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CHAPTER 3
Category A Diseases and Agents
Abstract
This chapter offers a comprehensive overview of Health and Human Services Category A agents, the most serious of all biological threats. Category A agents are those that lead to high morbidity and mortality of their victims, may be easily disseminated or spread from person to person, may cause panic and/or social disruption, and require special precautions for public health. Within this chapter, the signs and symptoms of anthrax, plague, tularemia, smallpox, viral hemorrhagic fever, and botulism are covered in detail. In addition, clinical manifestations, prophylaxis and medical treatment strategies used to counter these diseases are also covered. From this information the reader will appreciate and understand the challenges that public health officials and emergency management practitioners face when an intentional release of a Category A agent occurs in their community.
Keywords
Anthrax; Arenavirus; Bacillus anthracis; Botulism; Bunyaviruses; Category A; Clostridium botulinum; Contact; Filovirus; Flavivirus; Francisella tularensis; Plague; Smallpox; Tularemia; Viral hemorrhagic fever; Yersinia pestis
The single biggest threat to man’s continued dominance on the planet is a virus.
Joshua Lederberg, PhD, Nobel Laureate
OBJECTIVES
The study of this chapter will enable you to:
1. List and explain the criteria used to define Category A agents.
2. Describe the signs and symptoms of anthrax, plague, tularemia, smallpox, viral hemorrhagic fever, and botulism.
3. Describe the clinical manifestations of anthrax, plague, tularemia, smallpox, viral hemorrhagic fever, and botulism.
4. Discuss prophylaxis and medical treatment strategies used to counter anthrax, plague, tularemia, smallpox, viral hemorrhagic fever, and botulism.
5. Understand the challenges that public health officials and emergency management practitioners face when an intentional release of a Category A agent occurs in their community.
Introduction
Terrorism experts are most concerned with Category A agents because they have the greatest potential for harm if used in a bioterrorist attack. These agents can be easily disseminated or transmitted, cause high mortality, severely affect the public health, might cause public panic and social disruption, and require special action for public health preparedness (Rotz et al., 2002). Six diseases are caused by Category A agents (refer to Table 3.1 for a summary): anthrax, plague, tularemia, smallpox, viral hemorrhagic fever (VHF), and botulism. All six of these diseases and the agents that cause them are detailed here.
Anthrax
Anthrax, a disease of both humans and other mammals, is caused by the bacterium Bacillus anthracis. Anthrax was the first disease for which a microbial etiology was firmly established (in 1876) and the first bacterial disease for which immunization was available (in 1881). Although anthrax has been known since antiquity, it was not always clearly distinguished from other diseases with similar manifestations. Scholars have characterized the fifth and sixth biblical plagues as well as the “burning plague” described in Homer’s Iliad as anthrax. However, it was Virgil (70–19 BC) who provided one of the earliest and most detailed descriptions of an anthrax epidemic in his Georgics. Virgil also noted that the disease could spread to humans (Sternbach, 2003).
Table 3.1
Category A diseases and their etiologic agents: a summary
Disease Agent Type of agent Zoonoses Contagious person to person?
Anthrax Bacillus anthracis Bacteria Yes No
Plague Yersinia pestis Bacteria Yes Yes, in pneumonic form
Tularemia Francisella tularensis Bacteria Yes No
Smallpox Variola major Virus No Yes
Viral hemorrhagic fever Several from Arenaviridae, Filoviridae, Bunyaviridae, and Flaviviridae Virus Yes Yes
Botulism Botulinum toxin from Clostridium botulinum Toxin No No
Over the next 1500 years Europe witnessed sporadic outbreaks of anthrax, with the most acute outbreaks occurring in 14th-century Germany and 17th-century Russia and central Europe. Despite the threat these outbreaks posed to livestock, it was only in 1769 that Jean Fournier classified the disease as anthrax or charbon malin, a name undoubtedly derived from the black lesions characteristic of cutaneous anthrax. Anthrax has also been commonly referred to as woolsorter’s disease, ragpicker’s disease, malignant carbuncle, and malignant pustule. The bacterium and its associated disease get their name from the Greek word for coal, or anthracite, because of the characteristic coal-black sore that is the hallmark of the most common form of the disease (Sternbach, 2003). In fact, the Greek word anthrakôsis means “malignant ulcer.”
The Etiologic Agent of Anthrax
B. anthracis is a gram-positive rod-shaped bacteria approximately 4 μm long by 1 μm wide. The anthrax bacterium is found nearly worldwide, with hundreds of different strains cataloged in numerous archives. The bacterium can take two forms: the vegetative bacilli and the spore. B. anthracis is highly dependent on the spore form for survival. Within infected hosts, spores germinate to produce the vegetative forms, which release toxins and multiply, eventually killing the host. A proportion of these vegetative bacilli released by the dying or dead animal into the environment (usually the soil under the carcass) sporulate, ready to infect another animal. Vegetative forms of B. anthracis grow and multiply readily in normal laboratory nutrient agars or broths (eg, sheep blood agar, MacConkey agar, trypticase soy broth).
When conditions are not conducive to growth and multiplication of the vegetative bacilli, B. anthracis forms spores. The process of sporulation occurs when vegetative cells encounter high temperature, low moisture, a nutrient-poor environment, or the presence of free oxygen. These spores are resistant to physical extremes of heat, cold, drying, pH, and even some of the chemicals used in disinfection or decontamination. Spores can survive for decades in soil, and it is through the uptake of spores that anthrax is contracted.
Humans appear to be relatively resistant to anthrax. Estimates as to how many anthrax spores must be inhaled to produce a fatal outcome in a human victim vary widely (2500–55,000 spores) and can be quite controversial. Bear in mind that lethality estimates are based on primate studies conducted decades ago with specific B. anthracis strains formulated by bioweapons specialists.
Anthrax: True Zoonoses
Anthrax is a disease that gravely affects humans and other animals. The disease most often occurs in herbivores (eg, cattle, sheep, goats, camels, and antelope) but can also occur in humans and other warm-blooded animals. Carnivores (eg, dogs, cats, and lions) and omnivores (eg, swine) may become infected by eating uncooked meat from infected animals; however, many carnivores appear to have a natural resistance. Herbivores may become infected by ingesting spores while grazing in areas of high soil contamination (Dixon et al., 1999).
Anthrax is most common in temperate agricultural regions. Areas of high risk include South and Central America, southern and Eastern Europe, Africa, Asia, the Caribbean, and the Middle East. Natural incidence is extremely low in the United States, although outbreaks have been reported in California, Louisiana, Mississippi, Nebraska, North Dakota, Oklahoma, South Dakota, and Texas.
Human anthrax has three major clinical forms: cutaneous, inhalation, and gastrointestinal. If left untreated, all three forms can result in septicemia and death. Human exposures are usually occupational, resulting from handling infected livestock, infected wild animals, or contaminated animal tissues or products. The best documented evidence of this comes from studies in the 1960s in mills in which unvaccinated workers “chronically exposed” to anthrax had annual case rates of 0.6–1.4% (Dahlgren et al., 1960). In a study of two such mills, B. anthracis was recovered from the nose and pharynx of 14% of healthy workers; in another study, workers were inhaling 600–1300 spores during the work day with no ill effect, although a well-documented outbreak of pulmonary anthrax occurred in one mill with a similar level of contamination (Albrink et al., 1960; Brachman et al., 1966).
Cutaneous anthrax, rare in the United States, is common in parts of Asia and sub-Saharan Africa. Cutaneous anthrax results when B. anthracis gains entry to the body through an abrasion or open lesion of the victim. A typical cutaneous anthrax lesion is depicted in Fig. 3.1. Ingestion of undercooked meat from anthrax-infected animals results in gastrointestinal anthrax (AVMA, 2006a). Inhalation anthrax has been a hazard associated with slaughterhouse and textile workers; immunization has virtually eliminated this hazard in the Western nations. Anthrax as a weapon would most likely be delivered via an aerosol, resulting in inhalation anthrax.
FIGURE 3.1 Photograph depicts cutaneous anthrax lesion on the neck of a patient. Note the coal-like appearance of the lesion. Cutaneous anthrax is the most common clinical manifestation of anthrax, with most patients having some occupational exposure to a contaminated or infected animal product. Courtesy of the Centers for Disease Control Public Health Image Library.
The incubation period for inhalational anthrax in humans is 1–7 days. In the initial phase, it appears as a nonspecific illness characterized by mild fever, malaise, myalgia, nonproductive cough, and some chest or abdominal pain. The illness progresses within 2–3 days, leading to fever, painful cough, cyanosis, wheezing, mediastinal widening, and subcutaneous edema of the chest and neck. The second stage of inhalation anthrax occurs within 24–36 h and is characterized by high fever, difficulty breathing, cyanosis (a bluish discoloration of the skin and mucous membranes resulting from inadequate oxygenation of the blood), and shock (Swartz, 2001). Chest-wall edema and hemorrhagic meningitis may be seen late in the course of the disease.
Anthrax Bacterium as a Terrorist Threat
The anthrax bacterium has several characteristics that make it a formidable bioterrorist threat. These characteristics include its stability in spore form, its ease of culture and production, its ability to be aerosolized, the seriousness of the disease it causes, and the lack of sufficient vaccine for widespread use (Eitzen, 1997).
Early antibiotic treatment of cutaneous and gastrointestinal anthrax is usually curative; however, even with antibiotic therapy, inhalational anthrax is a potentially fatal disease. Although case-fatality estimates for inhalational anthrax are based on incomplete information, the historical rate is considered to be high (∼75%) for naturally occurring or accidental infections, even with appropriate antibiotics and all other available supportive care (Cieslak and Eitzen, 1999). During the entire 20th century there were 18 diagnosed cases of inhalation anthrax, 16 of which were fatal (Sternbach, 2003). The best chance for survival is to receive antibiotics and medical care within the first 48 h of the onset of signs. Interestingly, the survival rate after the recent intentional exposure to anthrax in the United States was 60% for the first 10 cases (Thompson, 2003).
Cutaneous anthrax cases in the United States early in the 20th century averaged 200 cases per year. During the second half of the century this decreased to approximately six cases per year. Since the 2001 Amerithrax incident, there have been five cases of human cutaneous anthrax and one case of inhalation anthrax (CDC, Morbidity and Mortality Weekly Report (MMWR) summaries). All of these anthrax cases occurred in drum makers and were associated with the victims handling infected goat skins (MMWR, 2006; ProMED Mail, 2007).
A more recent clinical manifestation, injectional anthrax, has been noted in some drug abusers. Since 2009 anthrax has emerged among heroin users in Europe. The source of their infection comes from contaminated heroin, which has been distributed throughout Europe (Berger et al., 2014). Before 2009 only one case was reported. However, in 2012 and 2013 new cases of injectional anthrax were diagnosed in Denmark, France, Germany, and the United Kingdom. Overall, 70 confirmed cases have been reported, with 26 them being fatal (a 37% case-fatality rate).
Anthrax in Animals
Anthrax occurs in several forms in animals, defined mostly by the length of the clinical course of the disease. The incubation period of natural infection in animals is typically 3–7 days, with a range of 1–14 or more days. In cattle and sheep the peracute course of the illness may last only 1–2 h, during which one of the first clinical indications of disease may be the animal’s sudden death. Clinical signs, such as fever up to 107°F, muscle tremors, respiratory distress, and convulsions, often go unnoticed. After death, there may be bloody discharges from the natural openings of the body, rapid bloating, and a lack of rigor mortis; blood may not clot (AVMA, 2006a).
The acute form of anthrax in ruminants may run a course of 24–48 h. Affected animals may exhibit a high fever, complete anorexia, diarrhea, severe depression, and listlessness. Pregnant cows may abort, milk production may drop severely, and what milk there is may be yellow or blood stained.
Outbreaks in the United States are most often associated with alkaline soil, and there are some areas where it is more endemic. Wet conditions followed by hot, dry weather in summer or fall are considered good conditions under which anthrax cases in livestock (cattle primarily) are likely to be seen.
Diagnosis of Anthrax
Anthrax is diagnosed by isolating B. anthracis from the blood, skin lesions, or respiratory secretions or by measuring specific antibodies in the blood of persons with suspected cases. An enzyme-linked immunosorbent assay was developed by the Centers for Disease Control (CDC) for anthrax and was quickly qualified during the outbreak in the fall of 2001 (Quinn et al., 2002). It proved to be accurate, sensitive, reproducible, and quantitative. The nasal swab test was used as a screening tool during the 2001 Amerithrax outbreak to determine if anyone associated with the case patient might have been exposed. In this setting, the nasal swab method was used for a rapid assessment of exposure and as a tool for rapid environmental assessment. When the source of exposure is not known, nasal swabs can help investigators screen potential contacts. However, these tests are for screening purposes only and are not used for definitively diagnosing anthrax. Furthermore, they are not 100% effective in determining all who may have been exposed.
Acts of Biological Terrorism
Previous acts of biological terrorism have been small in scale.
The Potential
A 1993 report by the US Congressional Office of Technology Assessment estimated 130,000 to 3 million deaths after the aerosolized release of 100 kg of anthrax spores upwind of Washington, DC.
The Reality
In the aftermath of the 2001 Amerithrax incident the CDC conducted a telephone survey of 40 state and territorial health officials. According to the results of the survey, during the time period September 11 to October 17, 2001, more than 7000 reports of suspicious powders were received at the health departments. Approximately 4800 of these reports required phone follow-up, and 1050 reports led to testing of suspicious materials at a public health laboratory. In comparison, the number of anthrax threats reported to public health authorities from 1996 to 2000 did not exceed 180 reported threats per year.
The antibiotic ciprofloxacin was offered to many people in the aftermath of anthrax mailings in 2001. According to one report, 5343 people were prescribed ciprofloxacin for 60 days. Only 44% of those given the drugs adhered to the 60-day regimen. Amazingly, 57% of those taking the drug experienced side effects (diarrhea, abdominal pain, dizziness, nausea, and vomiting) from taking the drug.
Penicillin has been the drug of choice for anthrax for many decades, and only very rarely has penicillin resistance been found in naturally occurring isolates. Preliminary data from the Florida, New York, and Washington, DC isolates showed possible resistance to penicillin; therefore treatment with ciprofloxacin was recommended. Considerations for choosing an antimicrobial agent include effectiveness, resistance, side effects, and cost. No evidence demonstrates that ciprofloxacin is more or less effective than doxycycline for antimicrobial prophylaxis to B. anthracis. Widespread use of any antimicrobial will promote resistance. However, fluoroquinolone resistance is not yet common in these organisms. To preserve the effectiveness of fluoroquinolone against other infections, use of doxycycline for prevention of B. anthracis infection among populations at risk may be preferable.
In the United States, human anthrax vaccine is a cell-free filtrate produced from an avirulent strain. The vaccine contains no whole bacteria, dead or alive. The vaccine was developed during the 1950s and 1960s for humans and was licensed by the Food and Drug Administration (FDA) in 1970. Since 1970, it has been administered to at-risk wool mill workers, veterinarians, laboratory workers, livestock handlers, and military personnel. The vaccine is manufactured by BioPort Corporation. Vaccine side effects include injection site reactions. Approximately 30% of men and 60% of women experience mild local reactions, which is a similar finding with other vaccinations. Approximately 1–5% of individuals experience moderate local reactions. Large local reactions occur at a rate of 1%. Beyond the injection site, from 5% to 35% of people will notice fever, muscle aches, joint aches, headaches, rash, chills, loss of appetite, malaise, and nausea. Serious events, such as those requiring hospitalization, are rare and happen approximately once per 200,000 doses. There have been no patterns of long-term side effects from the vaccine and neither persistent nor delayed side effects.
Plague
Plague is caused by the bacterium Yersinia pestis. Its potential as a biological weapon is based on an ability to produce and aerosolize large amounts of bacteria and its transmissibility from person to person in certain forms. An additional factor is the wide distribution of samples of the bacteria in research laboratories throughout the world. Y. pestis is easily destroyed by sunlight and drying. However, it can survive briefly in the soil and longer in frozen or soft tissues. In addition, it is able to survive for up to 1 h (depending on conditions) when released into air. This could increase its threat and aid in its dispersal as a potential bioterrorism weapon.
Plague has a very detailed past and long history. Throughout history, plague has caused several outbreaks (pandemics and epidemics) that led to many deaths (Riedel, 2005a). Justinian’s Constantinople pandemic lasted from AD 540 to AD 590 and resulted in approximately 10,000 deaths per day at its height. It also contributed greatly to the fall of the Roman Empire. In the 14th century plague was carried from outbreaks in India and China to Italy by merchants returning home. Soon after, plague spread to the rest of Europe (Slack, 1998). During this time, Venice instituted a 40-day period of detainment for docking ships, which gave us what is now known as the quarantine. Despite these efforts, plague quickly spread throughout all of Europe. Over one-third of the European population died during the Black Death pandemic. The decline in the population aided in the fall of the feudal system of government (Eckert, 2000). Another important plague epidemic occurred in 1665. Although limited to England, it killed approximately 100,000 (of the 500,000) inhabitants of London. During this outbreak, some of our modern public health practices were initiated (ie, disease reporting, closing up of homes).
The Great Plague
The Great Plague, also known as the Black Death, killed nearly one-third of the population of Europe within a 4-year period (1347–1350).
The United States has not been immune to the influence of plague. It entered the United States by way of Hawaii and San Francisco in 1899 (Link, 1955). Plague spread from infected rats aboard vessels in Californian ports to indigenous, sylvatic wild rodents throughout the western United States. It is currently well established in the Four Corners region of the United States and parts of California. The last documented person-to-person transmission of plague occurred during the 1924 outbreak in Los Angeles.
Today, the World Health Organization (WHO) categorizes plague as a Class 1 quarantinable disease. This allows for detention and inspection of any vehicle or passenger originating from an area where a plague epidemic is in progress. Also, personnel of the CDC Division of Quarantine and Global Migration are empowered to apprehend, detain, medically examine, or conditionally release a suspect having this illness. Plague in humans is a reportable disease, and in many states plague in animals is also reportable. The US Public Health Service requires that all cases of suspected plague be reported immediately to local and state health departments and diagnosis be confirmed by the CDC. As required by the International Health Regulations, the CDC reports all plague cases to the WHO.
Epidemiology—Natural Reservoirs
Humans acquire plague most often through the bite of an infected flea. The flea ingests a blood meal from an infected, bacteremic animal. The bacteria multiply and block the foregut of the flea. When the flea attempts to feed again, it regurgitates bacteria into a human or animal mammalian host. The flea Oropsylla montana is the primary vector for naturally occurring cases of plague. This flea is found mostly in rural rodent species, particularly the rock squirrel in New Mexico and Arizona (Orloski and Lathrop, 2003). Urban plague from rats has not occurred in the United States in over 70 years. This is due to good public health surveillance and control and improved sanitation measures. If an urban plague event (natural) were to occur, the flea Xenopsylla cheopis, or the “oriental rat flea,” would be the most likely vector.
Urban (domestic) plague occurs when the infected fleas or rodents move into urban areas. Influx can also occur when there is significant development and expansion into wilderness areas (ie, interface building that borders a city and outlying wilderness), as is seen in some parts of the Southwest. The epizootics may cause high mortality in commensal (domestic) rat populations, thereby forcing infected fleas to seek alternative hosts, including humans or domestic cats. Domestic cats in homes bordering wilderness areas pose a significant threat to humans because they may become infected with plague (ie, hunting rodents) or transport rodent fleas into the home, thereby exposing their owners (AVMA, 2006b). Poverty, filth, and homelessness all contribute to urban plague transmission. The most common reservoirs for the bacteria are ground squirrels and wood rats.
Epidemiology—Transmission
Transmission occurs through the bite of an infected flea, respiratory droplets, or direct contact with a patient infected with pneumonic plague. Transmission by direct skin or mucous membrane contact with tissues and fluids of infected animals is less common. Infection via inhalation of infective respiratory droplets or aerosols is rare with naturally occurring plague in the United States, but it is the most likely route of transmission in a bioterrorist event. Becoming infected naturally through the respiratory route requires direct and close (within 6 ft) contact with an ill person or animal and has not occurred in the United States for decades.
Incidence in the United States
Since 1900 plague has been endemic in the United States. Between 1970 and 2003, 2% of plague has been pneumonic, 83% has been bubonic, and 15% has been septicemic. Approximately 5–15 cases occur each year in the United States. The greatest concentration occurs in Arizona, Colorado, and New Mexico. However, human cases have occurred in rural areas from the Pacific coastal region eastward to the Great Plains states. The last time person-to-person transmission occurred in the United States was during the epidemic of 1924–25 in Los Angeles. During this outbreak, 32 pneumonic cases were reported with 31 resulting in death. Human cases of plague typically occur in April through November, when fleas and their hosts are most active and people are more likely to be outdoors. Ninety-three percent of human cases in the United States occurred during this period.
Plague exists in rodent populations on every inhabited continent except Australia. Approximately 1500–3000 cases of human plague are reported annually worldwide.
Worldwide, most cases of plague occur in Africa, with limited outbreaks in Asia and South America. In 2006 an outbreak of more than 600 suspected cases of pneumonic plague in the Democratic Republic of the Congo claimed the lives of 42 people (WHO, 2006).
Clinical Manifestations of Human Plague
Infection by inhalation of even small numbers of virulent aerosolized Y. pestis bacilli can lead to pneumonic plague, a highly lethal form of plague that can be spread from person to person. Natural epidemics of plague have been primarily bubonic plague, which is transmitted by fleas from infected rodents (Boyce and Butler, 1995). Plague usually presents as one of three principal clinical syndromes: bubonic, septicemic, or pneumonic.
Bubonic Plague
Bubonic plague is the most common form and accounts for approximately 80% of cases. The incubation period is 2–6 days. Signs and symptoms include fever, malaise, chills, headache, and very swollen, painful lymph nodes (called a bubo). Vomiting, abdominal pain, nausea, and petechiae may also occur. Without treatment 50–60% of bubonic cases are fatal. Infection is transmitted by the bite of an infected flea or exposure to infected material through a break in the skin. Bubonic plague cannot be transmitted from person to person. If bubonic plague is not treated, then the bacteria can spread through the bloodstream and infect the lungs, causing a secondary infection of pneumonic or septicemic plague.
Septicemic Plague
Septicemic plague occurs when the bacteria enter the bloodstream and are dispersed throughout the body. This phase follows bubonic plague in most cases, but not all people will develop buboes. In addition to the preceding signs, prostration, circulatory collapse, septic shock, organ failure, hemorrhage, disseminated intravascular coagulation, and necrosis of extremities can be seen. This condition, often seen in the fingertips, tip of the nose, and toes, is the result of small blood clots blocking capillaries and the circulation to these areas (Fig. 3.2). Without treatment 100% of septicemic cases are fatal.
FIGURE 3.2 Hand of a plague patient displaying acral gangrene. Gangrene is one of the manifestations of plague and the origin of the term Black Death given to plague throughout the ages. Courtesy of the Centers for Disease Control Public Health Image Library.
Pneumonic Plague
Primary pneumonic plague occurs when Y. pestis is inhaled and the bacteria gain direct access to the lungs. Pneumonic is the least common form of plague, but it is the most fatal. Pneumonic plague patients must receive definitive medical treatment within 24 h of becoming symptomatic. If not, then pneumonic plague is considered to be universally fatal because of respiratory failure and shock. Pneumonic plague can be transmitted person to person through respiratory droplets with direct close contacts.
Primary pneumonic plague has a very rapid incubation period of 1–6 days. If septicemic plague is left untreated, then it progresses to pneumonic plague (secondary pneumonic plague). A person with secondary pneumonic plague who coughs on another person can transmit plague in an aerosol and infect that person with a primary pneumonic infection. Symptoms include fever, chills, headache, septicemia, respiratory distress, and hemoptysis. Pneumonic plague is the only form of plague that can be transmitted person to person, but it usually requires direct or close contact with the ill person or animal.
Treatment of plague requires prompt antibiotic treatment and supportive therapy. Without treatment most forms of plague are 100% fatal. Currently approximately 14% (1 in 7) of all plague cases in the United States are fatal. Fatalities in the United States are often linked to delay in seeking medical care or misdiagnosis. Penicillins and cephalosporins are not effective in treating plague. Prophylactic antibiotics should be administered to persons who have had close exposure (ie, within 2 m) to persons suspected of having pneumonic plague. Persons who have not had such exposure are unlikely to become infected, but they should be closely monitored. In 2015, the US Food and Drug Administration approved Avelox (moxifloxacin) to treat patients with plague (FDA, 2015).
Critical Thinking
Consider a case of bubonic plague in the emergency room of a New York City hospital. Why would this be a “red flag” event for public health officials?
With any plague case, natural or bioterrorist, public health authorities need to conduct investigations to identify close contacts that need prophylaxis and to look for any additional cases so that they may begin treatment as quickly as possible. By definition, a contact is anyone who has been within 2 m of a coughing pneumonic plague patient in the previous 7 days. If contacts are found to have fever or cough, then they will be referred for evaluation. Those contacts that do not have fever or cough will be placed on antibiotics for 7 days and monitored for the development of symptoms. Those that have contraindications to the antibiotics can be placed on a fever watch.
Short Case Study
On November 1, 2002, a 53-year-old man and his 47-year-old wife, traveled from Santa Fe County, New Mexico to New York City (NYC). Both became ill and sought medical care in an NYC emergency room on November 5. The man reported 2 days of fever, fatigue, and a painful swelling in his groin area. His blood work showed that he had a serious infection. A blood culture grew Y. pestis. Plague was diagnosed. The man’s treatment was initiated with several antibiotics (gentamicin, doxycycline, ciprofloxacin, and vancomycin). However, his condition deteriorated, he went into shock with septicemic plague, and he had to be admitted to the intensive care unit (ICU). His wife presented with fever, fatigue, myalgia, and a painful swelling in her groin. Her blood work was normal, but she was presumed to have plague based on her husband’s diagnosis. She was treated with antibiotics and recovered rapidly without complications. After 6 weeks in ICU, the man recovered and was discharged to a long-term care rehabilitation facility.
The New Mexico Department of Public Health and the CDC investigated the couple’s New Mexico property. Trapped rodents and their fleas were tested for Y. pestis, which was found and was indistinguishable from the Y. pestis isolated from the male patient. Any time plague is suspected or diagnosed out of its endemic area (southwestern United States), suspicions should be raised about the source of the infection. In this case, the patients both had come from the endemic area. What if they had been from Boston?
This case also emphasizes the importance of early detection and diagnosis. This is important not only for patient care but also for implementation of any isolation or precautionary measures that may need to be implemented. (Case details were taken from CDC Morbidity and Mortality Weekly Review 52 (31) (2003), 725–728).
Tularemia
Tularemia is a potential bioterrorist agent because of its high level of infectivity and its ability to be aerosolized. Tularemia is caused by Francisella tularensis, which is a gram-negative, non-spore-forming intracellular bacterium that can survive at low temperatures for weeks. The disease is not transmitted from person to person; it spreads naturally from small mammals or contaminated food, soil, or water to humans. Natural infection may occur after inhalation of airborne particles (Dennis et al., 2001).
Tularemia is also known as rabbit fever and deer fly fever. The etiologic agent of tularemia is one of the most infectious bacterial agents known to man. Less than 10 cells inhaled into the lungs is sufficient to produce a lethal infection. The bacterium multiplies within white blood cells (macrophages) and the major target organs are the lymph nodes, lungs, spleen, liver, and kidney. The organism is relatively resistant in the environment, surviving 3–4 months in mud, water, or dead animals. Rabbit meat frozen at 5°F has remained infective for more than 3 years. Chlorination of water during water treatment will kill the organism. The organism is also easily destroyed by various disinfectants, including 1% hypochlorite (bleach), 70% ethanol, and formaldehyde. It can be inactivated by moist heat (121°C for at least 15 min) and dry heat (160–170°C for at least 1 h). There are several subspecies (or biovars) of F. tularensis, which vary in virulence and distribution. Two of the four subspecies account for most human illness: F. tularensis biovar tularensis (or Jellison type A) and F. tularensis biovar palaearctica (or Jellison type B). The other subspecies of F. tularensis are mediasiatica and novicida.
Tularemia was first described in humans in 1907. The disease was then discovered in the United States in 1911 in California ground squirrels suffering a plague-like illness. The organism was originally named Bacterium tularense named after Tulare County, California, where these first cases occurred. During the 1930s and 1940s, the Soviet Union and Europe experienced large waterborne outbreaks. In 1947 the organism was renamed Francisella tularensis in honor of Edward Francis, a US Public Health Service surgeon who had dedicated his career (since 1914) to the study of all aspects of tularemia. In the 1950s and 1960s, the US military was striving to develop bioweapons that aerosolized the organism.
The largest recorded airborne tularemia outbreak occurred in Sweden in 1966–67. More than 600 patients were infected with the Type B strain. Most of those infected were exposed while doing farmwork that created contaminated aerosols, particularly when rodent-infested hay was being sorted and moved from field storage sites to barns. Most had the typical acute symptoms of fever, fatigue, chills, headache, and malaise. Although airborne exposure would be expected to principally manifest as pleuropneumonic infection, only 10% had symptoms of pneumonia, such as dyspnea and chest pains. Other “forms” of tularemia were noted in a variable proportion of patients: 32% has various skin exanthemas, 31% had pharyngitis, 26% had conjunctivitis, and 9% had oral ulcers. Patients responded well to treatment and no deaths were reported.
Tularemia is endemic on Martha’s Vineyard, an island off of the coast of Cape Cod, Massachusetts. In the 1930s, game clubs introduced cottontail rabbits from Arkansas and Missouri (endemic states) to Cape Cod and Martha’s Vineyard. Shortly after this introduction, the first cases of tularemia were reported in Martha’s Vineyard. The only two reported outbreaks of pneumonic tularemia in the United States occurred on Martha’s Vineyard in 1978 and 2000. In 1978 the cluster of cases involved seven persons who lived together in a cottage. Epidemiological investigation attributed exposure to a wet dog, which aerosolized F. tularensis when it shook itself inside of the cottage. During the outbreak in 2000, 15 cases were identified: 11 of had pneumonic tularemia, 2 had the ulceroglandular form, and 2 experienced only fever and malaise with no localized signs. Epidemiologic investigation determined that the cases were primarily in persons occupationally associated with landscaping. Risk factors were increased for those that engaged in lawn mowing and bush cutting, which was thought to generate aerosols of the organism for dispersal. Investigation also proposed that F. tularensis was shed in animal (rodent) excrement and infected people after it was mechanically aerosolized and inhaled. One patient remembered cutting brush around a dead rabbit.
Incredibly, 14 species of ticks, 6 species of flies, several mosquito species, more than 100 wild mammal species, and 25 species of birds serve as reservoirs for F. tularensis. A rodent-mosquito cycle has been described in Russia and Sweden. However, tularemia is commonly transmitted through the bite of an infected tick, including Dermacentor andersonii, Dermacentor variabilis, Amblyomma americanum, and less frequently the deer fly Chrysops discalis. Transovarial transmission occurs in ticks. This means that the pathogen can be passed from an adult female tick to her progeny. Once infected, ticks can be infective for life. Flies are a less common source of transmission and are only infective for approximately 14 days. Tularemia has been rarely transmitted via bites and scratches from coyotes, squirrels, skunks, hogs, cats, and a dog whose mouth was contaminated by eating an infected animal (AVMA, 2006c). Transmission is possible through contaminated blood; tissue; or water coming in contact with eyes, mouth, or breaks in the skin. Transmission has also been documented through handling or ingesting undercooked meat (especially rabbits). Waterborne outbreaks can result from contaminated drinking water in rural areas. Person-to-person transmission has not been documented. Airborne outbreaks can occur from moving rodent-contaminated hay, threshing corn, or laboratory accidents.
Tularemia occurs in the temperate regions of the Northern Hemisphere (North America, Europe, Soviet Union, China, Japan, and Mexico). In the United States, tularemia occurs year-round and is a nationally notifiable disease. Approximately 100 cases per year typically occur in the United States. Most cases occur from June to September (corresponding to peak arthropod season), but a slight increase in winter has been associated with rabbit hunting. Tularemia has been reported in every state except Hawaii. More than half of all cases are typically reported from four states: Arkansas, Missouri, South Dakota, and Oklahoma. Tularemia is considered endemic in these states and ticks and rabbits are usually the sources of human infection. In Utah, Nevada, and California, biting flies are common vectors, whereas ticks are the primary vectors in states along the Rocky Mountains. Tularemia became a nationally notifiable disease in 2000.
In humans the severity of infection and incubation period varies, depending on the subspecies, route of infection, and dose. The six clinical syndromes or manifestations of tularemia are based on the route of exposure to the agent. All forms initially present as flulike symptoms, including fever, chills, headache, and myalgia.
The ulceroglandular form is the most common presentation of tularemia. This usually occurs as a consequence of a bite from an arthropod that has previously fed on an infected animal. Some cases occur after the handling of infected meat, with infection occurring via cuts or abrasions. An ulcer develops at the site of infection, and the local lymph nodes are enlarged (Fig. 3.3). The lymph nodes are painful, swollen, and may rupture and ulcer. The ulcer may last from 1 week to several months. With a glandular presentation, there is no apparent primary ulcer, but there are one or more enlarged lymph nodes. Ulceroglandular and glandular presentations account for 75–85% of naturally occurring tularemia cases.
The oculoglandular form of tularemia is rare and occurs when the conjunctiva becomes infected. This may occur by either rubbing the eyes with contaminated fingers or splashing contaminated materials in the eyes. Cleaning carcasses or rubbing the area of a tick bite and then the eye can result in this form of tularemia. Clinical presentation involves initial flulike signs with conjunctivitis and painful swelling of the regional lymph nodes. In severe forms the conjunctiva may be ulcerated and ocular discharge may be present.
The oropharyngeal presentation of tularemia occurs after ingestion of the organisms in either undercooked meat (especially rabbit) or contaminated water. Hand-to-mouth transfer can also occur. Infection may produce painful pharyngitis (with or without ulceration), abdominal pain, diarrhea, and vomiting. A pseudomembrane may cover tonsils and can be mistaken for diphtheria.
The most severe forms (and most fatalities) of tularemia are the typhoidal and pulmonary forms. The typhoidal form involves systemic infection and can develop from the oropharyngeal form of tularemia. Pulmonary tularemia is due to inhalation of infectious organisms or dissemination of organisms through the bloodstream. The pulmonary form of the disease results from 10 to 15% of the ulceroglandular and approximately 50% of the typhoidal cases. Organisms can become airborne as animals are skinned or eviscerated. Inhalation of infectious material may be followed by pneumonic disease or a primary septicemic (typhoidal type) syndrome with a 30–60% case-fatality rate if untreated. Although there have been descriptions of a triad of findings for tularemic pneumonia—ovoid opacities, pleural effusions, and hilar adenopathy—these radiologic manifestations are neither sensitive nor specific enough to render them diagnostically useful. In addition, respiratory signs and symptoms may be minimal or absent and, when present, are often nonspecific.
F. tularensis is susceptible to various antibiotics. Streptomycin is the antibiotic of choice, but gentamicin, doxycycline, and ciprofloxacin have also been used. The prognosis for tularemia varies with the form of disease that manifests and the subspecies of the organism. Type A (F. tularensis tularensis) organisms are more virulent, with an overall case-fatality rate of 5–15%. Typhoidal and pulmonary forms of disease account for most of these cases. Type B (F. tularensis holarctica) is less virulent and, even without treatment, produces few deaths. If untreated, general symptoms usually last 1–4 weeks but may continue for months. The mortality rate for all types of untreated tularemia is less than 8% and drops to less than 1% when treated. However, treatment is usually delayed because of misdiagnosis. After recovery from infection, antibody titers can persist for years and subsequent infections may occur (Feldman, 2003).
Smallpox
Smallpox is considered one of the most dangerous potential biological weapons because it is easily transmitted from person to person, no effective therapy exists, and few people carry full immunity to the virus. The word variola (smallpox) comes from the Latin word varius, meaning “stained,” or from varus, meaning “mark on the skin.” It was also referred to by Native Americans as “rotting face.” Although a worldwide immunization program eradicated smallpox disease in 1977, small quantities of smallpox virus still exist in two secure facilities in the United States and Russia. However, it is likely that unrecognized stores of smallpox virus exist elsewhere in the world. Today, any confirmed case of smallpox would constitute an international emergency and should be immediately reported to public health authorities (Barquet and Domingo, 1997).
The smallpox virus is a double-stranded DNA virus in the genus Orthopoxvirus. Smallpox disease can be caused by Variola major or Variola minor. Variola major is the more common and severe form, causing an extensive rash and a higher fever. Variola minor is much less common and causes a less severe disease. Other orthopoxviruses include cowpox, vaccinia, monkeypox, and others. Variola is stable outside of the host and retains its infectivity. Animals have never been found infected with or showing signs of smallpox; therefore it is not a zoonotic disease.
Smallpox is believed to have appeared around 10,000 BC during the first agricultural settlements in northeastern Africa. The earliest evidence of skin lesions resembling those of smallpox is found on the faces of mummies (1570–1085 BC) and in the well-preserved mummy of Ramses V, who died as a young man in 1157 BC. Although poxvirus was never isolated or identified in tissue samples from Ramses V, skin lesions were consistent with smallpox (Riedel, 2005b).
The devastating effects of smallpox gave rise to one of the first examples of biological warfare. In a letter written in 1763, Sir Jeffrey Amherst, commander-in-chief of British forces in North America, suggested grinding the scabs of smallpox pustules into blankets that were to be distributed among disaffected tribes of Indians. In the late 18th century in Europe, 400,000 people died of smallpox each year and one-third of the survivors went blind. The case-fatality rate associated with smallpox varied between 20% and 60% and left most survivors with disfiguring scars. Many persons went blind as a result of corneal infection. The case-fatality rate in the infant population was even higher; among children younger than 5 years of age in the 18th century, 80% of those in London and 98% of those in Berlin who developed the disease died.
Physicians realized that smallpox survivors became immune to the disease. Thus the method of variolation began, which involved taking samples (vesicles, pus, ground scabs) from benignly diseased patients and introducing the material into susceptible patients via the nose or skin. In China, powdered scabs of smallpox pustules were blown into the nostrils of healthy persons through a tube. Also in China, 100 years before Edward Jenner, healthy persons took pills made from the fleas of cows to prevent smallpox; this is the first recorded example of oral vaccination. In India, variolation took several forms, the most common of which was the application of scabs or pus from a person with smallpox to the intact or scarified skin of a healthy person. Children were exposed to organisms from persons with mild cases of smallpox, and various forms of material from persons with smallpox were administered to healthy adults in different ways. It was well known that milkmaids became immune to smallpox after developing cowpox. Variolation was practiced in England in the early 1700s. Variolation also spread to the New World, where in 1721 Boylston used the technique to stop the smallpox epidemic in Boston. By 1777 George Washington had all of his soldiers variolated before beginning new military operations.
In Gloucestershire, England, on May 14, 1796, Jenner extracted fluid from a pustule on a milkmaid and used it to inoculate a healthy 8-year-old boy (James Phipps). Six weeks later, Jenner variolated the child but produced no reaction. Jenner, along with George Pearson and others, developed a vaccine using cowpox (see Fig. 3.4). This prevented the vaccinee from developing smallpox if variolated or exposed to smallpox. Vaccination done by using pustule fluid spread rapidly. By 1800 it had reached most European countries and approximately 100,000 persons had been vaccinated worldwide. Cows were first used in the early 19th century for vaccine production. By 1801 more than 100,000 persons in England had been vaccinated. In 1805 Napoleon himself insisted that all of his troops who had not had smallpox should be vaccinated with the “Jennerian vaccine.” He ordered the vaccination of French civilians 1 year later.
The WHO began a smallpox eradication program in 1967 (Fenner et al., 1988). In that year an estimated 10 million cases of smallpox caused 2 million deaths. However, the greatest triumph in public health history was realized in 1980 when smallpox was officially declared to be eradicated by the WHO. The total cost for this program was only approximately $400 million. By comparison, it cost $24 billion for the United States to put a man on the Moon. The United States discontinued smallpox vaccinations in 1972 (World Health Organization, 1980).
Eradication of smallpox was made possible for several reasons: a good, protective vaccine was available; there was no animal reservoir for smallpox; vaccinees were easily identifiable and could “vaccinate” friends and family through contact; and those who acquired smallpox were easily identifiable.
To sustain itself the virus must pass from person to person in a continuing chain of infection, and it is spread by inhalation of respiratory droplets, typically within 2 m or less. In general, direct and fairly prolonged face-to-face contact is required to spread smallpox from one person to another. Smallpox can also be spread through direct contact with infected bodily fluids or contaminated objects, such as bedding or clothing. Rarely, smallpox has been spread by virus carried in the air in enclosed settings, such as buildings, buses, and trains. Smallpox spreads most readily during the cool, dry winter months, but it can be transmitted in any climate and in any part of the world. Smallpox is not transmitted by insects or animals.
A person with smallpox is sometimes contagious with onset of fever (prodromal phase), but the person becomes most contagious with the onset of rash (during the first 7–10 days). At this stage the infected person is usually very sick and not able to move around in the community. The infected person is contagious until the last smallpox scab falls off. The incubation period for smallpox is 7–17 days but generally averages 12–14 days. Small red spots in the mouth and on the tongue are the initial signs of smallpox. Around the time the sores in the mouth break down a rash appears on the skin, starting on the face. It then spreads to the arms and legs and then to the hands and feet. The rash usually spreads to all parts of the body within 24 h. As the rash appears the fever usually falls and the person may start to feel better.
The two major forms of smallpox are V. major and V. minor. V. major is the more common and severe form, causing an extensive rash and a higher fever (see the patient image in Fig. 3.5). There are four forms of V. major: ordinary, modified, flat, and hemorrhagic. V. minor is much less common and causes a less severe disease. In the ordinary (or discrete) form of V. major smallpox disease, the pustules remain separate and distinct from one another. This is the most frequent form of smallpox.
Hemorrhagic smallpox occurs in less than 3% of patients. There are two types of hemorrhagic smallpox, early and late, based on the time during the disease at which the hemorrhage appears. It causes the appearance of extensive petechiae, mucosal hemorrhage, and intense toxemia; death usually intervenes before the development of typical pox lesions can occur (McClain, 1997).
A patient with chickenpox has many pocks on his torso but very few on his arms or hands. A patient with smallpox manifests pocks more densely localized on the arms and legs than on the trunk. In smallpox, pocks are usually present on the palms of the hands and the soles of the feet. In chickenpox, there may be few or no lesions on the palms of the hands or the soles of the feet.
If a patient has been exposed to smallpox but is showing no signs of disease, then vaccination within 3 days of exposure will prevent or significantly lessen the severity of symptoms in the vast majority of people and affords almost complete protection against death. Vaccination 4–7 days after exposure likely offers some protection from disease or may modify the severity of disease. This person should also be quarantined and monitored for signs of disease. If the person is showing signs of smallpox, then isolation and supportive care are essential.
Case fatality for smallpox caused by V. major ranges between 20% and 40%. The flat and hemorrhagic forms are usually fatal. Fatality rates in vaccinated persons are approximately 3%. Blindness and limb deformities could also be sequelae from smallpox. V. minor is a much less severe disease and had a case-fatality rate of 1%. Persons who recover from smallpox possess long-lasting immunity, although a second attack could occur in 1 in 1000 persons after an intervening period of 15–20 years.
The only prevention for smallpox is vaccination. As described earlier, the practice of vaccination with vaccinia virus began in the early 20th century. The origins of vaccinia virus remain unknown, but this virus is distinct from variola and cowpox. Some speculate the vaccinia virus is a hybrid between cowpox and variola. Vaccinia vaccine, derived from the calf lymph, was used in the United States until 1972. It is a lyophilized, live-virus preparation of infectious vaccinia virus. It contains no smallpox (variola) virus. The needle is dipped into the vaccine and then the vaccinee is jabbed 2 or 3 times on the upper arm (deltoid muscle) for the initial vaccine (15 times for a booster). Smallpox vaccination provides high-level immunity for 3–5 years and decreasing immunity thereafter. If a person is vaccinated again later, immunity lasts even longer. Historically, the vaccine has been effective in preventing smallpox infection in 95% of those vaccinated. There is some evidence to indicate that some degree of immunity lasts much longer than 3–5 years.
If the vaccination is successful, then a red, itchy bump develops at the vaccine site in 3 or 4 days. In the first week, the bump becomes a large blister, fills with pus, and begins to drain. During the second week, the blister begins to dry up and a scab forms. The scab falls off in the third week, leaving a small scar. People who are being vaccinated for the first time have a stronger reaction than those who are being revaccinated.
The ring vaccination strategy is the strategy that will be used if a case of smallpox were to break out in the United States. Contacts of the case will be found and vaccinated, as will contacts of those contacts. This appears to be the most effective way to contain an outbreak. There is currently enough vaccine available to vaccinate all Americans should the need arise.
Because of the events of September 11, 2001, the threat of a terrorist act on the United States was amplified. Government officials felt the threat of a smallpox attack on the United States was a real possibility. To protect its citizens, President Bush recommended, on December 13, 2002, that smallpox vaccination of health-care personnel and the military begin. In January 2003 the CDC began distributing smallpox vaccine and bifurcated needles to the states for voluntary vaccination of first responders in the health-care system. A relatively new antiviral drug, Brincidofovir, is being evaluated for use as a postexposure treatment for smallpox infection. Phase III clinical trials in support of a New Drug Application with the FDA were conducted in 2014 (Chimerix Inc., 2014).
Viral Hemorrhagic Fevers
VHF refers to a group of illnesses caused by several distinct families of viruses that affect humans and nonhuman primates. VHF is a severe multisystem syndrome characterized by diffuse vascular damage. Bleeding often occurs and, depending on the virus, may or may not be life threatening. Some VHFs cause mild disease, whereas others may cause severe symptoms and death. VHFs encompass a group of similar diseases caused by four types of viruses:
• arenaviruses, associated with Argentine, Bolivian, and Venezuelan hemorrhagic fevers, Lassa fever, and Sabia-associated hemorrhagic fever;
• bunyaviruses, including Crimean-Congo hemorrhagic fever (CCHF), Rift Valley fever (RVF), and hantavirus infection;
• filoviruses, comprising Ebola and Marburg hemorrhagic fevers; and
• hemorrhagic flaviviruses, including yellow fever, dengue hemorrhagic fever (DHF), Kyasanur Forest disease, and Omsk hemorrhagic fever.
These viruses pose a risk from intentional exposure because, with very few exceptions, no vaccines or proven treatments exist, and many of the diseases are highly fatal. Natural infections occur when people come in contact with rodents or insects that are infected or act as vectors. After human infection occurs, some VHFs can be transmitted from person to person through close contact or contaminated objects, such as syringes and needles.
VHFs are caused by a long list of viral pathogens from several viral groups. We concentrate on those that are most likely candidates for bioterrorism or biowarfare.
VHF viruses are members of four distinct families: arenaviruses, bunyaviruses, filoviruses, and flaviviruses. All are ribonucleic acid viruses enveloped in a lipid coating. The survival of these viruses is dependent on their natural reservoir, which in most cases is an animal or an insect host.
Arenaviruses
The first arenavirus was isolated in 1933 during an outbreak of St. Louis encephalitis virus. In 1958 the Junin virus was isolated in the plains of Argentina in agricultural workers. It was the first arenavirus found to cause hemorrhagic fever. Others soon followed, including Machupo virus in Bolivia in 1963 and Lassa virus in Nigeria in 1969. Since 1956 a new arenavirus has been discovered every 1–3 years, but not all cause hemorrhagic fever.
New and Old World rats and mice are chronically infected with arenaviruses. The virus is vertically transmitted from adult host to offspring with most viruses in this family. Transmission among adult rodents may also occur through bites and other wounds. Rodents shed the viruses into the environment through urine and fecal droppings. Humans can become infected when coming into contact with rodent excreta or contaminated materials such as contact through abraded skin or ingestion of contaminated food. Inhalation of rodent excreta may also result in disease. Person-to-person transmission has been documented in health-care settings through close contact with infected individuals and contact with infected blood and medical equipment.
Arenaviruses are found worldwide; however, the viruses responsible for causing hemorrhagic fever are restricted to two continents. Lassa virus is endemic to the region of West Africa, whereas Junin, Machupo, Guanarito, and Sabia viruses are all found in South America. The latter are grouped together as the Latin American hemorrhagic fevers. Humans who have frequent contact with rodent excreta have an increased risk of developing an infection with an arenavirus. Agricultural and domestic exposures are the most common. Case fatality for arenaviruses ranges from 5% to 35%. Lassa and Machupo can cause serious hospital-acquired outbreaks. The incubation period for arenaviruses is typically between 10 and 14 days. Disease onset begins with a fever and general malaise for 2–4 days. Most patients with Lassa fever recover after this stage; however, those infected with the Latin American hemorrhagic fever typically progress to more severe symptoms. The hemorrhagic stage of the disease quickly follows and leads to hemorrhaging, neurologic signs, leukopenia, and thrombocytopenia.
Bunyaviruses
RVF virus was first isolated in 1930 from an infected newborn lamb as part of an investigation of a large epizootic of disease causing abortion and high mortality in sheep in Egypt. CCHF virus was first recognized in the Crimean peninsula, located in southeastern Europe on the northern coast of the Black Sea, in the mid-1940s, when a large outbreak of severe hemorrhagic fever among agricultural workers was identified. The outbreak included more than 200 cases and a case fatality of approximately 10%. The discovery of hantaviruses traces back to 1951–53, when United Nations troops were deployed during the border conflict between North and South Korea. More than 3000 cases of acute febrile illness were seen among the troops, approximately one-third of which exhibited hemorrhagic manifestations, and an overall mortality of 5–10% was seen. The family now consists of five genera, which contain 350 viruses that are significant human, animal, and plant pathogens.
Most bunyaviruses except for hantaviruses utilize an arthropod vector to transmit the virus from host to host. In some cases the virus may be transmitted from adult arthropods to their offspring. Humans are generally dead-end hosts for the viruses and the cycle is maintained by wild or domestic animals. CCHF virus is transmitted by ixodid ticks, and domestic and wild animals (eg, hares, hedgehogs, and sheep) serve as amplifying and reservoir hosts. In contrast, RVF virus is transmitted by Aedes mosquitoes, resulting in large epizootics in livestock. Humans are incidentally infected when bitten by infected mosquitoes or when coming into contact with infected animal tissues. The virus is believed to be maintained by transovarial transmission between the mosquito and its offspring. Hantaviruses cycle in rodent hosts, and humans become infected by coming into contact with rodent urine. Aerosolization of viruses and exposure to infected animal tissues are also two less common modes of transmission for some bunyaviruses.
Bunyaviruses are found worldwide, but each virus is usually isolated to a local region. RVF is found primarily in sub-Saharan Africa and was isolated in Saudi Arabia and Yemen in 2000. The case-fatality rate in humans is generally approximately 1%. CCHF is found in most of sub-Saharan Africa, Eastern Europe, and Asia. The case-fatality rate is 30%, and nosicomial outbreaks have been documented through exposure to infected blood products. Hantaviruses are divided into two groups based on location: Old World viruses are found in Eastern Europe and eastern Asia, whereas New World viruses are found in North and South America. Depending on the virus, the case-fatality rate can vary between 1% and 50%.
Most humans suffering from RVF experience flulike symptoms and recover with no complications after an incubation period of 2–5 days. In 0.5% of cases, hemorrhagic fever develops after the initial febrile stage. Another 0.5% of cases develop retinitis or encephalitis 1–4 weeks after infection. Most human infections occur 1–2 weeks after the appearance of abortion or disease in livestock. In contrast to RVF, most humans infected with CCHF develop hemorrhagic fever. The incubation for the disease is 3–7 days, and most patients will develop hemorrhagic fever 3–6 days after the onset of flulike symptoms. Hantaviruses generally cause one of two clinical presentations: (1) hemorrhagic fever with renal syndrome, generally caused by Old World hantaviruses, or (2) hantavirus pulmonary syndrome, generally caused by New World hantaviruses. The incubation period is 7–21 days followed by a clinical phase of 3–5 days. The severity of the illness depends on the virus.
RVF causes severe disease in livestock animals. Abortion rates can reach 100%. Mortality rates in animals younger than 2 weeks of age can be greater than 90%, with most animals succumbing to disease within 24–36 h from the onset of fever. Older animals also suffer from a less severe febrile illness, with mortality rates ranging from 5% to 60%. In contrast, CCHF virus causes an unapparent or subclinical disease in most livestock species and is maintained in the herds through the bite of a tick. Rodents are persistently infected with hantaviruses but show no clinical signs. The virus is transmitted from rodent to rodent through biting, scratching, and possible aerosolization of rodent urine.
Filoviruses
Marburg virus was first isolated in 1967 from several cases of hemorrhagic fever in European laboratory workers in Germany and the former Yugoslavia working with tissues and blood from African green monkeys imported from Uganda. Ebola virus (see Fig. 3.6) was first reported simultaneously in Zaire and Sudan in 1976 when two distinct subtypes were isolated in two hemorrhagic fever epidemics. Both subtypes, later named Zaire and Sudan, caused severe disease and mortality rates greater than 50%. A third subtype of Ebola (Reston) was later found in macaques imported from the Philippines into the United States in 1989 and Italy in 1992. Four humans were asymptomatically infected and recovered with no signs of hemorrhagic fever. In 1994 a fourth subtype of Ebola was isolated from an animal worker in Côte d’Ivoire who had performed a necropsy on an infected chimpanzee. Scattered outbreaks have occurred periodically, with the latest being an outbreak of Ebola in West Africa in 2014. At the time of preparation of this manuscript, the outbreak was ongoing with sporadic cases in Liberia, Sierra Leone, and Guinea. This outbreak will be covered in depth as a case study in chapter Case Studies of this book.
The reservoir for Ebola virus is likely to be several different species of fruit bats (Leroy et al., 2009). Bats have also been implicated for Marburg virus (Towner et al., 2007). Intimate person-to-person contact is the main means of transmission of filoviruses for humans. Nosicomial transmission has been a major problem in outbreaks in Africa through the reuse of needles and syringes and exposure to infected tissues, fluids, and hospital materials. Aerosol transmission has been observed in primates but does not seem to be a major means in humans.
Marburg and Ebola subtypes Sudan, Zaire, and Cote d’Ivoire appear to be found only in Africa, and all three Ebola subtypes have been isolated from human cases only in Africa. The case-fatality rate for Marburg ranges from 23% to 33% and 53–88% for Ebola, with the highest rates found in Ebola Zaire. The presence of Ebola Reston in macaques from the Philippines marked the first time a filovirus was found in Asia. The pattern of disease of humans in nature is relatively unknown except for major epidemics.
Filoviruses cause the most severe hemorrhagic fever in humans. The incubation period for Marburg and Ebola is generally 4–10 days followed by abrupt onset of fever, chills, malaise, and myalgia. The patient rapidly deteriorates and progresses to multisystem failure. Bleeding from mucosal membranes, venipuncture sites, and the gastrointestinal organs occurs followed by disseminated intravascular coagulation. Death or clinical improvement usually occurs around day 7–11. Survivors of the hemorrhagic fever are often plagued with arthralgia, uveitis, psychosocial disturbances, and orchitis for weeks after the initial fever.
Filoviruses cause severe hemorrhagic fever in nonhuman primates. The signs and symptoms found are identical to humans. The only major difference is that Ebola Reston has a high mortality in primates (∼82%), whereas it does not seem to be pathogenic to humans.
Flaviviruses
Flaviviruses can cause an array of clinical manifestations. However, we concentrate on those causing hemorrhagic fever. Yellow fever was first described in 1648 in the Yucatan. It later caused huge outbreaks in tropical Americas in the 17th–20th centuries. The French failed to complete the Panama Canal because their workforce was decimated by yellow fever. Yellow fever virus was the first flavivirus isolated (1927) and the first virus proven to be transmitted by an arthropod vector. Dengue virus, which was also found to be transmitted by an arthropod, was isolated in 1943. Major outbreaks of dengue with hemorrhagic fever occurred in Australia in 1897, Greece in 1928, and Formosa in 1931. Since the cessation of the use of dichlorodiphenyltrichloroethane to control mosquito vectors, dengue has now spread to most of the tropical regions of the world.
Omsk hemorrhagic fever virus was first isolated in 1947 from the blood of a patient with hemorrhagic fever during an epidemic in Omsk and Novosibirsk Oblasts of the former Soviet Union. Kyasanur Forest virus was isolated from a sick monkey in the Kyasanur Forest in India in 1957. Since its recognition, 400–500 cases a year have been reported.
Flaviruses utilize an arthropod vector to transmit disease. Yellow fever is a zoonotic disease that is maintained in nonhuman primates. The virus is passed from primate to primate through the bite of an infected mosquito. This is known as the sylvatic cycle. Humans contract the disease when bitten by an infected mosquito, usually Aedes aegypti, and the disease can then be epidemically spread from human to human by these mosquitoes. This cycle is known as the urban cycle. Dengue virus is maintained in the human population and is primarily transmitted from human to mosquito to human, thereby concentrating cases in an urban setting.
Kyasanur Forest virus is transmitted by an ixodid tick. The tick can pass the virus from adult to eggs and from one stage of development to another. The basic transmission cycle involves ixodid ticks and wild vertebrates, principally rodents and insect-eating animals. Humans become infected when bitten by an infected tick. The basic transmission cycle of the Omsk hemorrhagic fever virus is unknown.
The yellow fever virus is found throughout sub-Saharan Africa and tropical South America, but activity is intermittent and localized. The annual incidence is believed to be approximately 200,000 cases per year worldwide. Case-fatality rates range, greatly depending on the epidemic, but they may reach up to 50% in severe yellow fever cases. Dengue virus is found throughout the tropical Americas, Africa, Australia, and Asia. Cases of DHF have been increasing as the distribution of Aedes aegypti increases after the collapse of mosquito control efforts. Case-fatality rates for DHF are generally low (1–10%), depending on available treatment. Kyasanur Forest virus is confined to the Mysore state of India but is spreading. The case-fatality rate is 3–5%. Omsk hemorrhagic fever virus is still isolated to the Omsk and Novosibirsk regions of the former Soviet Union. The case fatality is 0.5–3%.
Yellow fever can cause a severe hemorrhagic fever. The incubation period in humans is 3–6 days. The clinical manifestations can range from mild to severe signs. Severe yellow fever begins abruptly with fever, chills, severe headache, lumbosacral pain, generalized myalgia, anorexia, nausea and vomiting, and minor gingival hemorrhages. A period of remission may occur for 24 h followed by an increase in the severity of symptoms. Death usually occurs on day 7–10. Dengue virus causes a mild, flulike illness on first exposure. If the person is then infected by a different serotype, then DHF can occur. The disease begins like a normal infection of dengue virus, with an incubation period of 2–5 days, but it quickly progresses to a hemorrhagic syndrome. Rapid shock ensues but can be reversed with appropriate treatment. Kyasanur Forest virus in humans is characterized by fever, headache, myalgia, cough, bradycardia, dehydration, hypotension, gastrointestinal symptoms, and hemorrhages. Recovery is generally uncomplicated with no lasting sequelae. Omsk hemorrhagic fever virus has a similar presentation to Kyasanur Forest virus; however, hearing loss, hair loss, and neuropsychiatric complaints are commonly reported after recovery.
Yellow fever is maintained in nonhuman primates. Depending on the species, yellow fever may be an unapparent infection or a severe hemorrhagic illness. Dengue has been isolated from several nonhuman primates in Africa but does not cause clinical signs. Livestock may develop a viremia with Kyasanur Forest disease virus but generally do not show clinical signs. Omsk hemorrhagic fever virus is maintained in rodents but does not cause clinical signs.
Clinical Disease in Humans
Specific signs and symptoms vary by the type of VHF, but initial signs and symptoms often include marked fever, fatigue, dizziness, muscle aches, loss of strength, and exhaustion. More severe clinical symptoms include bleeding under the skin causing petechiae, ecchymoses, and conjunctivitis. Bleeding may also occur in internal organs and from orifices (eg, the eye, nose, or mouth). Despite widespread bleeding, blood loss is rarely the cause of the death.
Clinical microbiology and public health laboratories are not currently equipped to make a rapid diagnosis of any of these viruses, and clinical specimens in an outbreak need to be sent to the CDC or the US Army Medical Research Institute of Infectious Diseases, located in Frederick, Maryland. These are the only two Level D laboratories in the Laboratory Response Network. These laboratories can conduct serology, polymerase chain reaction, immunohistochemistry, viral isolation, and electron microscopy of VHF viruses.
VHF patients receive supportive therapy, with special attention paid to maintaining fluid and electrolyte balance, circulatory volume, blood pressure, and treatment for any complicating infections. There is no other established treatment. No antiviral drugs have been approved by the FDA for the treatment of VHF. Treatment with convalescent-phase plasma has been used with success in some patients with Junin, Machupo, and Ebola. If infection with a VHF virus is suspected, then it should be immediately reported to health authorities. Strict isolation of a patient is required.
Prevention of VHFs is done by avoiding contact with the host species. Because many of the hosts that carry VHFs are rodents, prevention should involve rodent control methods. Steps for rodent prevention include the control of rodent populations, discouraging their entry into homes, and safe cleanup of nesting areas and droppings. For VHFs that are spread by arthropod vectors, prevention efforts should focus on community-wide insect and arthropod control. In addition, people are encouraged to use insect repellant, proper clothing, bed nets, window screens, and other insect barriers to avoid being bitten.
The only established and licensed vaccine is for yellow fever. This live vaccine is safe and effective and provides immunity lasting 10 or more years. An experimental vaccine is under study for Junin virus, which provides some cross protection to Machupo virus. Investigational vaccines are in the development phase for RVF, hantavirus, and dengue. For VHFs that can be transmitted person to person, including the Arenaviridae, the Bunyaviridae (excluding RVF), and the Filoviridae, close physical contact with infected people and their body fluids should be avoided. One infection control technique is to isolate infected individuals to decrease person-to-person transmission.
Wearing protective clothing is also needed to reduce transmission between people. The WHO and CDC have developed practical, hospital-based guidelines that are provided within Infection Control for Viral Hemorrhagic Fevers in the African Health Care Setting. The manual can help health-care facilities recognize cases and prevent further hospital-based disease transmission using locally available materials and few financial resources. Other infection control recommendations include proper use, disinfection, and disposal of instruments and equipment used in treating or caring for patients with VHF, such as needles and thermometers. Any disposable items, including linens, are placed in a double plastic bag and saturated with 0.5% sodium hypochlorite (1:10 dilution of bleach). Sharps are placed in the sharps container and saturated with the 0.5% solution, and the containers are wiped with the 0.5% solution and sent to be incinerated.
Botulism
Botulinum toxin, which is produced by the spore-forming anaerobic bacterium Clostridium botulinum, is a highly toxic substance that presents a major threat from intentional exposure. The toxin is highly lethal and easily produced and released into the environment. Botulinum toxin is absorbed across mucosal surfaces and irreversibly binds to peripheral cholinergic nerve synapses. Seven antigenic types (A–G) of the toxin exist. All seven toxins cause similar clinical presentation and disease; botulinum toxins A, B, and E are responsible for the vast majority of foodborne illnesses in the United States.
Botulinum Toxin
Botulinum toxin is reported to be the most toxic substance known. Comparatively, it is 10–15,000 times more toxic than VX nerve agent.
Assuming that it was possible to evenly disperse the toxin for inhalation, 1 g of pure toxin is sufficient to kill 1 million people; however, such dispersion is technically impossible to achieve. The deadly toxin irreversibly blocks acetylcholine release from peripheral nerves, resulting in muscle paralysis. It has been developed as a biological weapon by many government research programs. As a biological weapon, it is a potent substance that is easy to produce and transport. A large population of victims requiring intensive care could easily overwhelm our health-care system (Horton et al., 2002).
Botulism is caused by poisoning from a toxin produced by the bacterium Clostridium botulinum. It is a gram-positive, spore-forming, obligate anaerobic bacillus. The clostridial spores are ubiquitous in soil and are very resistant to heat, light, drying, and radiation. Spores may survive boiling for several hours at 100°C; however, exposure to moist heat at 120°C for 30 min kills the spores. Specific conditions are required for the germination of spores. These include anaerobic conditions (eg, rotting carcasses or canned food), warmth, and mild alkalinity.
After germination, clostridial spores release neurotoxins. The seven antigenic types of neurotoxins are classified A–G. Typically, different neurotoxin types affect different species. Only a few nanograms of these toxins can cause severe illness. All cause flaccid paralysis in the species affected. Toxin is produced in improperly processed, canned, low-acid, or alkaline foods and in pasteurized and lightly cured foods held without refrigeration, especially in airtight packaging.
Botulism was first discovered by the German physician Justinius Kerner in 1793. He called the substance wurstgift because he found it in spoiled sausages. During this period of time, sausage was made by filling a pig’s stomach with meat and blood, boiling it in water then storing it at room temperature. These were ideal conditions for clostridial spores to survive. Botulism gets its name from botulus, which is Latin for sausage. In 1895 Emile von Ermengem identified C. botulinum as the actual source of a botulism outbreak in Belgium. Several outbreaks of botulism in the United States have led to federal regulations for food preservation. In 1919 an outbreak from canned olives (15 deaths) led to the use of high temperatures as industry standards for preserving foods. In 1973 an outbreak from canned soup led to further regulations for the safe processing of canned foods.
Botulism typically occurs through ingestion of the organism, neurotoxin, or spores. If the organism is ingested, then it incubates in the stomach and produces spores, which then germinate to release neurotoxin. If spores are ingested, then germination follows and neurotoxin is released. Finally, if spores have germinated within contaminated food, then the neurotoxin itself is ingested, causing rapid progression of the disease. Other forms of transmission involve contamination of open wounds with clostridia spores. In addition, inhalation of the neurotoxin is possible. This is the most likely bioterrorism method that would be used for this agent. No instance of secondary person-to-person transmission has been documented.
In the United States, on average, there are 110 cases of botulism per year. Typically, approximately 25% are food-related illnesses. Approximately 72% are the infant botulism form, and the remainder is wound related. To date the largest botulism outbreak in the United States occurred in 1977 in Michigan. Fifty-nine people were affected after eating poorly preserved jalapeno peppers. Approximately 27% of US foodborne botulism cases occur in Alaska. During 1950–2000 Alaska recorded 226 cases of foodborne botulism from 114 outbreaks. All cases were in Alaska Natives and were associated with eating fermented foods, which is a part of their culture. Because of changes in the fermentation process (use of closed storage containers), an increase in botulism rates occurred in Alaska from 1970 to 1989.
Human botulism illness can occur in three forms: foodborne illness, infant botulism, and wound contamination. These forms vary by how the toxin is obtained. All forms of the disease can be fatal and should be considered a medical emergency. The incubation period can range from 6 h to 2 weeks. However, signs typically occur 12–36 h after toxin release. Humans can be affected by types A, B, E, and rarely F neurotoxins.
Foodborne botulism occurs when the preformed neurotoxin is ingested. The most common source of the preformed toxin is contaminated food, usually from improperly home-canned vegetables (see Fig. 3.7) or fermented fish. Fifty percent of foodborne outbreaks in the United States are caused by type A toxins. The most commonly isolated neurotoxin is type A for canned foods and type E for improperly fermented fish products.
The most common form of human botulism occurs in infants. Annual incidence in the United States is 2 cases per 100,000 live births. Spores are ingested, germinate, release their toxin, and colonize the large intestine. It occurs predominantly in infants less than 1 year old (94% are less than 6 months old). The spores are obtained from various sources, such as honey, food, dust, and corn syrup.
Wound botulism is rare and occurs when the organism gets into an open wound and develops under anaerobic conditions. The organism typically comes from ground-in dirt or gravel. C. botulinum, its spores, and neurotoxin cannot penetrate intact skin. This form has also been associated with addicts of black-tar heroin. It is thought to be contaminated with dirt or boot polish during its preparation process. There have been clusters of cases each year in these drug users, some resulting in fatalities.
In humans the clinical signs of botulism are similar for all forms of the disease. Gastrointestinal signs (ie, nausea, vomiting, and diarrhea) are usually the first to appear. They are followed acutely by neurological signs, such as bilateral cranial nerve deficits. The victim has double vision and difficulty seeing, speaking, and swallowing. This soon develops into a descending weakness to symmetrical flaccid paralysis. This paralysis can affect the respiratory muscles and lead to death.
Children less than 1 year of age with the following clinical signs should be suspected of infant botulism (sometimes referred to as floppy baby syndrome). These include lethargy, poor feeding, weak cry, bulbar palsies, failure to thrive, and progressive weakness. This can lead to impaired respiration and sometimes death if not treated promptly.
Clinical signs can provide a tentative diagnosis for botulism intoxication. The definitive diagnosis in humans involves identifying the toxin in serum, stool, gastric aspirate, or the suspected food if available. Feces are usually the most reliable clinical sample in foodborne or infant botulism. In addition, cultures of stool or gastric aspirate samples may produce the organism but can take 5–7 days. Electromyography can also be diagnostic. The most widely used and sensitive test for detecting botulism toxin is the mouse neutralization test. Serum or stool with the suspected botulism organism is injected into a mouse and observed for clinical signs of the disease. Results are available in 48 h.
Airborne Botulinum Toxin
It is estimated that a point source aerosol release of botulinum toxin could incapacitate or kill 10% of persons within half a kilometer downwind of the point of release (Journal of the American Veterinary Medical Association 285 (2001), 1059–1070). However, the CDC maintains a well-established surveillance system for reporting human botulism cases that would promptly detect such an event.
Most cases of botulism require immediate intensive care treatment. Because of respiratory paralysis, a mechanical ventilator is needed if respiratory failure occurs. An intravenous equine-derived botulinum antitoxin is available on a case-by-case basis from the CDC through state and local health departments. Botulism immune globulin was approved for use on October 23, 2003, for the treatment of infant botulism caused by types A and G.
Botulinum toxin has been used as an attempted bioweapon. Between 1990 and 1995 the Japanese cult Aum Shinrikyo used botulinum toxin aerosols at multiple sites in Tokyo. Fortunately, these attempts failed. As a potential bioterrorism agent, botulism toxin is extremely potent and lethal. It is easily produced and transported. Signs of a deliberate release of the toxin, either via aerosol or food, would be a large number of acute cases from no common source and occurring as a cluster. In addition, uncommon toxin types, such as C, D, F, or G, may raise suspicion.
Critical Thinking
Discuss the reasons why each of the Category A agents discussed here is a threat to society. Apply the four Category A criteria to each of the agents and diseases.
Conclusion
Chapter 3 offered a comprehensive overview of Health and Human Services Category A agents, the most serious of all biological threats. Category A agents are those that lead to high morbidity and mortality of their victims, may be easily disseminated or spread from person to person, may cause panic and/or social disruption, and require special precautions for public health. Within this chapter we covered the signs and symptoms of anthrax, plague, tularemia, smallpox, VHF, and botulism. In addition, clinical manifestations, prophylaxis, and medical treatment strategies used to counter these diseases were also covered. From this information we should now appreciate and understand the challenges that public health officials and emergency management practitioners face when an intentional release of a Category A agent occurs in their community.
Essential Terminology
• Anthrax. A serious zoonotic disease caused by B. anthracis, a bacterium that forms spores. The three clinical manifestations of human anthrax are cutaneous, inhalation, and gastrointestinal. Typically, the disease affects cattle and sheep in areas where it is endemic. The disease is not spread from human to human.
• Botulism. The result of poisoning from ingestion with botulinum toxin, which is produced by the bacterium C. botulinum. Numerous cases occur in the United States every year because of adulterated food products.
• Plague. A serious zoonotic disease caused by Y. pestis, a bacterium. The three main clinical manifestations of human plague are bubonic, pneumonic, and septicemic. There are two lesser forms: plague meningitis and pharyngeal. Normally, the disease affects rodent species and is transmitted by the bite of an infected flea. The pneumonic form of plague is highly contagious from human to human.
• Smallpox. A serious, but eradicated, disease caused by smallpox virus. This pathogen is no longer found in nature because a successful vaccination program eliminated it from human populations. It is not a zoonotic disease. A single case of smallpox today would prompt the World Health Organization to declare an international public health emergency.
• Tularemia. A serious zoonotic disease caused by F. tularensis, a bacterium. The six clinical manifestations of human tularemia are pneumonic, glandular, ulceroglandular, oculoglandular, oropharyngeal, and typhoidal. Normally, the disease affects rabbits and is transmitted by the bite of an infected flea. Tularemia is not spread by human-to-human contact.
• Viral hemorrhagic fever (VHF). A group of illnesses caused by several distinct families of viruses that affect humans and nonhuman primates. VHF is a severe multisystem syndrome characterized by diffuse vascular damage. Bleeding often occurs and, depending on the virus, may or may not be life threatening. Some VHF viruses cause mild disease, whereas others may cause severe symptoms and death.
Discussion Questions
• What are the four criteria of Health and Human Services Category A? Select any Category A agent and then apply the four criteria to it.
• Why would a single case of smallpox be considered an incident of national significance, indeed an incident of international significance?
• In what ways could plague be used as a biological weapon?
• What is the most deadly biological toxin and how could it be practically used to affect a large number of people?
Websites
US Department of Health and Human Services, Centers for Disease Control and Prevention, Emergency Preparedness and Response, Bioterrorism: A thorough listing of all agents covered in this chapter can be found at http://www.bt.cdc.gov/bioterrorism/factsheets.asp.
