General Description The historic infectious disease referred to as the plague is caused by the bacteria called Yersinia pestis. Y. pestis can typically be found in small rodents and their fleas. However, it is a zoonose, which means it’s a disease that is passed from animals to humans through direct or indirect contact 1. Yersinia pestis is accidentally introduced into the human population. Humans typically contract plague after being bitten by a rodent flea that is infected with Y. pestis or by handling an animal infected with plague. According to Pathogen Profile Dictionary, Y. pestis is a Gram-negative bacillus belonging to the Enterobacteriaceae family which also includes Salmonella and Escherichia coli. Yersinia pestis is a non-spore-forming, anaerobe that is immobile at room temperature. The most favorable temperature for this particular bacterium is 28 degrees Celsius. Y. pestis is catalase-positive, oxidase-negative, urease-negative, and indole-negative 2. Septicemic, Pneumonic, and Bubonic (the most common plague found in humans) are the three different types of infections caused by this bacterium. If left untreated, bubonic plague claims about half of its victims. The other two forms are almost invariably fatal without antibiotics. Depending on sanitary conditions or lung infection plague can be spread in the air, direct contact, or very rarely by contaminated undercooked food.SignificanceYersinia pestis has an extraordinary place in history and has had enormous effects on the development of modern civilization. Some scholars have even suggested that the fall of the Roman Empire may be linked to the spread of plague. As a result of Roman soldiers returning home from the Persian Gulf battle in 165 AD. Yersinia pestis unknowingly represented disaster for people living in Asia, Africa and Europe. Plague outbreaks contributed to massive panic in cities and countries where it appeared. Several references in literature, art and monuments verify the horrors and devastation of past plague epidemics3. The Justinian plague arrived in Constantinople around 542 CE, almost a year after the disease first appeared in the outer provinces of the empire. The outbreak continued to sweep throughout the Mediterranean world for another 225 years. Yersinia pestis originated in China and northeast India then carried to the Great Lakes region of Africa by way of trade routes. Egypt was the point of origin regarding Justinian’s plague. Procopius of Caesarea (500-565 CE), a Byzantine historian, identified the beginning of the plague in Pelusium on the Nile River’s northern and eastern shores4. Procopius reported in his Secret History of nearly 10,000 deaths per day afflicting Constantinople. However, modern historians estimate around 5,000 deaths per day in city’s capital. Nevertheless, 20-40% of Constantinople’s population eventually perished from the disease. Nearly a quarter of the rest of the empire’s population died with estimates ranging from 30-50 million people in total, about half the world’s population at that time4,5. The most infamous of all outbreaks, The Black Death, a medieval pandemic struck around 800 years later. Yersinia pestis swept through Asia and Europe. Between 1347 and 1350, one in every four people in Europe perished due to the plague. The Black Plague had wiped out a third of Europe’s population by 1352 and would continue to occasionally spread death for the next three centuries6. It reached Europe in the late 1340s, killing an estimated 25 million people. The Black Death lingered around for centuries afterward, particularly in cities. Such as, the Great Plague of London (1665-66), where in which one out of every five residents died7.The most recent plague outbreaks have been reported in India during the early 20th century, and in Vietnam in the 1960s and 1970s during the wartime. More commonly plague is found in sub-Saharan Africa and Madagascar. These areas now account for over 95% of reported cases according to the CDC. One of these most recent outbreaks of plague was reported to occur in Madagascar between 2014 and 2015, with a peak in November 2014 when over 335 cases and 79 deaths were reported8,9.Obviously, with that being said plague still exists in various parts of the world. In 2003, more than 2,100 human cases and 180 deaths were recorded, nearly all of them in Africa. The last reported serious outbreak was in 2006 in the Democratic Republic of the Congo, where there was at least 50 casualties. The United States, China, India, Vietnam, and Mongolia are among the other countries that have confirmed human plague cases in recent years7.General SymptomsBubonic is the plague’s most common form, and refers to painful swollen lymph nodes called buboes that appear around the armpit, neck, or groin. After a few days to a week, the victim will experience weakness, fever, chills, and swollen lymph glands. If left untreated, bubonic plague kills about 50 percent of those it infects 7,9. Pneumonic is the plague’s most infectious type; when the bacteria infects the lungs and cause pneumonia. Pneumonic plague is also an advanced stage of bubonic plague. This is when the disease begins to be passed directly from person to person. This transmission is done through airborne droplets coughed from the infected individual’s lungs. Symptoms can begin within a few hours after infection and may cause respiratory failure and shock within two days of infection. Signs and symptoms may include the following: cough with bloody sputum, difficulty breathing, nausea and vomiting, high fever, headache,and weakness. Untreated pneumonic plague is frequently fatal7,9,10. Septicemic plague is the rarest of the three plague varieties. Septicemic plague spreads in the bloodstream and can be contracted from contact with plague-infected body matter or an infected flea/rodent bite. It involves bloodstream dissemination to all areas of the body. Buboes do not occur. Symptoms are endotoxic shock and disseminated intravascular coagulation. Other grim side effects may include fever and chills, extreme weakness, abdominal pain, diarrhea and vomiting, bleeding from your mouth, nose or rectum, or under your skin, shock, and gangrene blackening of your extremities (most commonly your fingers, toes, and nose)7,9,10.PathogenesisAs mentioned before bubonic plague is fatal about half of the time. The other two forms are almost always fatal without treatment with antibiotics. Yersinia pestis is exceptionally poisonous, even in comparison to bacteria similarly related. Due to the fact, that it’s a mutant variety it is at a disadvantage. Firstly, it is not able to survive outside the animals it infects. Secondly, it also has an inability to penetrate and hide in its host’s body cells. However, to compensate Y. pestis gains strength in numbers and the ability to disable its victim’s immune system. Yersinia pestis injects toxins into defense cells such as macrophages. Once these cells are inactive, the bacteria can multiply rapidly. Infected individuals are so overwhelmed that they’re nearly poisoned to death as the bacilli gather in thick clots under the skin awaiting a flea to continue on to the next victim. 7Plague is an acute, contagious, febrile illness transmitted accidentally to human hosts by the bite of an infected rat flea. Primarily, Y. pestis is a rodent pathogen. However, the flea draws viable Y. pestis organisms into its intestinal tract. These organisms multiply in the flea and block the flea’s proventriculus. Flea’s regurgitate some Y. pestis when they feed on their next meal thus transferring the infection to a new host. Y. pestis loses its capsular layer while growing in the flea. Once, in the human host most of the organisms are phagocytosed and killed by the polymorphonuclear leukocytes. A few bacilli are taken up by tissue macrophages. These macrophages are unable to kill Y. pestis and end up providing a protected environment for the organisms to synthesize their virulence factors11,12.Next, the organisms kill the macrophage and are released into the extracellular environment, where they resist phagocytosis (YopH and YopE; Yersinia outer membrane protein) by the polymorphs. The Y. pestis quickly spread to the draining lymph nodes, which become hot, swollen, tender, and hemorrhagic. A few hours after the initial flea bite the infection spills out into the bloodstream. This step leads to involvement of the liver, spleen, and lungs. The patient then develops a severe bacterial pneumonia. Large numbers of organisms enter the air when the patient coughs. Fifty to sixty percent of victims perish if they remain untreated. If the epidemic of bubonic plague develops, it eventually shifts into a predominately pneumonic form, which has a considerably higher mortality rate12.Laboratory DiagnosisWhen plague is suspected treatment should not be delayed. However, pre-treatment specimens should be taken if possible. Specimens should be obtained from appropriate sites for isolating the bacteria. The preferred specimen for microscopic examination and isolation from a bubonic case is material from the affected bubo, which should contain numerous organisms that can be evaluated microscopically and by culture. Organisms may be seen in blood smears if the patient is septicemic. Typically, early blood smears taken from suspected bubonic plague patients are negative for the bacteria, but may be positive by culture13. Culture is possible from sputum of very ill pneumonic patients. However, blood is usually culture-positive at this time as well. Throat specimens are not ideal for isolation of plague. This is due to the fact that these specimens often contain many other bacteria that mask the presence of plague. In cases, such as postmortem, where live organisms are unculturable lymphoid, spleen, lung, and liver tissue or bone marrow samples may provide evidence of plague infection. By direct detection methods such as direct fluorescent antibody (DFA) or PCR13.Under examination utilizing Gram, Wright, Giemsa, or Wayson’s stained smears Y. pestis may be identified. Visualization of bipolar-staining, ovoid, Gram-negative organisms with a “safety pin” appearance permits a rapid presumptive diagnosis of plague. If plague is still suspected and cultures yield negative results, serologic testing is possible to confirm the diagnosis13.Treatment Untreated plague can progress rapidly and has a high risk of mortality. Therefore, timely appropriate antibiotic treatment is critical. Appropriate IV therapy should be administered as soon as plague is suspected. Preferred primary treatments in the United States typically include Gentamicin and fluoroquinolones. Treatment duration is usually 10-14 days or until two days after patient’s fever subsides. Oral therapy may be substituted once the patient improves. Regimens are guidelines only and may need to be adjusted depending on a patient’s age, medical history, underlying health conditions, or allergies13. PreventionMake your home and outbuildings rodent-proof. This includes reducing rodent habitat (junk, rock piles, and brush) around your home, workplace, and recreational areas. Remove pet and wild animal food, because these products become possible rodent food supplies. Wear protective gloves if you are handling potentially infected animals. Use insect repellent if you think you could be exposed to rodent fleas during outdoor activities. Protect your pets by applying flea control products. Outdoor pets that wander freely are more likely to come in contact with plague infected animals or fleas and could bring them into homes. If your pet becomes sick, seek veterinarian care as soon as possible. A plague vaccine is no longer available in the United States. Although, new plague vaccines are in development they are not expected to be commercially available in the immediate future14.