargy, and respiratory failure. Adults – weak jaw clench, difficulty speaking and swallowing, drooping eyelids, descending proximal to distal muscle weakness, and respiratory failure.
• Treatment: Supportive and antitoxin for severe symptoms.
• Biologic Warfare: The neurotoxin Botulinum is one of the deadliest toxins. It is produced by the bacterium Clostridium botulinum. Passive immunity with human hyperimmune globulin or equine botulinum antitoxin, and endogenous immunity with botulinum toxoid. Standard precautions. High risk for use as a biologic weapon.

PLAGUE: BUBONIC

Bubonic plague is a highly contagious, acute,  febrile illness transmitted to humans by the bite of a rat flea. Human-to-human transmission is rare. The disease is caused by a rod-shaped bacteria known as Yersinia pestis.

Plague is distributed worldwide and is more commonly reported in developing countries. Survival of the bacillus depends on flea-rodent interaction; human infection does not contribute to the bacteria’s survival in nature[5].

• Signs/Symptoms: Enlarged tender lymph nodes called buboes, fever, chills, fatigue, myalgias, hypotension, pulmonary edema, abdominal pain, organ failure; may progress to septicemia, pneumonia, meningitis, ocular, or pharyngeal plague.
• Treatment: Ciprofloxacin, doxycycline, gentamycin, and streptomycin. Supportive care.
• Biologic Warfare: Yersinia pestis is a bacterium that causes the plague in humans. Rodents are the host, and the disease is transmitted by flea bites although it can be aerosolized. Droplet precautions until 48 to 72 hours of antibiotics then standard precautions. High fatality without treatment. It caused the Black Death in Medieval Europe. Due to its high death rate and potential for aerosolization, it is considered a to have a high potential for bioterrorism.

SMALLPOX (Variola Major) [6]

Smallpox is a highly contagious acute disease caused by the variola virus, an Orthopoxvirus in the Poxviridae family.

• Signs/Symptoms: Fever, myalgia, vesicular rash (all in the same stage of progression from papular to pustular) on the face and extremities developing over 2-4 days.
• Treatment: Supportive, fluids, antibiotics for secondary infection, vaccination with 2 to 5 days will decrease the incidence of the disease and decrease the incidence of death.
• Biologic Warfare: Smallpox is very contagious. Those infected need to be quarantined, and airborne and droplet precautions until scabs have separated at 3 to 4 weeks. The fatality rate is 20% to 40%. Smallpox was eradicated according to the WHO in 1980. As a weapon smallpox is particularly dangerous because it is highly contagious. Due to the infrequency with which vaccines are administered most people are unprotected in the event of an outbreak.

TULAREMIA OR “RABBIT FEVER”

Tularemia or rabbit fever is caused by Francisella tularensis which is a bacteria spread by ticks, deer flies, or contact with infected animals. It may be also be spread by breathing contaminated dust or drinking contaminated water[7].

• Signs/Symptoms: Fever, severe, life-threatening pneumonia and systemic infection.
• Treatment: Tularemia is difficult to diagnose and can easily be mistaken for other, more common, illnesses. Blood tests and cultures can help confirm the diagnosis. Antibiotics used to treat tularemia include streptomycin, gentamicin, doxycycline, or ciprofloxacin. Treatment usually lasts 10 to 21 days. Streptomycin is the drug of choice. Gentamicin is considered an acceptable alternative. Tetracyclines are an alternative to aminoglycosides for patients who are not as ill. Tetracyclines are static agents and should be given for at least 14 days to avoid relapse. Ciprofloxacin and other fluoroquinolones are not FDA-approved for treatment of tularemia but have shown good efficacy.
• Biologic Warfare – Low fatality rate if treated. The disease is caused by the Francisella tularensis bacterium through contact with insect bites, fur, inhalation, or ingestion of contaminated. If weaponized, the bacteria would likely be made airborne for inhalation infection

VIRAL HEMORRHAGIC FEVER (Marburg, Ebola, Lassa, and Machupo viruses)

Viral hemorrhagic fevers caused by a viral infection. They are caused by five families of RNA viruses: Arenaviridae, Bunyaviridae, Filoviridae, Flaviviridae, and Rhabdoviridae. Fever and bleeding disorders characterize all types, and all can progress to high fever, shock, and death[8].

• Signs/Symptoms: Fever and bleed, facial and chest flushing, petechiae, edema, hypotension, malaise, muscle pain, nausea, vomiting, headache, progresses to multiple organ failures and hypovolemic shock in the form of bleeding diathesis and circulatory compromise.
• Treatment: No cure exists, treatment is supportive.
• Biologic Warfare: Ebola virus is the most dangerous, with fatality rates ranging from 25% to 90%. The viruses are spread to humans through a respiratory route, and there is a potential for weaponization and aerosol dissemination.

Category B – Low Risk

ABRIN TOXIN FROM ABRUS PRECATORIUS (ROSARY PEAS)[9]

Abrin is a toxic toxalbumin that is found in the seeds of the rosary pea. It is more toxic than ricin. Abrin is a ribosome inhibiting protein similar to the ricin.

• Signs/Symptoms: The major symptoms depend on the route of exposure and the dose. Symptoms appear between hours to days after exposure. Initial symptoms of inhalation may occur within 8–24 hours; and may be fatal within 36 to 72 hours. Symptoms include a cough, fever, mouth pain, airway irritation, chest tightness, diaphoresis, pulmonary edema, nausea, vomiting, diarrhea, abdominal cramps, cyanosis, GI bleeding, hematuria, and respiratory failure. Abrin as a powder or mist can cause eye redness, lacrimation, retinal hemorrhage, vision impairment, blindness, and lead to systemic toxicity.
• Treatment: Supportive as there is no antidote, oxygen therapy, airway management, assisted ventilation, monitoring, IV fluids, and electrolyte replacement. For recent ingestion, administration of activated charcoal and gastric lavage are both options. Flushing the eye with saline helps to remove abrin.
• Biologic Warfare: Abrin is a ribosome inhibiting toxic protein toxalbumin found in the seeds of the rosary pea or jequirity pea, Abrus precatorius. It is approximately 30 times more toxic than ricin and has a potential to be weaponized.

BRUCELLOSIS (BRUCELLA SPECIES)

Brucellosis is a very contagious zoonosis that may be contracted by consumption of undercooked meat, unpasteurized milk, or contact with other secretions. It is also known as Mediterranean fever, Malta fever, or Undulant fever. Brucella is small gram-negative, nonmotile, non spore-forming, rod-shaped coccobacilli bacteria. It is a facultative intracellular parasite resulting in chronic disease.

• Signs/Symptoms: Fever, sweating (the foul smell of wet hay), arthralgia, myalgia, muscular pain, night sweats, nausea, vomiting, diarrhea, decreased appetite, weight loss, abdominal pain, constipation, an enlarged liver, liver inflammation, liver abscess, and an enlarged spleen. Duration of the disease from a few weeks to years. Blood tests reveal a low RBC and WBC, elevation of liver enzymes such as aspartate aminotransferase (AST) and alanine aminotransferase (ALT), and demonstrate positive Bengal Rose and Huddleston reactions. Brucella infection may cause arthritis, spondylitis, thrombocytopenia, meningitis, uveitis, optic neuritis, endocarditis, and neurobrucellosis.
• Treatment: Tetracycline, rifampin, streptomycin, and gentamicin are effective if given for several weeks as bacteria incubate within cells. Multiple antibiotics may be necessary. The gold standard treatment is streptomycin 1 g for 14 days and oral doxycycline 100 mg twice daily for 45 days. Another regimen is doxycycline plus rifampin twice daily for 6 weeks. A triple therapy of doxycycline, with rifampin and co-trimoxazole, has been used successfully to treat neurobrucellosis.
• Biologic Warfare: In endemic areas, vaccination is used to reduce the incidence of infection. Brucella has been weaponized by several countries.

EPSILON TOXIN OF CLOSTRIDIUM PERFRINGENS

Epsilon toxin is produced by Clostridium perfringens types B and D is one of the most potent poisonous substances known. Epsilon toxin binds to endothelial cells of brain capillary vessels before passing through the blood-brain barrier.

• Signs/Symptoms: In humans expected development would be over 6 to 24 hours, a refined version might act quicker, it would quickly cause devasting neurologic signs and symptoms and might result in sudden death. If weaponized, it would probably be dispersed by aerosolizing.
• Treatment: There has been very little progress toward the assembly of a good human immunogen against C. perfringens or any type of anti-toxin, and within the event of a terrorist attack, no prophylactic measures would possibly be accessible to be used by the general public.
• Biologic Warfare: C. perfringens epsilon toxin could be a fatal bioterrorism weapon. If used effectively, this agent might cause important morbidity and mortality because of a lack of therapeutic or preventive measures exist as medical countermeasures.

FOOD BACTERIUM (ESCHERICHIA COLI O157: H7, SALMONELLA, SHIGELLA)

The foodborne disease usually results from food contaminated by pathogenic bacteria, viruses, or parasites; or toxins such those found in poisonous mushrooms. The incubation period ranges from hours to day depending on the agent and the amount of consumption.

• Signs/Symptoms: Nausea, vomiting, diarrhea, abdominal cramping, and severe dehydration.
• Treatment: Supportive with antibiotics for severe cases.
• Biologic Warfare: Infections created from consumed food have been a time-honored method of assassination, siege, and terrorism. The food system is vulnerable to adulteration and contamination. Food is a natural vehicle for pathogenic microbes and toxins.  Contamination of food and water for select target populations. Bioterrorists would be able to disrupt the life of localities by contaminating water supplies or food.  An outbreak of diarrheal disease could shut down schools, a police force, fire departments, an aircraft carrier, or a military base. Schools and military basis with their centralized kitchens are a prime target for a food bioterrorism.  Schools are such a public concern that any hostile act against them can destroy a community. Food-borne pathogens are a “natural” weapons. Using organisms as weapons require the opportunity to insert them into the food system so that they will be viable and virulent. All it takes to make food into a weapon is basic microbiologic information and access to soil, manure, and untreated water.

GLANDERS (BURKHOLDERIA MALLEI)

Glanders is an infectious disease usually affecting donkeys, horses, and mules but it can be contracted by cats, dogs, goats, and humans. It is caused by Burkholderia mallei from contaminated feed or water.

• Signs/Symptoms: Incubation 1 to 14 days, may cause septicemia, pulmonary infection, and acute localized infection. Nodules and abscesses with ulcers in the mucous membranes and lymphangitis with suppuration is common. Expect fever, chills, sweats, malaise, headache, nausea, vomiting, diarrhea, dizziness, myalgia, pustular rash, cellulitis, cyanosis, jaundice, photophobia, and tachycardia. Hepatomegaly and splenomegaly may develop. Disseminated infections often progress to septicemia and multi-organ failure is common; death can occur rapidly.
• Treatment: Use standard precautions to prevent human-to-human transmission. Oral amoxicillin/clavulanate, doxycycline, or trimethoprim/sulfamethoxazole may be used for 30 to 150 days depending on the degree of the infection. Add streptomycin when initiating treatment if plague cannot be excluded.
• Biologic Warfare: Due to the high mortality rate in humans it is regarded as a potential biological warfare agent.

MELIOIDOSIS (BURKHOLDERIA PSEUDOMALLEI)

Melioidosis is an infection caused by gram-negative Burkholderia pseudomallei found in the soil and water. It is phylogenetically related closely to Burkholderia mallei which causes glanders. 

• Signs/Symptoms: In acute melioidosis, the incubation period is 1 to 21 days, but can be decades. It is known as the “Vietnam time-bomb.” There are 4 general types of infection: localized, pulmonary, blood-borne, or disseminated. Patients typically present with fever, cough pleuritic chest pain, bone or joint pain, with cellulitis. Intra-abdominal liver, splenic, or prostatic abscesses do not usually have focal pain. As a result, ultrasound or computed tomography should be performed. B. pseudomallei abscesses may have a characteristic “honeycomb” or “swiss cheese” architecture on CT. Parotid abscesses characteristically occur in Thai children, and prostatic abscesses are found in Australian males. Risk factors include diabetes, thalassemia, alcohol use, or renal disease. Chronic melioidosis occurs when symptoms last greater than 2 months. The clinical presentation of chronic melioidosis includes chronic skin infections, chronic lung nodule, and pneumonia. Chronic melioidosis closely mimics tuberculosis.
• Treatment: Initially intravenous ceftazidime should be administered 10 to 14 days. Meropenem, imipenem, and cefoperazone-sulbactam combination are also active. Intravenous amoxicillin-clavulanate may be used if none of the above four drugs is available. Eradication or maintenance treatment with co-trimoxazole and doxycycline is recommended for 12 to 20 weeks to reduce the rate of recurrence. Co-amoxiclav is an alternative for those unable to take co-trimoxazole and doxycycline (e.g., pregnant women and children under the age of 12), but is not as effective. Surgical drainage is usually indicated for prostatic and parotid abscesses and septic arthritis.
• Biologic Warfare: Melioidosis has the potential to be developed as a biological weapon. Without antibiotics, the septicemic form mortality rate exceeds 90%. With appropriate antibiotics, the mortality rate is about 10% for uncomplicated cases but up to 80% for cases with sepsis.

PSITTACOSIS (CHLAMYDIA PSITTACI)

Psittacosis, parrot fever, or ornithosis is caused by Chlamydia psittaci and contracted from infected parrots.

• Signs/Symptoms- Incubation period of 5–19 days, usually presenting as atypical pneumonia. Expect prostrating high fevers, cough, headache with nuchal rigidity, joint pains, diarrhea, conjunctivitis, nose bleeds, and low level of white blood cells. Rose spots (Horder’s spots) may develop. Splenomegaly is common towards the end of the first week. Diagnosis should be suspected if respiratory infection associated with splenomegaly and/or epistaxis.
• Treatment: The infection is treated with tetracycline or chloramphenicol. For initial treatment of ill patients, doxycycline hyclate may be administered intravenously. Remission is usually evident within 48 to 72 hours, but treatment must continue for at least 10 to 14 days after fever subsides.
• Biologic Warfare: Psittacosis has been considered as a possible biologic weapon.

Q FEVER (COXIELLA BURNETII)

Coxiella burnetii causes Q fever. The bacteria is found in cattle, goats, sheep, cats, and dogs. Infection occurs from inhalation from a spore-like variant and contact with feces, milk, semen, and urine of infected animals. The disease may also tick-borne. The bacterium is an obligate intracellular parasite.

• Signs/Symptoms: Incubation is usually 2 to 3 weeks. Expect flu-like symptoms with fever, malaise, perspiration, headache, muscle pain, joint pain, loss of appetite, upper respiratory problems, dry cough, pleuritic pain, chills, confusion, nausea, vomiting, and diarrhea. It may progress to atypical pneumonia with life-threatening acute respiratory distress syndrome. It may cause granulomatous hepatitis, which may be asymptomatic or cause liver enlargement and pain in the right upper quadrant of the abdomen. Retinal vasculitis is a rare manifestation. The chronic form can cause endocarditis months to years later.
• Treatment: Antibiotics include doxycycline, tetracycline, chloramphenicol, ciprofloxacin, ofloxacin, and hydroxychloroquine. Chronic Q fever may require up to four years of treatment with doxycycline and quinolones or doxycycline with hydroxychloroquine.
• Biologic Warfare: C. burnetii has been developed as a biological weapon. It can be contagious and is stable in aerosols in a wide range of temperatures. Q fever microorganisms may survive on surfaces up to 60 days. It is considered a good agent in because its ID50 is considered to be one, making it the lowest known of any biologic toxin.

RICIN: RICINUS COMMUNIS (CASTOR BEANS)

Ricin is a toxic lectin produced by the castor oil plant and found in the seeds. A dose the size of a few grains of table salt can kill a human. The LD 50 is about 22 micrograms per kilogram of body weight. Injection or inhalation is more toxic than oral ingestion.

• Signs/Symptoms: Toxic if inhaled, injected, or ingested. It causes abdominal pain, coughing, diarrhea, fever, nausea, necrotizing pneumonia, pulmonary edema, shock, tracheobronchitis, vomiting, and weakness.
• Treatment: Charcoal lavage and supportive care.
• Biologic Warfare: Several countries have considered or attempted to weaponized ricin. Given ricin’s extreme toxicity it is noteworthy that the production of the toxin is rather difficult to limit. The castor bean plant from which ricin is derived is a common ornamental and can be grown at home without any special care.

STAPHYLOCOCCUS AUREUS (Enterotoxin Type B)

S. aureus is a gram-positive bacterium frequently found in the flora of the nose, respiratory tract, and skin. It is a common cause of abscesses, food poisoning, respiratory infections and sinusitis. Pathogenic strains produce virulence factors such as protein toxins and cell-surface protein that binds and inactivates antibodies. Antibiotic-resistant methicillin-resistant S. aureus (MRSA) is a worldwide problem.

• Signs/Symptoms: Enterotoxin produced by the gram-positive Staphylococcus aureus causing severe diarrhea, nausea, and intestinal cramping within a few hours of ingestion. Gastroenteritis occurs because it is a superantigen, causing the immune system to release large cytokines that lead to significant inflammation that can result in toxic shock syndrome with high fever, hypotension, dizziness, rash, and peeling skin.
• Treatment: Antibiotics such as oxacillin, cefazolin, clindamycin, vancomycin, or linezolid with supportive care.
• Biologic Warfare: It is possible enterotoxin type B could be weaponized.

TYPHUS (RICKETTSIA PROWAZEKII)

Typhus, also known as typhus fever, is caused by Rickettsia prowazekii which is spread by body lice and Orientia tsutsugamushi, spread by chiggers, and Murine typhus, due to Rickettsia typhi spread by fleas.

• Signs/Symptoms: Sudden onset of fever with flu-like symptoms about 1 to 2 weeks after being infected. Once the symptoms have started, five to nine days later a rash typically begins on the trunk and spreads to the extremities sparing the face, palms, and soles. Signs of meningoencephalitis begin with the rash and continue with the development of photophobia, delirium, or coma. Untreated cases are often fatal.
• Treatment: Without treatment, death may occur in 10% to 60% of patients with epidemic typhus, with patients over age 60 having the highest risk of death. Death is rare if doxycycline and supportive care are provided.
• Biologic Warfare: Rickettsia prowazekii is highly infectious, but it cannot be passed from person to person. Numerous countries have considered it as a potential biological weapon.

VIRAL ENCEPHALITIS (VENEZUELAN EQUINE ENCEPHALITIS, EASTERN EQUINE ENCEPHALITIS, WESTERN EQUINE ENCEPHALITIS)

Encephalitis is an acute inflammation of the brain caused by either a viral infection or the immune system mistakenly attacking brain tissue. Encephalitis refers to an acute, diffuse, inflammatory process. While meningitis is an infection of the meninges, a combined meningoencephalitis can occur. An infection by a virus is the most common cause of encephalitis.

• Signs/Symptoms: Typically mosquito-borne viral pathogen that causes progressive central nervous system disorders. Patients experience flu-like symptoms, such as high fevers and headaches. People with weakened immune systems, the very young, and old can become severely ill and die. Diagnosing encephalitis is challenging because many of the symptoms are shared with other illnesses. Confirmations may require a sample of cerebral spinal fluid or brain tissue although CT scans and MRI scans are used to detect encephalitis.
• Treatment: Supportive
• Biologic Warfare: Many countries have considered weaponizing these viruses.

WATER SUPPLY THREATS (VIBRIO CHOLERAE, CRYPTOSPORIDIUM PARVUM)

The water supply and water treatment facilities are a possible target for terrorists.

• Signs/Symptoms: Ingestion of water born agents typically leads to nausea, vomiting, and diarrhea.
• Treatment: Depends on the pathogen. Most are supportive, but antibiotics may shorten the course.
• Biologic Warfare: Agents released into the water supply are a potential biologic weapon.

Category C [9]

Category C agents are emerging pathogens that could be engineered for mass dissemination because of their availability, ease of production and dissemination, mortality rate, and ability to cause a substantial health impact.

H1N1 INFLUENZA

Influenza A (H1N1) virus is a subtype of influenza A and a common cause of the human flu. It is an orthomyxovirus that contains haemagglutinin and neuraminidase. Haemagglutinin causes red blood cells to clump together. Neuraminidase is a glycoside hydrolase enzyme that moves the virus particles through the infected cell.

• Signs/Symptoms: Influenza-like illness with chills, fever, sore throat, muscle pains, headache, cough, weakness, and general discomfort. The recommended time of isolation is five days.
• Treatment: Supportive.
• Biologic Warfare: Due to high virulence and rapid distribution in the community it is possible it could be weaponized.

HANTAVIRUS

Hantaviruses or orthohantaviruses are single-stranded, enveloped, negative-sense RNA viruses within the Hantaviridae family of the order of Bunyavirales. These viruses have the potential to kill humans. Humans become infected from contact with rodent feces, saliva, or urine.

• Signs/Symptoms: Hemorrhagic fever with renal syndrome is caused hantaviruses. In hantavirus-induced hemorrhagic fever, incubation time is 2 to 4 weeks. The severity of symptoms depends on the viral load. Hantavirus pulmonary syndrome is an often-fatal pulmonary disease. Prodromal symptoms include flu-like symptoms such as fever, cough, muscle pain, headache, and lethargy. It is characterized by shortness of breath with rapidly evolving pulmonary edema that is often fatal despite mechanical ventilation.
• Treatment: Supportive treatment with oxygen and mechanical ventilation during the acute pulmonary stage. Administration of human neutralizing antibodies during acute phases of Hantavirus might also prove effective.
• Biologic Warfare: Hantavirus hemorrhagic fever has not been shown to transfer from person to person. Transmission is by aerosolized rodent excreta to humans, and in the hospital setting transmission would be unlikely with universal precautions. It is possible it could be weaponized.

HIV/AIDS

Human immunodeficiency virus and acquired immune deficiency syndrome are conditions caused by infection with human immunodeficiency virus.

• Signs/Symptoms: Acute seroconversion manifests as a flu-like illness, with fever, malaise, and a generalized rash. The asymptomatic phase is generally benign. Generalized lymphadenopathy is common and may be a presenting symptom.
• Treatment: Depends on the stage of the disease and any concomitant opportunistic infections. In general, the goal of treatment is to prevent the immune system from deteriorating using antiretroviral therapy (HAART). In addition, prophylaxis for specific opportunistic infections is indicated.

NIPAH VIRUS

Nipah virus (NiV) infection is a zoonosis that causes severe disease in humans. The natural host of the virus is the fruit bats of the Pteropodidae family, Pteropus genus. Human-to-human transmission has also been documented. NiV infection in humans has a range of clinical presentations, from asymptomatic infection to acute respiratory syndrome and encephalitis.

• Signs/Symptoms: Cough, fever, headache, drowsiness, abdominal pain, nausea, vomiting, weakness, difficulty swallowing, blurred vision, seizures, and about 60% become comatose and need mechanical ventilation. Patients with severe disease may develop hypertension, tachycardia, and a very high temperature.
• Treatment: Supportive measures as there is no definitive treatment. Ribavirin may help.
• Biologic Weapon: Transmission may be human-to-human transmission. The reservoir is Pteropid fruit bats, Pteropus vampyrus (Large Flying Fox), and Pteropus hypomelanus (Small flying fox), found in Malaysia. The transmission of Nipah virus from flying foxes to pigs is thought to be due to increasing overlap between bat habitats and pig farms. It is possible it could be weaponized.

SARS

Severe acute respiratory syndrome (SARS) is a zoonotic viral respiratory disease caused by the SARS coronavirus.

• Signs/Symptoms: High fever, body aches, diarrhea, and dry cough. Often progresses to pneumonia.
• Treatment: Supportive care with oxygen and ventilation. Antiviral medications and steroids may reduce lung swelling.
• Biologic Weapon: Spread is by close person-to-person contact. The virus that causes SARS is thought to be transmitted by respiratory droplets produced when an infected person coughs or sneezes. Due to its high infectivity, it is possible it could be weaponized.

CHEMICAL WEAPONS

A chemical weapon is a specialized munition that uses chemicals formulated to inflict harm or death. Chemical weapons are classified as weapons of mass destruction, and they are distinct from nuclear weapons, biological weapons, and radiological weapons. Chemical weapons can be dispersed in a gas, liquid, and solid forms.

• Lethal chemical agents and munitions are volatile, and they constitute a class of hazardous chemical weapons that have been stockpiled by many nations.
• Unitary agents are effective on their own and do not require mixing with other agents. The most dangerous of these are nerve agents (GA, GB, GD, and VX) and vesicant (blister) agents, which include sulfur mustard such as H, HT, and HD. They all are liquids at normal room temperature but become gaseous when released.

Under the Chemical Weapons Convention, there is a worldwide ban on the production, stockpiling, and use of chemical weapons. Notwithstanding, large stockpiles of chemical weapons exist, usually justified as a precaution against an aggressor.

Types of Chemical Agents [10]

BLISTER: Distilled mustard, mustard gas, lewisite, mustard/lewisite, mustard/T, nitrogen mustard, phosgene oxide, and sulfur mustard

A blister agent or vesicant is named for its ability to cause severe chemical painful water blisters on the bodies of those affected. Vesicants have potential medical uses including wart removal, but they are fatal if small amounts are ingested.

• Signs/Symptoms: Burning, itching, nausea, vomiting, shortness of breath, pulmonary edema, tearing, and upper airway sloughing.
• Treatment: Mustard no antidote, lewisite – British Anti-Lewisite and supportive care.
• Other: Vesicants are oily reactive chemicals that combine with DNA and proteins to cause cellular changes within minutes to hours after exposure. Garlic, onion, or mustard smell.

BLOOD AGENTS: Cyanogen chloride, hydrogen cyanide

A blood chemical agent is a toxic compound that affects the body by being absorbed into the blood. They are fast-acting, highly lethal toxins that are typically volatile colorless gases with a faint odor. They are usually either arsenic or cyanide-based.

• Signs/Symptoms: Convulsions, cyanosis, fatigue, headache, hyperventilation, hypotension, lightheadedness, loss of consciousness, metabolic acidosis, palpitations, nausea, vomiting, and death in 1 to 20 minutes.
• Treatment: 100% O2, sodium thiosulfate injection – 12.5 g/50 mL (2 vials), sodium nitrate – 300 mg/10 mL (2 ampules), amyl nitrite inhalant 0.3 mL (12 ampules), and hydroxocobalamin 5 g

CHOKING AGENTS: Chlorine, chloropicrin, nitrogen oxides, phosgene, and sulfur dioxide

Chemical agents which attack lung tissue, primarily causing pulmonary edema, are classed as lung-damaging or choking agents.

• Signs/Symptoms: Chest tightness, dermal irritation, laryngospasm, mucosal irritation, pulmonary edema, shortness of breath, and wheezing
• Treatment: Manage secretions, oxygen, intubate and treat pulmonary edema with PEEP to maintain pO2 greater than 60 mm Hg. High-dose steroids to treat pulmonary edema for nitrogen oxide.

INCAPACITATION: BZ, CS, CN, and LSD

An incapacitation agent that produces temporary physiological or mental effect which will render individuals incapable of the performance of their duties.

• Signs/Symptoms: Confusion, dizzy, dry mouth, hypertension, runny nose, shortness of breath, skin burns, sweating, tachycardia, and tremors
• Treatment: Flush eyes and skin, treat symptomatically

NERVE: Organic pesticides, sarin, soman, and tabun

Nerve agents are organic chemical (organophosphates) that disrupt nerve transfer messages to organs by blocking acetylcholinesterase, an enzyme that catalyzes the breakdown of acetylcholine. Nerve agents are easily vaporized, and may enter through the respiratory system. The skin can also absorb them. A full body suit is required for exposure protection.

• Signs/Symptoms: Bronchial constriction, cramps, diarrhea, dyspnea, increased secretions, miosis, respiratory arrest, sweating, tremors, convulsions, paralysis, and loss of consciousness.
• Treatment: Atropine every 5 to 10 minutes until secretions stop; 2-PAM CL up to 3 injections within minutes if possible.
• Other: The Military Mark I kit is often available and is preloaded with 2 mg of atropine and 600 mg of 2-PAM CL

Plague Microbiology and Pathogenesis

The Agent

General Characteristics

Y. pestis is a Gram-negative, microaerophilic, pleomorphic coccobacillus (1.0-2.0 μm × 0.5 μm) belonging to the family Enterobacteriacae (Perry and Fetherston, 1997). In direct smears, Y. pestis presents as single cells or short chains of cells, characteristically appearing as plump bacilli exhibiting a bipolar staining (closed safety-pin) appearance when treated with Wayson, Giemsa, or Wright stains.

The bacillus is nonmotile and non-sporulating. It does not ferment lactose and is catalase-positive, and urease-, oxidase-, and indole-negative. Y. pestis is relatively nonreactive, and automated biochemical systems may lead to misidentifications unless correctly programmed (Wilmoth et al., 1996).

Growth occurs in a variety of media at a wide range of temperatures (4–40°C; optimal 28-37°C) and pH values (5.0-9.6; optimal 6.8-7.6). However, Y. pestis grown at 28-30°C and with pH over 7.2 is more stable under natural conditions and in an aerosol form (K. Alibek, personal communication). Y. pestis is relatively slow growing in culture, with pinpoint colonies usually visible after 24 hours of growth at 28°C on sheep blood agar and later on MacConkey agar.

The colonies are raised and opalescent in appearance, developing a hammered copper-appearing surface and irregular borders as they grow larger. In broth culture, a stalactite pattern of growth occurs along the sides of the vessel and settles to the bottom in clumps if disturbed.

Almost all naturally occurring Y. pestis strains have been found to be susceptible in vitro to tetracyclines, chloramphenicol, sulfonamides, aminoglycosides, and fluoroquinolones (Frean et al., 1996, 2003; Smith et al., 1995).

Rarely, isolates from several areas of the world have shown incomplete susceptibility to one or more antimicrobials recommended for treating plague (Rasoamanana et al., 1989); these have occurred in isolated instances, have not been followed by a recognized wider emergence of these strains, and have not required modifications of standard protocols for treatment and control.

However, of greater concern was the identification in 1995 of a strain of Y. pestis from a patient in Madagascar who was multiply resistant to the principal recommended antimicrobials used in treating plague, and the resistance was plasmid-mediated and transferable (Galimand et al., 1997).

This finding elicited calls for intensified surveillance of patients and the environment (Dennis and Hughes, 1997), which fortunately have not led to identification of other such strains in Madagascar or elsewhere.

Molecular Genetics

Gene sequencing comparisons of multiple strains of Y. pestis, Y. pseudotuberculosis, and Y. enterocolitica show that Y. pestis, a blood-borne organism, only recently (1,500– 20,000 years ago) evolved from Y. pseudotuberculosis, an enteric pathogen (Achtman et al. 1999).

Decoding of the entire genome of Y. pestis (consisting of 4.65 Mb chromosome and three plasmids of 96.2 kb, 70.3 kb, and 9.6 kb) disclosed that the evolution of Y. pestis was made possible by the acquisition of virulence determinants suitable for systemic invasion of mammalian hosts and replication in the flea, and by the inactivation of genes required for enteric survival (Parkhill et al., 2001).

These genomic studies suggest that Y. pestis is a pathogen that has undergone large-scale genetic flux and provide a unique insight into how new and highly virulent pathogens evolve. Three classic biovars of Y. pestis have been identified, including biovar Antiqua, Medievalis, and Orientalis, linked respectively to the three historical pandemics.

Results of typing by restriction fragment-length polymorphism analysis of rRNA genes (ribotyping) support these distinctions and have shown chromosomal rearrangements in the Orientalis biotype that occurred following its spread around the world about 100 years ago (Guiyoule et al., 1994). Further studies of polymorphisms show considerable genome plasticity, even within strains from one geographic area (Guiyoule et al., 1997; Radnedge et al., 2002).

Pathogenicity of Y. pestis

Virulence Factors

Y. pestis is among the most pathogenic bacteria known. Although it is a facultative intracellular pathogen that normally grows in extracellular environments, virulence is in part dependent on invasion and multiplication within cells, including phagocytes that transport the bacterium in the initial phases of infection (Hinnebusch, 1997; Perry and Fetherston, 1997). Both chromosomal and plasmid-encoded gene products are associated with adaptability to its various hosts and to virulence (Carniel, 2003; Hinnebusch, 1997; Hinnebusch et al., 2002; Koornhof et al., 1999; Perry and Fetherston, 1997; Smego et al., 1999).

Chromosomal genes of Y. pestis express a potent lipopolysaccharide endotoxin and a factor that controls the absorption of exogeneous iron. Of the three major plasmids, the pes-ticin (pst) plasmid (~9.5 kb) has genes that encode for a plasminogen activator (Pla) and a bacteriocin or pesticin (Pst).

The low calcium response or Lcr plasmid (~70 kb), which is shared with other yersiniae, encodes products that activate the V and W antigens and outer surface proteins (Yops) under low calcium conditions.

The caf operon of the pFra (Tox) plasmid (~110 kb) encodes the F1 glycoprotein envelope antigen (Caf1) and a murine toxin (Ymt) unique to Y. pestis. F1 antigen is produced only when Y. pestis grows at 30°C or greater; strains expressing F1 antigen are able to resist phagocytosis in the absence of opsonizing antibodies. In summary, Y. pestis virulence factors are thought to mediate the following responses between invading organism and the human host:

• The lipopolysaccharide endotoxin activates complement and triggers the release of kinins and other proinflammatory mediators;
• The chromosomally mediated hemin storage molecule (Hms) enhances Y. pestis survival in phagocytes and facilitates uptake of the bacillus into eukaryotic cells;
• Another chromosomally encoded product, the pH 6 antigen (Psa), inhibits Y. pestis phagocytosis;
• The plasminogen activator (Pla) is a single surface protease that degrades fibrin and other extracellular proteins, facilitating systemic spread of Y. pestis;
• The V and W antigens block phagocytosis of Y. pestis, and the V antigen promotes survival of Y. pestis in macrophages;
• Yops expressed by the 70-kb plasmid inhibit phagocytosis and platelet aggregation, and block an effective inflammatory response;
• The 110-kb plasmid-associated 17-kDa polypeptide F1 antigen (produced optimally at 37°C) is antiphagocytic and also elicits a strong humoral immune response.

Several factors have been identified that are selectively expressed by Y. pestisin the gut of fleas. For example, hemin storage locus (hms) products expressed at <30°C enable the bacteria to form blockages of the flea gut necessary for efficient transmission. Expression in the midgut of murine toxin (recently identified as phospholipidase D) protects Y. pestis from cytotoxic digestion by blood plasma products (Perry, 2003).

Pathology of Infection

The virulence of Y. pestis is expressed in a wide spectrum of disease that reflects the portal of pathogen entry and the organ systems targeted (Butler, 1972, 1983; Crook and Tempest, 1992; Dennis and Gage, 2004; Dennis and Meier, 1997; Hull et al., 1987; Welty et al., 1985; Wu, 1926).

Plague organisms inoculated through the skin or mucous membranes typically are transported within lymphatic vessels to afferent, regional nodes, where they multiply. In the early stages of infection, affected nodes show vascular congestion, edema, and minimal inflammatory infiltrates or vascular injury; later, however, nodes may contain enormous numbers of infectious plague organisms and demonstrate vascular breaks, hemorrhagic necrosis, and infiltration by neutrophilic leukocytes.

These affected nodes (buboes) are typically surrounded by a collection of serous fluid, often blood-tinged. When several adjacent lymph nodes are involved, a boggy, edematous mass can result. In later stages, abscess formation and spontaneous rupture of buboes may occur.

Y. pestis can invade and cause disease in almost any organ, and untreated infection usually results in widespread and massive tissue destruction. Diffuse interstitial myocarditis with cardiac dilatation, multifocal necrosis of the liver, diffuse hemorrhagic necrosis of the spleen and involved lymph nodes, and fibrin thrombi in renal glomeruli are commonly found in fatal cases (Butler, 1972; Dennis and Meier, 1997; Finegold, 1968).

Pneumonitis, pleuritis, and meningitis occur less frequently. Abcesses may form in affected organs. Disseminated intravascular coagulation (DIC) is associated with generation of microthrombi, thrombocytopenia, necrosis, and bleeding in affected tissues (Butler, 1972).

Petechiae and ecchymoses commonly appear in the skin, and on mucosal and serosal surfaces. Ischemia and gangrene of acral parts, such as fingers and toes, may occur in the late stages of this process (Dennis and Meier, 1997; Pollitzer, 1954; Wu, 1926).

Primary plague pneumonia resulting from inhalation of infective respiratory particles usually begins as a lobular process and then extends by confluence, becoming lobar and then multilobar. Typically, plague organisms are numerous in the alveoli and in pulmonary secretions.

Secondary plague pneumonia arising from hematogeneous seeding of the lungs may begin more diffusely as an interstitial process. In untreated cases of both primary and secondary plague pneumonia, disease progresses to diffuse pulmonary congestion, hemor-rhagic necrosis of pulmonary parenchyma, and infiltration by neutrophilic leukocytes (Wu, 1926). In advanced untreated stages, the alveolae are filled with fluid containing massive numbers of plague bacilli.

Clinical Spectrum

Bubonic Plague

Bubonic plague is characterized by the development of one or more swollen, tender, inflamed lymph nodes termed buboes, from the Greek bubon, meaning groin. Bubonic plague has a usual incubation period of 2–6 days, occasionally longer.

Typically, bubonic plague is heralded by the sudden onset of chills, fever that rises within hours to 100.4F (38°C) or higher, accompanied by headache, myalgias, arthralgias, and a profound lethargy. Soon, usually within a few hours of symptom onset, increasing swelling, tenderness, and pain occur in one or more regional lymph nodes proximal to the portal of entry.

The femoral and inguinal groups of nodes are most commonly involved, axillary and cervical nodes less frequently, varying with the site of inoculation. Buboes occur at a single site in about 90% of cases; sometimes, more than one regional gland grouping may be affected, and bacteremic spread can result in a generalized lymphadenopathy.

Typically, the patient guards against palpation and limits movement, pressure, and stretching around the bubo. The surrounding tissue often becomes edematous, sometimes markedly; and the overlying skin is typically reddened, warm, tense, and occasionally desquamated.

The bubo of plague differs from lymphadenitis of most other causes by its rapid onset, extreme tenderness, surrounding edema, accompanying signs of toxemia, and usual absence of cellulitis or obvious ascending lymphangitis. Inspection of the skin surrounding the bubo or distal to it may reveal the site of bacterial inoculation marked by a small papule, pustule, scab, or ulcer (phlyctenule).

A large furuncular lesion at site of entry, resulting in an ulcer that may be covered by an eschar, occurs occasionally (Figure 2.1). Presenting manifestations in a series of 40 Vietnamese bubonic plague patients were as follows (Butler, 1972):

• Fever (100%; mean of 39.4°C in 32 patients)
• Bubo (100%): groin (88%); axilla (15%); cervical (5%); and epitrochlear (3%)
• Headache (85%)
• Prostration (75%)
• Chills (40%)
• Anorexia (33%)
• Vomiting (25%)
• Cough (25%)
• Skin rash, including petechiae, purpura, and papular eruptions (23%)
• Abdominal pain (18%)
• Chest pain (13%)

Altered brain function—manifest as lethargy, confusion, delirium, seizures—was also common in patients in the Vietnam series.

If treated with an appropriate antimicrobial agent, uncomplicated plague responds quickly, with resolution of fever and other systemic manifestations over a 2- to 5-day period.

Buboes often remain enlarged and tender for a week or more after treatment has begun, and infrequently become purulent and fluctuant, and may require incision and drainage.

Untreated, they may spontaneously rupture and drain. Without effective antimicrobial treatment, bubonic plague patients typically become increasingly toxic, with fever, tachycardia, lethargy leading to prostration, agitation and confusion, and, occasionally, convulsions and delirium.

In the preantibiotic era, the case fatality ratio for bubonic plague was greater than 50%, and it is now about 5%. Mild forms of bubonic plague, called pestis minor, have been described in South America and elsewhere; in these cases, the patients are ambulatory and only mildly febrile and have subacute buboes (Legters et al., 1970).

The epidemiology and pathophysiology of these mild cases are poorly described, and the syndrome has been attributed to immunological tolerance rather than to a lesser virulence of infecting strains.

There is some evidence from serological studies in endemic areas that subclinical Y. pestis infections do occur in endemic populations (Ratsitorahina et al., 2000a, 2000b).

Differential diagnostic possibilities for bubonic plague include streptococcal or staphylococcal adenitis, tularemia, cat scratch disease, mycobacterial infection, acute filar-ial lymphadenitis, aspergillosis and other fungal conditions, chancroid and other sexually transmitted diseases that cause regional lymphadenitis, and strangulated inguinal hernia.

Septicemic Plague

Plague sepsis is manifest as a rapidly progressive, overwhelming endotoxemia (Butler et al., 1976; Hull et al., 1987). Plague sepsis in the absence of signs of localized infection, such as a bubo, is termed primary septic plague.

It can result from direct entry of Y. pestis through broken skin or mucous membranes, or from the bite of an infective flea. Secondary septic plague can occur in the course of bubonic or pneumonic plague when lymphatic or pulmonary defenses are breached, and the plague bacillus enters and multiplies within the bloodstream.

Bacteremia is common in all forms of plague; sep-ticemia is less common and is immediately life threatening. A diagnosis of primary plague sepsis is often not made until results of blood culture are reported by the laboratory, since there is little to clinically distinguish plague sepsis from other causes of sepsis.

Occasionally, plague organisms are visible in stained peripheral blood smears, indicating a poor prognosis (Butler et al., 1976; Hull et al., 1987; Mann et al., 1984). The clinical diagnosis of plague sepsis may be obscured by prominent gastrointestinal symptoms, such as nausea, vomiting, diarrhea, and abdominal pain (Hull et al., 1986).

If not treated early with appropriate antibiotics and aggressive supportive care, septic plague is usually fulminating and fatal. Petechiae, ecchymoses, bleeding from puncture wounds and orifices, and subsequent ischemia and gangrene of acral parts are some manifestations of DIC (Figure 2.2).

Refractory hypotension, renal shut down, stupor, and other signs of shock are preterminal events. Acute respiratory distress syndrome, which can occur at any stage of septic plague, may be confused with other conditions, such as the hantavirus pulmonary syndrome.

Presenting manifestations of septicemic plague in a case series of 18 patients in New Mexico (Hull et al., 1987) include:

• Fever (100%); mean temperature 38.5°C, range 35.4–40.4°C
• Any gastrointestinal symptom (72%)
• Chills (61%)
• Vomiting (50%)
• Nausea (44%)
• Headache (44%)
• Diarrhea (39%)
• Abdominal pain (39%)

Because the diagnosis of plague is often made late, the case fatality ratio is 25% or greater among septicemic patients treated in the US (Crook and Tempest, 1992; Dennis and Chow, 2004; Hull et al., 1987) and approaches 100% in those not receiving appropriate antibiotics.

Differential diagnostic possibilities include any other overwhelming systemic infection, including Gram-negative sepsis with agents other than the plague bacterium, meningococcemia, and bacterial endocarditis.

Pneumonic Plague

Pneumonic plague is the most rapidly developing and fatal form of plague (Doll, 1994; Laforce et al., 1971; Meyer, 1961; Ratsitorahina et al., 2000a; Tieh et al., 1948; Wu, 1926; Wu et al., 1922; Wynne-Griffith, 1948). The incubation period for primary pneumonic plague is usually 3–5 days (range 1–7 days) (Wu, 1926; Wu et al., 1922; K. Alibek, personal communication).

The onset is typically sudden, with severe headache, chills, fever, tachycardia, body pains, weakness, dizziness, and chest discomfort. Abdominal pain, nausea, and vomiting may also be present.

Cough, sputum production, increasing chest pain, tachypnea, and dyspnea typically predominate on day 2 of the illness, and these features may be accompanied by bloody sputum, increasing respiratory distress, cardiopulmonary insufficiency, and circulatory collapse.

In primary plague pneumonia, the sputum is most often watery or mucoid, frothy, and blood-tinged, but it may become frankly bloody. Chest signs in primary plague pneumonia may indicate localized pulmonary involvement in the early stage; a rapidly developing segmental consolidation may be seen before bronchopneumonia occurs in other segments and lobes of the same and opposite lung (Figure 2.3).

Liquefaction necrosis and cavitation may develop at sites of consolidation and leave significant residual scarring.

Plague pneumonia arising from metastatic spread is more likely to present in early stages as an interstitial pneumonitis in which sputum production is at first scant. The disease progresses rapidly, however, and chest radiographs described for nine cases of secondary plague pneumonia showed alveolar infiltrates in all cases and pleural effusions in more than half of patients (Alsofrom et al., 1981).

Advanced cases often develop refractory pulmonary edema and sepsis syndrome. In the US, there have been no recorded cases of person-to-person transmission of plague since 1924, although more than 50 cases of pneumonic plague have occurred in that time period, with several thousand persons potentially exposed to infection from these patients (Centers for Disease Control, 1984; Centers for Disease Control and Prevention, unpublished data).

Differential diagnostic possibilities include other bacterial pneumonias, such as mycoplasma pneumonia, Legionnaire’s disease, staphylococcal or streptococcal pneumonia, tularemia pneumonia, and Q fever. Severe viral pneumonia, including hantavirus pulmonary syndrome and acute respiratory syndrome from coronavirus infection, could be confused with plague.

TREATMENT OPTIONS AND PREVENTION

Streptomycin was approved by the Food and Drug Administration (FDA) for plague; historically, it has been the preferred treatment (25). When administered early in the disease, streptomycin has reduced the overall mortality from plague to the 5%-to-15% range (32).

Because US supplies of streptomycin are limited, many experts have suggested gentamicin as an alternative form of treatment, although it is not FDA approved for this indication. Its efficacy was equal to or better than that of streptomycin in some in vitro as well as in vivo studies in mice (43).

In addition, gentamicin is widely available, inexpensive, and can be given as a single daily dose. In a contained casualty setting, streptomycin and gentamicin are the preferred choices for treatment of adults and children, and gentamicin is the preferred choice for pregnant women. However, both drugs have to be administered via intramuscular or intravenous injection.

In a mass casualty setting, oral drugs may be needed. The Working Group on Civilian Biodefense (3a) has recommended several oral drugs for the treatment and prophylaxis of plague, acknowledging that many are not FDA approved for that indication.

These other antibiotics are tetracycline, doxycycline, chloramphenicol, and fluoroquinolones. Within the latter group, preference is given to ciprofloxacin, which has been shown to be at least as efficacious as aminoglycosides and tetracyclines.

Chloramphenicol has been recommended for the treatment of plague meningitis because of its ability to cross the blood-brain barrier (25).

Beta-lactam antibiotics are not effective in the treatment of plague. Antibiotics that have been shown in animal studies to have poor efficacy against Y. pestis include rifampin, aztreonam, ceftazidime, cefotetan, and cefazolin.

These antibiotics should therefore not be used in the treatment of plague. Resistance patterns must be considered when choosing an antibiotic for the treatment of plague, and antibiotic susceptibility testing should be performed at a reference laboratory because of the lack of standardized susceptibility procedures for Y. pestis (44).

Consensus recommendations were made for special groups based on the clinical and evidence-based judgments of the working group (3a); again, these recommendations do not necessarily correspond to FDA-approved use, indications, or labeling.

In contained and/or mass casualty settings, children should be treated with streptomycin or gentamicin. Chloramphenicol is also considered safe in children aged ≥2 years. In mass casualty settings, children aged ≥8 years may be safely treated with tetracyclines. Given the adverse effects of tetracyclines and fluoroquinolones, the working group agreed that in mass casualty settings children can be safely treated with doxycycline (3, 45).

Special recommendations have also been made for pregnant women, in whom aminoglycosides should be avoided (45). However, in cases of severe illness and/or in a contained casualty setting, treatment with gentamicin is recommended for pregnant women (3a).

Balancing the risks of pneumonic plague infection with those associated with doxycycline and ciprofloxacin use during pregnancy, the working group recommended that in pregnant women doxycycline should be used if gentamicin is not available.

No specific recommendation have been made for the treatment of immunocompromised patients due to a lack of studies or animal models of pneumonic plague infection in the immunosuppressed population. At this point, the best recommendation is to proceed with the treatment option given to immunocompetent adults and children (3a).

Postexposure prophylaxis for plague should be administered to individuals with close contact (<2 m) with an infectious case and to those who had potential respiratory exposure.

The recommended regimen is doxycycline or ciprofloxacin given for 7 days on the same schedule as for treatment. The working group recommends doxycycline as the first-choice antibiotic for post-exposure prophylaxis (3a).

In addition, all persons developing a temperature of 38.5°C or higher or with symptoms of a new-onset cough should promptly begin antibiotic treatment. For infants in this setting, tachypnea would also qualify as an indication for immediate treatment.

In a mass casualty setting, special consideration should be given to surveillance of the targeted population in order to identify individuals and communities at risk requiring postexposure prophylaxis. Many of these individuals may not be aware of the outbreak and therefore require special assistance.

Currently, no preexposure prophylaxis or vaccine is available for plague. Until 1999, a formalin-killed whole-cell vaccine was available in the USA for military personnel and researchers; however, it was discontinued after studies found that the vaccine was protective only for bubonic plague and completely lacked protection for pneumonic plague.

A similar vaccine was in use in Canada, the United Kingdom, and Australia. With the reemergence of the bioterrorism threat, new efforts have been made to develop a new, possibly genetic-based, vaccine.

The recent efforts have focused on the development of immunity to the F1 capsular protein and the V antigen (46, 47). Research in the pursuit of developing a vaccine that can effectively protect against primary pneumonic plague is ongoing in military research institutions in the USA, Israel, and the United Kingdom. Further information on vaccine development is available from these institutions and will hopefully be available through publication soon.

To date, no evidence exists that plague bacilli pose an environmental threat to the population. In fact, Y. pestis is very sensitive to sunlight and heat and does not survive long outside the host (39).

Although some reports suggest that Y. pestis may survive in the soil and decaying animal carcasses, there is no evidence suggesting an environmental risk to humans in this specific setting. In the WHO risk analysis (39), it was estimated that a plague aerosol would remain effective and infectious for as long as 1 hour after its release.

In the setting of a clandestine attack with plague, the aerosol would therefore long be dissipated before the first patient of pneumonic plague would come to hospital emergency departments.

Modern experience with person-to-person transmission of pneumonic plague is extremely limited. In large plague epidemics in earlier centuries, wearing masks prevented pneumonic plague transmission. Given the available historical evidence, the working group recommends that patients should remain isolated for the first 48 hours of antibiotic therapy and until clinical improvement occurs.

Other standard respiratory droplet precautions such as gown, gloves, and eye protection should be implemented as well. In mass casualty settings, individual isolation of patients may become impossible. In this scenario, patients with (pneumonic) plague may be cohorted in isolation while undergoing antibiotic treatment.

Should there be a need to transport patients to other facilities, the patients should wear surgical masks. Bodies of patients who have died from plague should be handled with strict routine precautions. However, aerosol-generation procedures such as bone sawing associated with surgery or postmortem examination is not recommended, since those activities are associated with a high risk of disease transmission. If such procedures are ultimately necessary, high-efficiency particulate air-filtered masks and negative-pressure rooms should be used (48).

In recent years, there is increased concern that a possible bioterrorism attack with plague might employ a natural or bio-engineered drug-resistant strain. Natural resistance of Y. pestis to antibiotics was rare; however, in 1995 a plague isolate from Madagascar contained a multidrug-resistant transferable plasmid (49).

The organism produced TEM-1 (β-lactamase, chloramphenicol acetyltransferase, and a streptomycin-modifying enzyme. Later that year, a second strain was identified with a plasmid that encoded for the streptomycin-modifying phosphotransferase gene, which resulted in high-level streptomycin resistance (50).

Both organisms were shown to contain plasmids that were easily transferred to other strains of Y. pestis as well as to Escherichia coli. Y. pestis is a member of the Enterobacteriaceae family, and as such it will be able to exchange genetic material with multiple genera within this family of organisms.

As there are reports that the bioweapons operations of the former Soviet Union engineered multidrug-resistant and fluoroquinolone-resistant strains of Y. pestis (3a, 40), this new evidence of naturally occurring drug resistance in isolates of Y. pestis underlines the importance of continuous reevaluation of guidelines for diagnosis and treatment of plague. More research is needed for effective treatment and vaccine development.

REFERENCE

3.Edwards DS, Barnett-Vanes A, Narayan N, Patel HD. Prophylaxis for blood-borne diseases during the London 7/7 mass casualty terrorist bombing: a review and the role of bioethics. J R Army Med Corps. 2016 Oct;162(5):330-334. [PubMed]

4.Joseph B, Brown CV, Diven C, Bui E, Aziz H, Rhee P. Current concepts in the management of biologic and chemical warfare causalities. J Trauma Acute Care Surg. 2013 Oct;75(4):582-9. [PubMed]

5.Bossi P, Bricaire F. [The plague, possible bioterrorist act]. Presse Med. 2003 May 17;32(17):804-7. [PubMed]

6.Voigt EA, Kennedy RB, Poland GA. Defending against smallpox: a focus on vaccines. Expert Rev Vaccines. 2016 Sep;15(9):1197-211. [PMC free article] [PubMed]

7.Barras V, Greub G. History of biological warfare and bioterrorism. Clin. Microbiol. Infect. 2014 Jun;20(6):497-502. [PubMed]

8.Cenciarelli O, Gabbarini V, Pietropaoli S, Malizia A, Tamburrini A, Ludovici GM, Carestia M, Di Giovanni D, Sassolini A, Palombi L, Bellecci C, Gaudio P. Viral bioterrorism: Learning the lesson of Ebola virus in West Africa 2013-2015. Virus Res. 2015 Dec 02;210:318-26. [PubMed]

9.Moran GJ. Threats in bioterrorism. II: CDC category B and C agents. Emerg. Med. Clin. North Am. 2002 May;20(2):311-30. [PubMed]

10.Kotora JG. An assessment of Chemical, Biological, Radiologic, Nuclear, and Explosive preparedness among emergency department healthcare providers in an inner city emergency department. Am J Disaster Med. 2015 Autumn;10(3):189-204. [PubMed]

3a. Alsofrom D.J., Mettler F.A., Jr., Mann J.M. Radiographic manifestations of plague in New Mexico, 1975–1980: a review of 42 proved cases. Radiology. 1981;139:561–565. [PubMed] [Google Scholar]
American Society of Microbiology, Biological Weapons Resources Center. (2003). http://www.asmusa.org.

32. Centers for Disease Control and Prevention Biological and chemical terrorism: strategic plan for preparedness and response. Recommendations of the CDC Strategic Planning Workgroup. MMWR Morb. Mortal. Wkly. Rep. 2000;49(RR-4):1–14. [PubMed] [Google Scholar]

39 Chanteau S., Rahalison L., Ratsitorahina M., Mahafaly Rasolomahoro M., Boisier P., O’Brien T., Aldrich J., Keleher A., Morgan C., Burans J. Early diagnosis of bubonic plague using F1 antigen capture ELISA assay and rapid immunogold dipstick. Int. J. Med. Microbiol. 2000;290:279–283. doi: 10.1016/S1438-4221(00)80126-5. [PubMed] [CrossRef] [Google Scholar]

40 Chanteau S., Ratsifasoamanana L., Rasoamanana B., Rahalison L., Randriambelosoa J., Roux J., Rabeson D. Plague, a reemerging disease in Madagascar. Emerg. Infect. Dis. 1998;4:101–104. doi: 10.3201/eid0401.980114. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

41 Christie A.B., Chen T.C., Elberg S.S. Plague in camels and goats: their role in human epidemics. J. Infect. Dis. 1980;141:724–726. doi: 10.1093/infdis/141.6.724. [PubMed] [CrossRef] [Google Scholar]

42 Craven R.B., Maupin G.O., Beard M.L., Quan T.J., Barnes A.M. Reported cases of human plague infections in the United States, 1970–1991. J. Med. Entomol. 1993;30:758–761. [PubMed] [Google Scholar]

43 Crook L.D., Tempest B. Plague—a clinical review of 27 cases. Arch. Intern. Med. 1992;152:1253–1256. doi: 10.1001/archinte.1992.00400180107017. [PubMed] [CrossRef] [Google Scholar]

44 Cunha B.A. Doxycyline for community-acquired pneumonia. Clin. Infect. Dis. 2003;37:870. doi: 10.1086/377615. [PubMed] [CrossRef] [Google Scholar]

45 Dellinger R.P. Inflammation and coagulation: implications for the septic patient. Clin. Infect. Rev. 2003;36:1259–1265. doi: 10.1086/374835. [PubMed] [CrossRef] [Google Scholar]

46 Dennis D.T., Chow C.C. Plague. Pediatr. Infect. Dis. 2004;23:69–71. doi: 10.1097/01.inf.0000106918.18570.dd. [PubMed] [CrossRef] [Google Scholar]

47 Dennis D., Meier F. Plague. In: Horsburgh C.R., Nelson A.M., editors. Pathology of Emerging Infections. Washington, D.C.: ASM Press; 1997. pp. 21–47. [Google Scholar]

48 Dennis D.T. Plague in India. Br. Med. J. 1994;309:893–894. doi: 10.1136/bmj.309.6959.893. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

49 Dennis D.T. Plague as an emerging disease. In: Scheld W.M., Craig W.A., Hughes J.M., editors. Emerging Infections. Washington, D.C.: ASM Press; 1998. pp. 169–183. [Google Scholar]

50 Dennis D.T. Plague. In: Rakel R.E., Bope E.T., editors. Conn’s Current Therapy, 2001. Philadelphia: W.B. Saunders; 2001. pp. 115–117. [Google Scholar]