Microbial Cardiovascular and Systemic Diseases

         Microbial Cardiovascular and Systemic Diseases Structures of the Cardiovascular System Movement of Blood and Lymph LE A R N I N G O UTC O M E 21.4 Trace the flow of fluid through the cardiovascular and LE A R N I N G O U TC O M E S 21.1 Distinguish the functions of arteries, veins, and capillaries. 21.2 Identify the major arteries and veins. The heart, blood, and blood vessels compose the cardiovascular system, which, along with the lymphatic structures, transports fluids throughout the body. Chapter 16 covers the lymphatic system in detail. In this chapter, we consider the cardiovascular system and some of its more prominent diseases. The cardiovascular system is a closed system in which the heart pumps blood into arteries connected via capillaries to veins. Veins carry blood back to the heart. The main arteries are the pulmonary arteries, which carry blood to the lungs, and the aorta, which carries blood to the rest of the body. The main veins are the pulmonary veins, which return blood from the lungs to the heart, and the superior vena cava and inferior vena cava, which carry blood from the upper and lower parts of the body, respectively (Figure 21.1a). The heart also has its own coronary arteries and veins. Blood is a tissue composed of plasma—the liquid part of blood containing dissolved nutrients, gases, and proteins—and so-called formed elements: erythrocytes (red blood cells), leukocytes (white blood cells), and small fragments of cells called platelets, which are important in coagulation (blood clotting). Serum is the liquid remaining when formed elements and clotting proteins are removed from blood. Structure of the Heart LE A R N I N G O U TC O M E lymphatic systems. Veins called the superior and inferior venae cavae carry blood to the right atrium, which then pumps the blood through the right atrioventricular (tricuspid) valve to the right ventricle. The right ventricle pumps blood through the pulmonary semilunar valve to the lungs, where oxygen enters the blood and carbon dioxide diffuses out. Oxygenated blood returns via pulmonary veins to the left atrium, which pumps the blood through the left atrioventricular (mitral) valve to the left ventricle. The left ventricle, which is the most muscular of the four chambers of the heart, pumps blood through the aortic semilunar valve into the aorta, and from there through a series of smaller and smaller branched arteries into capillaries. Heart valves prevent backflow of blood. Capillaries, which are extremely tiny vessels about 8 mm in diameter, are the part of the vascular system where oxygen and nutrients diffuse into surrounding tissues. Capillaries also leak fluid into spaces between cells, called interstitial spaces. Lymphatic vessels pick up this interstitial fluid and return it to the heart as lymph via a one-way system of lymphatic vessels. (Chapter 16 covers lymphatic vessels, the flow of lymph, lymphatic cells, and their roles in immunity.) Blood is normally germ free (axenic7, ā-zēn′ik); that is, it contains no microbes. However, breaks in the skin or mucous membranes provide a route for microbes to enter the blood. Many of these invaders are benign, but others cause diseases of the cardiovascular and lymphatic systems. The blood and lymph may also spread such microbes throughout the body to cause widespread diseases. The following sections examine such diseases. We begin our survey with cardiovascular and systemic diseases caused by bacteria. 21.3 Describe the structures and functions of the heart and ell T 1Latin, meaning “hall.” meaning “little belly.” 3From Latin valva, meaning “folding door.” 4From Greek peri, meaning “around,” and kardia, meaning “heart.” 5From Greek mys, meaning “muscle.” 6From Greek endon, meaning “within.” 2Latin, M21_BAUM7206_05_SE_C21.indd 630 M Why Bacteria infecting the mouth can enter the blood through small cuts resulting from normal brushing and flossing. Why would these bacteria reach the right atrioventricular valve before the other heart valves? IGURE The heart is an exquisite set of two muscular, parallel pumps that act together to pump blood. Each side of the heart is composed of two chambers: an upper atrium1 and a lower ven­ tricle,2 which are separated by valves 3 (F 21.1b). The heart is composed of three layers: an outer fibrous pericar­ dium,4 a muscular myocardium,5 and a thin inner endocardium.6 The endocardium lines the atria and ventricles, extends to cover the valves, and is continuous with the linings of the blood vessels. e blood vessels. Bacterial Cardiovascular and Systemic Diseases Bacteria can infect the blood as well as the blood vessels and heart. The following sections examine bacterial effects on the cardiovascular system. 7 From Greek a, meaning “no,” and xenos, meaning “foreigner.” 11/23/16 3:41 AM       Bacterial Cardiovascular and Systemic Diseases Superior vena cava (main vein) Right pulmonary artery Pulmonary arteries Right pulmonary veins Pulmonary veins Valves (closed) Heart Vessels of liver Left atrium Right atrium Vessels of kidney Endocardium Valves (open) Aorta (main artery) Myocardium Pericardium Inferior vena cava (main vein) Right ventricle Left ventricle (b) The heart Vein Artery (a) ◀ Figure 21.1 The cardiovascular system. (a) Arteries carry blood from the heart to the body’s organs, tissues, and cells. Veins return blood to the heart. By convention, artists color vessels carrying oxygenated blood red, and vessels carrying unoxygenated blood blue; as a result, pulmonary arteries going from the heart to the lungs are colored blue, and pulmonary veins carrying oxygen from the lungs are colored red. (b) The heart is two functional pumps, each composed of two chambers separated by valves. The right side of the heart pumps unoxygenated blood to the lungs; the left side pumps oxygenated blood to the rest of the body. Septicemia, Bacteremia, and Toxemia LE A R N I N G O U TC O M E S 21.5 Distinguish among septicemia, bacteremia, and toxemia. 21.6 Describe the signs, symptoms, causes, diagnosis, treat- Septicemia8 refers to the presence of microbial infection of the blood that causes illness. Bacteremia refers specifically to bacterial septicemia, though many physicians use the terms bac­ teremia and septicemia interchangeably. When bacteria remain fixed at a site of infection but release toxins into the blood, the ment, and prevention of septicemia and toxemia. 21.7 Describe the actions of endotoxin (lipid A). M21_BAUM7206_05_SE_C21.indd 631 8From Greek sepein, meaning “to become putrid,” and haima, meaning “blood.” 11/23/16 3:41 AM apt       Ch er 21    Microbial Cardiovascular and Systemic Diseases condition is toxemia. Septicemia can lead to an infection of the lymphatic system in which inflamed lymphatic vessels become visible as red streaks under the skin, a condition known as lymphangitis (lim-fan-jī′tis) (Figure 21.2). Lymphocytes, particularly in lymph nodes, act to limit infection of lymphatic vessels and lymph nodes. Signs and Symptoms Septicemia is characterized by fever (over 38°C, 99°F), chills, nausea, vomiting, diarrhea, shortness of breath, malaise (feeling of general discomfort), and changes in mental status such as confusion, anxiety, and an impending feeling of doom. These signs and symptoms can progress rapidly to septic shock, a condition of extremely low blood pressure resulting from dilation of blood vessels. Decrease in body temperature, decrease in or absence of urine output, rapid breathing, aberrant blood clotting, increased heart rate, anxiety, and death characterize septic shock. The mortality from septic shock can exceed 50%, depending on the bacterium and the overall health of the patient. Bacterial septicemia can trigger petechiae (pe-tē′kē-ē)— minute hemorrhagic skin lesions—on the trunk and lower extremities (Figure 21.3). Petechiae may coalesce and combine with regions of cell death to form large black lesions. In some patients, however, septicemia produces only mild fever and arthritis. Septic bacteria can also invade bones, causing osteomyelitis9 (os′tē-ō-mī-ĕ-lī′tis), which is inflammation of the bone and its internal bone marrow. Pain in the infected bone accompanied by high fever characterizes osteomyelitis. In children, osteomyelitis typically occurs in areas with well-developed ▲ Figure 21.3 Petechiae, a sign of bacteremia. These skin lesions can be small and relatively diffuse or may coalesce to form large, black sores containing dead cells. blood supplies such as the growing regions of long bones. In adults, osteomyelitis is more commonly seen in vertebrae. Toxemia manifests differently according to the toxins involved. Exotoxins, which are released from living microbes, include cell-killing cytotoxins and neurotoxins, such as botulism toxin that prevents muscular contraction and tetanus toxin that prevents muscular relaxation (see Figures 20.6 and 20.8). Dying Gram-negative bacteria disintegrate, releasing endotoxin, which is the lipid A portion of lipopolysaccharide (LPS) from the outer layer of a Gram-negative cell’s outer membrane, into the blood. A severe form of toxemia with septic shock is streptococcal toxic shock syndrome (TSS), in which a patient’s blood pressure drops precipitously and the patient may suffer from dizziness, confusion, difficulty in breathing, and a weak and rapid pulse. The liver and kidneys may fail. Pathogens and Virulence Factors ­ Numerous bacteria are capable of causing septicemia or toxemia. In every case, the bacterium must have one or more virulence factors that allow it to resist the body’s defenses long enough to multiply and upset the body’s normal structures and functions, producing signs and symptoms. For example, bacteria that form capsules may resist phagocytosis or intracellular digestion, allowing them to reproduce and metabolize in the blood. Some bacteria have the ability to “steal” iron (which is necessary for bacterial metabolism) by the use of siderophores from carrier proteins in the plasma. Other bacteria destroy erythrocytes, releasing iron from hemoglobin into the blood and making it available for bacterial growth. Various Gramnegative bacteria release different kinds of endotoxin molecules. Some endotoxins are relatively harmless, whereas others cause serious signs and symptoms because they stimulate the body to release chemicals that trigger fever, inflammation, diarrhea, hemorrhaging, blood coagulation, or shock. Frequently, bacteria causing septicemia are opportunistic— normal members of the microbiome that become pathogenic. Such organisms can cause healthcare-associated diseases. Examples include the Gram-negative aerobes Pseudomonas ▲ Figure 21.2 Lymphangitis, a sign of septicemia. As microbes travel through lymphatic vessels from a site of infection, localized inflammation occurs. How does bacteremia differ from septicemia? Figure 21.2 Septicemia refers to any microbial infection of the blood; bacteremia is bacterial septicemia. Some health care providers use the terms synonymously. 9From Greek osteon, meaning “bone”; myelos, meaning “marrow”; and itis, meaning “inflammation.” M21_BAUM7206_05_SE_C21.indd 632 11/23/16 3:41 AM       Bacterial Cardiovascular and Systemic Diseases aeruginosa (soo-dō-mō′nas ā-roo-ji-nō′să) and Neisseria meningit­ idis (nī-se′rē-ă me-nin-ji′ti-dis); facultative anaerobes from the intestinal tract such as Escherichia coli (esh-ĕ-rik′ē-ă kō′lī) and species of Salmonella (sal′mō-nel′ă); and strictly anaerobic species of Bacteroides (bac-ter-oy′dēz), which make up a large portion of the normal bacterial microbiome of the colon. Though Gram-negative bacteria are more commonly associated with septicemia, Gram-positive bacteria such as Staphylococcus aureus (staf′i-lō-kok′ŭs o′rē-ŭs) and Streptococcus pneumoniae (strep-tō-kok′ŭs nū-mō′nē-ī) can also be opportunistic causes of septicemia. Streptococcus pyogenes (pī-oj′en-ēz) causes streptococcal toxic shock syndrome (TSS). Streptococcal infections of the skin or wounds, rather than “strep throat” infections, are associated with TSS. (Streptococcal toxic shock syndrome should not be confused with staphylococcal toxic shock syndrome, which is associated with tampon use and is caused by Staphylococcus; see Chapter 24.) Pathogenesis and Epidemiology Septicemia begins with direct inoculation of bacteria into the blood, such as can occur during medical procedures, via nonsterile needle use by drug users, from an infection elsewhere in the body, or through small abrasions in the respiratory or digestive tracts. Septicemia is commonly associated with prolonged venous needle placement, the use of inadequately sterilized kidney dialysis machines, surgical wounds, infected teeth, and urinary tract infections. Healthcare-associated infections (HAI), such as biofilms that form on urinary catheters, account for about half of all cases of staphylococcal septicemia. Healthy people with normal immune systems rarely have septicemia; that is, bacterial blood infections in these patients spontaneously abate. However, people with suppressed immune systems due to alcoholism, other drug abuse, malnutrition, stress, or HIV infection cannot effectively fight bacterial infections; therefore, septicemia is more likely to develop in such patients. Medical procedures that enhance the growth of bacterial strains resistant to antimicrobial drugs or that introduce virulent strains into the blood make septicemia more likely. Gram-negative bacteria are more likely to cause severe septicemia because lipid A released from the outer membrane of dying Gram-negative bacteria is a potent activator of defensive reactions by the body. Endotoxin activates nearly all nonspecific defensive responses of the body, including complement via the alternative pathway (see Chapter 15, Figure 15.8), coagulation (blood clotting), and inflammation. Endotoxin also initiates the release of potent cytokines from macrophages, monocytes, B cells, and other defensive cells when the toxin binds to the cytoplasmic membranes of these cells. Coagulation can be widespread and severe, a condition called disseminated intravascular coagulation (DIC), which can be fatal. Released cytokines, including tumor necrosis factor (TNF), interleukins (ILs), and platelet activating factor (PAF), normally elicit defensive reactions at localized infections, but they become life threatening when carried to an extreme throughout the body in septicemia. TNF causes tissue damage and is pyrogenic (fever producing). IL-1 also triggers fever and causes the bone marrow to release a large number of immature neutrophils, which attach to and damage blood vessel walls. IL-6 and IL-8 damage circulating neutrophils and further injure cells lining blood vessels, allowing plasma to escape the vascular system, which precipitously reduces blood pressure. The drop in blood pressure reduces blood flow and oxygen delivery to vital organs, which can succumb, resulting in death. PAF is another potent trigger for coagulation. Figure 21.4 summarizes the effects of endotoxin on a patient. ◀ Figure 21.4 Potential effects of endotoxin. Endotoxin (lipid A of LPS) What type of bacteria produces endotoxin? Figure 21.4 Gram-negative bacteria produce endotoxin, which is found in the outer layer of the bacterial cell’s outer membrane. Platelet activating factor (PAF) Leukocytes release cytokines Tumor necrosis factor (TNF) and Interleukin 1 (IL-1) Interleukin 1 (IL-1) Blood-clotting reactions Interleukins 6 and 8 (IL-6, IL-8) Release of immature neutrophils Fever Disseminated intravascular coagulation (DIC) Inflammation Damage blood vessel walls Plasma loss, reduction of blood pressure M21_BAUM7206_05_SE_C21.indd 633 Complement (C3a and C5a) Shock 11/23/16 3:41 AM apt       Ch er 21    Microbial Cardiovascular and Systemic Diseases The Centers for Disease Control and Prevention (CDC) does not require reporting of cases of septicemia, bacteremia, or toxemia, so the full extent of these conditions in the United States is unknown; however, researchers estimate about 600,000 deaths per year, mostly among the elderly (over 65 years of age), children under age one, and cancer, AIDS, and diabetic patients. Morbidity and mortality depend upon the cause; for example, Haemophilus influenzae (hē-mof′i-lŭs in-flu-en′zī) in the blood attacks the meninges (covering membranes of the brain and spinal cord), causing meningitis in children, about 4% of whom die; Streptococcus pneu­ moniae is associated with bacteremia that is 0.8% fatal; whereas mortality from either Gram-negative bacterial toxemia or streptococcal toxic shock syndrome can be greater than 50%. Diagnosis, Treatment, and Prevention Physicians diagnose septicemia based upon signs and symptoms. Clinicians are able to culture bacteria from the blood of fewer than half of patients with characteristic signs and symptoms of sepsis; the majority of patients therefore have occult10 septicemia, a term referring to the fact that the exact bacterial cause is hidden. Treatment generally involves prompt diagnosis and treatment with appropriate antimicrobial drugs against the specific bacterial cause; elimination of the initial infection (for example, removal of an abscessed tooth); and intravenous fluid replacement to mitigate the fluid loss caused by endotoxin. Prevention of septicemia depends upon prompt treatment of infections, particularly in patients whose immune system is impaired. If treatment is delayed, bacteria multiply, and the use of antimicrobial drugs can worsen a patient’s condition by causing the release of large amounts of endotoxin. Newer treatments utilizing monoclonal antibodies against LPS and TNF show some small success in mitigating the effects of endotoxin. Endocarditis LE A R N I N G O U TC O M E 21.8 Describe the signs, symptoms, causes, diagnosis, treat- ment, and prevention of endocarditis. Bacteria in the blood can infect the endocardium, which is a thin lining inside the heart chambers, covering the valves, and continuous with the linings of the blood vessels leaving and entering the heart. Bacterial colonization of the endocardium triggers inflammation—endocarditis—and the formation of vegetations, which are bulky masses of platelets and clotting proteins that surround and bury the bacteria (see Disease at a Glance 21.1 on p. 636), hiding them from defensive cells, antibodies, and antimicrobial drugs. Signs and Symptoms Patients with endocarditis typically have fever, extreme fatigue, malaise, and breathing difficulty. A health care provider may detect tachycardia11 (faster-than-normal heart rate) and murmurs, which are sounds of abnormal blood flow through the heart. Endocarditis may lead to complications such as blood clots, stroke, and the complete destruction of the heart valves, resulting in heart failure. Endocarditis most commonly affects the left atrioventricular (mitral) valve, followed by the aortic semilunar valve. The signs and symptoms of endocarditis may develop slowly over a period of weeks or months—a condition called subacute endocarditis—or they may develop quickly (acute endocarditis). Pathogens Normal microbiota from elsewhere in the body are the usual causes of bacterial endocarditis; about half the cases are caused by so-called viridans12 streptococci (vir′i-danz strep-tō-kok′sī), which are named for the greenish pigment they produce when cultured on blood. Viridans streptococci are not highly invasive but can enter the blood through surgical wounds; small lesions in the lungs during pneumonia; or lacerations of the gums, including undetectable cuts produced by dental procedures, chewing hard candy, or brushing the teeth. Other opportunistic bacteria are Staphylococcus epidermidis (ep-i-der-mid′is) and S. aureus from the skin, Streptococcus pneu­ moniae from the pharynx, and Enterococcus (en′ter-ō-kok′ŭs) and Escherichia from the digestive tract. Dozens of pathogenic and opportunistic bacteria, including Neisseria, Pseudomonas, Bartonella (bar-tō-nel′ă), Mycobacterium (mī′kō-bak-tēr′ē-ŭm), and Mycoplasma (mī′kō-plaz-mă), can also cause endocarditis. “Culture negative” endocarditis is a condition in which the causative agent either has not been cultured or remains unknown. Pathogenesis and Epidemiology Most patients with endocarditis have obvious sources of infection such as an infected tooth, skin lesion, or intravascular catheter; however, some patients have no obvious focal site of bacterial infection. Intravenous drug users are at high risk of infection from contaminated syringes. Patients with abnormal hearts, including those who have birth defects, scarring from previous bacterial infections, or heart valve replacements, are more susceptible to endocarditis because a damaged heart provides sites for bacterial colonization. Vegetations also form roughened spots on the endocardium that provide places for bacteria to lodge and grow, producing additional layers of vegetations. Fragments of vegetations and blood clots, each called an embolus,13 can break off and travel via the blood to lodge in small blood vessels of the brain, kidneys, lungs, or abdominal organs, interrupting the flow of blood and causing severe damage. A stroke is such an interruption of blood flow through the brain. Greek tachys, meaning “quick.” Latin viridis, meaning “green.” 13From Greek embolos, meaning “plug.” 11From 12From 10From Latin occultare, meaning “to hide.” M21_BAUM7206_05_SE_C21.indd 634 11/23/16 3:41 AM b ic l M ro e icia Benef s       Bacterial Cardiovascular and Systemic Diseases When a Bacterial Infection Is a Good Thing Diagnosis, Treatment, and Prevention Physicians diagnose over 40,000 cases of endocarditis each year in the United States based on symptoms, confirmed by visualization of vegetations via an echocardiogram, which is an image of the heart produced by using sound waves, and by culturing the bacterium from the patients’ blood. A history of intravenous drug abuse, heart disease, or recent dental work; a new heart murmur; or hemorrhages visible under the nails or on the retina of the eye may indicate that a patient has endocarditis. Physicians treat endocarditis by administering intravenous antibacterial drugs, which requires hospitalization as sources of infection must be drained of pus and cleansed. Treatment for weeks is common. Physicians choose an antibacterial drug based on susceptibility tests (see Figure 10.9). Early treatment is usually successful; delayed diagnosis and treatment increase the risk of valve damage, heart failure, and the production of emboli. Surgical removal of vegetations and abscesses and repair or replacement of damaged heart valves is requisite. Patients with known risk factors should ask their physician about preventive use of antimicrobial drugs before dental procedures or surgeries. Good daily dental hygiene is equally important for such patients. Intravenous drug users should seek treatment for their addictions and in the interim always use clean needles. Disease at a Glance 21.1 summarizes features of bacterial septicemia and endocarditis. To this point, we have considered bacteria that infect the blood and the heart. However, blood and lymph can carry pathogens throughout the body to cause systemic diseases, that is, diseases that affect the whole body rather than a local area. Next, we examine some bacterial systemic diseases. M21_BAUM7206_05_SE_C21.indd 635 victim. Bdellovibrio daughters quickly attack other cells, reducing the victim’s population a hundredfold in short order. Micavibrio also attaches to its victim’s outer membrane, but it remains outside the cell, replicating by binary fission while literally sucking the life (and cytoplasm) from its target. The predators can attack both freeswimming and biofilm-associated Gram-negative bacteria. Scientists hope to identify, isolate, and utilize the unusual enzymes that allow Bdellovibrio and Micavibrio to exclusively attach to and kill Gram-negative bacteria. Alternatively, researchers are considering using the bacterial predators as living antimicrobial poultices on skin or wound infections or as living, intravenous, antimicrobial treatments for cardiovascular infections—a patient would be infected to get rid of an infection. Brucellosis LE A R N I N G O UTC O M E S 21.9 Describe the signs, symptoms, and cause of brucellosis. 21.10 Define zoonosis, and explain the role of animal hus- bandry in the spread and prevention of brucellosis. Brucellosis (brū-sel-ō′sis) is a zoonosis, that is, a disease of animals that can transfer to humans under normal conditions. Brucellosis has had a variety of other names, including Bang’s disease, after microbiologist Bernhard Bang (1848–1932), who investigated the disease; and Malta fever, rock fever of Gibraltar, and fever of Crete, all of which were named after localized epidemics in those locales. Signs and Symptoms Brucellosis is characterized by a fluctuating fever that spikes at about 40°C (104°F) every afternoon, giving the disease another of its common names—undulant14 fever. The patient also has chills, sweating, headache, myalgia15 (muscle pain), and weight loss. Pathogen and Virulence Factors Brucella (broo-sel′lă) is a genus of nonmotile, aerobic, Gramnegative coccobacilli that lack capsules. Although brucellosis in humans has been ascribed to four species of Brucella, rRNA analysis has revealed the existence of only a single true species: Brucella melitensis (me-li-ten′sis); the other variants are strains of ­ ­ H 2 µm ­ Gram-negative bacteria are common opportunistic and nosocomial pathogens of the cardioBdellovibrio (pink) vascular system, producing bacteremia, attacks Gram-negative toxemia, endocarditis, and other serious bacteria such as E. coli conditions. owever, Gram-negative bacte(seen here in blue). ria can themselves be the target of bacterial pathogens, specifically cells of Bdellovibrio (del-ō-vib´rē-ō) and Micavibrio (mī-kă-vib´rē-ō). These Gram-negative predators are voracious devourers of other Gram-negative bacteria; in fact, their Gramnegative cousins are their only diet! Bdellovibrio latches onto a Gram-negative bacterium such as Escherichia coli or the hard-to-treat Pseudomonas aeruginosa, enters its prey’s periplasm, digests its host, feasts, replicates, and lyses its SEM Latin undula, meaning “small wave,” referring to the wavy appearance of a graph of the patient’s temperature over time. 15From Greek mys, meaning “muscle,” and algos, meaning “pain.” 14From 11/23/16 3:41 AM c Gl n e a eA a apt er 21    Microbial Cardiovascular and Systemic Diseases t is D e as       Ch 21.1 Bacteremia/Endocarditis N Causes umerous bacteria may cause bacteremia or endocarditis. Common opportunistic or nosocomial causes of bacteremia are Pseudomonas aeruginosa, Neisseria meningitidis, Escherichia coli, Salmonella species, Staphylococcus aureus, and Streptococcus pneumoniae. About half the cases of bacterial endocarditis are caused Vegetations by viridans streptococci. Bartonella, Mycobacterium, and Mycoplasma species also cause the disease. Virulence factors Vary with pathogen but include attachment molecules, capsules, flagella, endotoxin, exotoxins, and antiphagocytic factors. Portal of entry Inoculation of bacteria into the blood via open wounds. E Heart valve. Signs and symptoms Bacteremia is characterized by fever, chills, nausea, vomiting, diarrhea, shortness of breath, malaise, and confusion or an impending sense of doom. ndocarditis symptoms include fever, extreme fatigue, malaise, difficulty breathing, and tachycardia. Incubation period Bacteremia symptoms can occur within hours to days following infection. Acute endocarditis can develop over days to a few weeks, whereas subacute bacterial endocarditis develops more slowly, over weeks or months. Susceptibility People with a suppressed immune system and patients requiring regular or prolonged invasive medical procedures, such as intravenous therapy or kidney dialysis. Treatment Prompt treatment and identification are important. Administration of appropriate antibiotics, elimination of the initial site of infection, and intravenous fluid replacement are the proper treatment for bacteremia. Treatment for endocarditis is similar: intravenous antibiotic therapy, often for a course of six weeks. Prevention Patients with known risk factors may be given prophylactic antibiotics before surgeries or dental procedures. Proper sterilization of medical instruments and proper wound care are also standard preventive measures. Pathogenesis and Epidemiology Humans become infected either by consuming unpasteurized contaminated dairy products or through contact with animal blood, urine, or placentas in workplaces such as slaughterhouses, veterinary clinics, and feedlots. The bacterium enters the body through breaks in mucous membranes of the digestive and respiratory tracts. Brucella travels inside phagocytic cells to organs of the body, including lymph nodes, spleen, bone marrow, liver, and heart. Arthritis, splenomegaly (enlarged spleen), enlarged testes, endocarditis, meningitis, and encephalitis may result. Because of immunization of livestock, destruction of infected animals, and quarantine of infected herds, brucellosis is less of a threat in the United States than in years past. In 2015, only 116 cases were reported. About half a million human cases occur worldwide each year. Diagnosis, Treatment, and Prevention Daily undulating fever can lead to a diagnosis of brucellosis. Since Brucella is difficult to culture in a laboratory, diagnosis is confirmed by serological tests showing a rising level of antibodies against Brucella. Most cases of brucellosis in animals and humans are mild and require no treatment. Physicians treat brucellosis with combinations of antibacterial drugs, including doxycycline and rifampin or streptomycin for several weeks. An attenuated vaccine for animals exists, but physicians do not administer it to humans because the vaccine sometimes causes brucellosis. With pasteurization of dairy products, immunization of uninfected domesticated animals, and the slaughter of infected ones, the threat of brucellosis for U.S. residents has been reduced. The remaining U.S. cases usually occur in immigrants or people who have traveled outside the country. Tularemia LE A R N I N G O UTC O M E 21.11 Describe the signs, symptoms, cause, diagnosis, treat- ment, and prevention of tularemia. this one species. Nevertheless, many clinicians and veterinarians still use the historical species names—B. melitensis, which infects goats and sheep, B. abortus (a-bort′us) in cattle, B. suis (soo′is) in swine, and B. canis (kā′nis) in dogs, foxes, and coyotes. In animal hosts, the Brucella lives as an intracellular parasite in organs such as the uterus and placenta, but these organs are not infected in humans. Infections in animals are either asymptomatic or cause a mild disease, though they sometimes cause sterility or spontaneous abortion. As a Gram-negative bacterium, Brucella has endotoxin that accounts for some of the signs and symptoms of brucellosis. The bacterium also has the ability to grow and multiply inside phagocytic cells, evading antibodies and some antibacterial drugs. M21_BAUM7206_05_SE_C21.indd 636 Tularemia16 (tū-lă-rē′mē-ă) is a zoonotic disease. Signs and Symptoms Within five days of infection, tularemia patients develop a skin lesion and swollen, tender, pus-filled lymph nodes near the site of infection. This is followed by ascending lymphangitis as bacteria are carried from the site. Patients may also exhibit any or all of the following: fever, chills, headache, malaise, fatigue, shortness of breath, joint stiffness, and myalgia. These general manifestations may last for months or years. Tularemia is fatal in about 5% of untreated patients and 1% of treated patients. 16Named for Tulare County, California. 11/23/16 3:41 AM       Bacterial Cardiovascular and Systemic Diseases Pathogen and Virulence Factors c Diagnosis of tularemia is difficult because the signs and symptoms are general and shared by many diseases. A history of contact with wild animals or of tick bites should prompt suspicion of infection with F. tularensis. Serological testing confirms a M21_BAUM7206_05_SE_C21.indd 637 S A construction worker in his mid-30s visited his physician, complaining of shortness of breath and a E. coli persistent cough for over three weeks. Upon examination, the doctor noted that the client had a history of asthma and intravenous drug use. Believing him to have an upper respiratory disturbance, the physician ordered a steroid to reduce swelling in the airways. Two weeks later, the LM construction worker’s signs 7 µm Blood smear. and symptoms were worse. e began to experience periods of dizziness and was extremely fatigued. Worried that something was terribly wrong and getting worse, he sought help at an emergency room. When he arrived, his heart rate was accelerated, and he appeared to be dehydrated. The staff administered a rapid intravenous infusion of fluids, took blood for analysis, and X-rayed his chest. Shortly after the infusion, the man’s respiratory situation deteriorated to the point that he was placed on a ventilator. The chest X-ray film revealed an abnormally enlarged heart and fluid throughout both lungs. The blood culture contained Escherichia coli. 1. How could the client have contracted bacteremia? 2. What had . coli done to the inner structures of his heart? 3. What factors in the medical treatment may have exacerbated the disease? Why? E Francisella is incredibly varied in the ways it spreads from its normal animal hosts to humans. Francisella, by virtue of its small size, can pass through apparently unbroken skin or mucous membranes. Most often, the bite of an infected tick or direct contact with an infected animal introduces the bacterium into the body. Francisella, an unusually infectious bacterium infection, requires as few as 10 cells when transmitted by a biting arthropod or through skin or mucous membranes. Bloodsucking flies, mosquitoes, and mites also transmit Francisella, and humans can be infected by consuming infected meat, drinking contaminated water, or inhaling bacteria in aerosols produced in the laboratory or during animal slaughter. Inhaling only about 50 cells can cause disease, though a person would have to consume 108 cells in food or drink to contract the disease via the digestive tract. Fortunately, human-to-human spread does not seem to occur. Hunters, trappers, taxidermists, and others who come in contact with dead wild animals are at greatest risk for tularemia. Only 244 cases were reported in 2015 in the United States, but the actual number of infections was probably much higher considering its virulence, prevalence in animals, and multiple modes of transmission. Tularemia frequently remains unsuspected because its signs and symptoms are not notably different from many other bacterial and viral diseases, and because it is difficult to confirm tularemia by using laboratory tests. Though it is typically innocuous, tularemia is fatal to about 5% of untreated patients. The Centers for Disease Control and Prevention removed tularemia from the list of nationally notifiable diseases in 1994, but concern about the possible use of Francisella as a bioterrorism weapon led officials to return tularemia to the list in 2000. A Heart-Rending Experience ER Pathogenesis and Epidemiology Diagnosis, Treatment, and Prevention Clini al Case tudy H ­ Francisella tularensis (fran′si-sel′ă too-lă-ren′sis) is a very small (0.2 mm * 0.2- 0.7 mm), nonmotile, strictly aerobic, Gramnegative coccobacillus that is found in temperate regions of the Northern Hemisphere living in water and as an intracellular parasite of animals. The bacterium has an amazingly diverse assortment of hosts. It lives in mammals, birds, fish, and bloodsucking ticks and insects. Indeed, one is hard pressed to find an animal that cannot be its host. The most common reservoirs in the United States are rabbits, muskrats, and ticks, which give the disease two of its common names—rabbit fever and tick fever. F. tularensis has a lipid capsule that discourages phagocytosis, but even when phagocytized, the bacterium survives by inhibiting the fusion of lysosomes with phagocytic vesicles. Endotoxin accounts for many of the signs and symptoms of tularemia. diagnosis. Culturing is not recommended because the organism is extremely virulent and easily contractible in the laboratory. F. tularensis produces β-lactamase, so penicillins and cephalosporins are ineffective, but other antimicrobial drugs have been used successfully. Currently, streptomycin or gentamicin is commonly used. An attenuated vaccine provides some protection for people at risk of exposure. Though the vaccine is not entirely effective, it can lessen the severity of the disease. To prevent infection, people should avoid the major reservoirs of Francisella (rabbits, muskrats, and ticks), especially in endemic areas. They can protect themselves from tick bites by wearing long clothing with tight-fitting sleeves, cuffs, and collars, and by using insect repellent containing DEET,17 picaridin,18 or IR3535.19 Francisella 17N,N-diethyl-meta-toluamide. as icaridin outside the United States. acid ethyl ester is a synthetic variant of the amino acid alanine. 18Known 193-(N-butyl-N-acetyl)-aminopropionic 11/23/16 3:41 AM c Gl n e a eA a apt er 21    Microbial Cardiovascular and Systemic Diseases t is D e as       Ch 21.2 Tularemia Cause Francisella tularensis (aerobic, Gram-negative coccobacillus). Virulence factors Intracellular pathogen of many mammals, birds, fish, arachnids, and insects; capsule discourages phagocytosis; inhibits lysosome fusion with phagosome; endotoxin. Portal of entry Via the bite of an infected tick, consumption of contaminated meat or water, inhalation, or direct Ulcer of tularemia. contact with an infected animal. Signs and symptoms Sudden fever, chills, headaches, diarrhea, muscle and joint pain, and progressive weakness and fatigue. Inhalation cases may also exhibit chest pain, bloody sputum, and difficulty breathing. Skin ulcers may develop near the site of an infected tick bite. Tender, swollen lymph nodes appear near the site of infection within five days of infection. Incubation period Generally three to five days but can be up to two weeks. Susceptibility Animal handlers and rabbit hunters are at greatest risk, especially in the endemic areas of the southeastern United States. Treatment Intramuscularly administered streptomycin and tetracycline. Prevention Use insect repellent, and check for ticks. Wash hands after handling animal carcasses. Cook game thoroughly, and ensure water is from a safe source or sterilized. the 1860s. The devastation from plague has been so great that, centuries later, the word can still provoke a sense of dread. Signs and Symptoms There are two main clinical manifestations of plague: The sudden appearance of smooth, enlarged, reddened, and painfully inflamed lymph nodes, called buboes20 (Figure 21.5), characterizes the first type and gives it its name—bubonic plague. Buboes commonly occur in the groin, armpits, or neck near the site of infection. Signs and symptoms of bubonic plague also include fever, chills, malaise, muscular pain, severe headache, bacteremia, and septicemia. The latter conditions result in increased heart rate, lowered blood pressure, disseminated intravascular coagulation, subcutaneous hemorrhaging, and death of tissues, which turn black as a result of secondary infection of gangrenous bacteria (discussed in Chapter 19). Because of the extensive darkening of dead skin, plague has been called “Black Death.” The second form of plague—pneumonic plague—occurs when plague bacilli in a patient with bubonic plague spread from the bloodstream to the lungs or are inhaled. Pneumonic plague develops very rapidly. Fever, malaise, severe cough, bloody and frothy sputum, and difficulty in breathing can arise within a few hours of infection. Pathogen and Virulence Factors Yersinia pestis (yer-sin′ē-ă pes′tis), the causative agent of plague, is a Gram-negative, rod-shaped bacterial pathogen of animals. This bacterium carries virulence plasmids that code for adhes­ ins, type III secretion systems, capsules, and antiphagocytic proteins. Adhesins are molecules that attach pathogens to their target cells, while type III secretion systems inject harmful proteins is present in tick saliva and feces, so prompt removal of ticks can reduce the chance of infection. Hikers and hunters should never handle ill-appearing wild animals or their carcasses, and they should wear gloves and masks when field dressing game. Disease at a Glance 21.2 summarizes the features of tularemia. Plague Bubo LE A R N I N G O U TC O M E S 21.12 Describe the cause, diagnosis, treatment, and prevention of plague. 21.13 Compare and contrast the signs and symptoms of bubonic and pneumonic plague. Plague (plāg) has caused several great pandemics. One major pandemic that lasted from the mid-500s a.d. to the late 700s is estimated to have claimed the lives of more than 40 million people. This devastation was surpassed during a second pandemic in the 14th century that killed about a third of the population of Europe in just five years. A third major pandemic spread from China across Asia, Africa, Europe, and the Americas in M21_BAUM7206_05_SE_C21.indd 638 ▲ Figure 21.5 Bubo. These swollen lymph nodes, such as this one on a 12-year-old from Madagascar, are a characteristic of bubonic plague. 20From Greek boubon, meaning “groin,” referring to a swelling in the groin. 11/23/16 3:41 AM       Bacterial Cardiovascular and Systemic Diseases IGURE IGURE Diagnosis, Treatment, and Prevention Because plague is deadly, often progresses rapidly, and can spread among people, it is a potential bioterrorism disease. Diagnosis and treatment must be rapid. The characteristic symptoms, especially in patients who have traveled in areas where plague is endemic, are usually sufficient for diagnosis. These observations can be verified by finding the Gram-negative bacteria in samples taken from lymph nodes. Although wild animals remain reservoirs, rodent and flea control and better personal hygiene have almost eliminated plague in industrialized countries. Many antibacterial drugs, prefer ably streptomycin or doxycycline, are effective against Yersinia. ­ ­ Rodents, such as rats, mice, ground squirrels, prairie dogs, and voles, are hosts for the natural endemic cycle of Y. pestis (Figure 21.6a); they harbor the bacterium but usually do not develop plague. In this cycle, approximately 30 species of fleas are the vectors for the spread of the bacteria among rodents. As bacteria multiply within a flea, they form a biofilm that blocks the esophagus such that the flea can no longer ingest blood from a host. As the starving flea jumps from host to host vainly seeking to alleviate its hunger with a blood meal, it infects each one with a bite. When other animals—including prairie dogs, rabbits, deer, camels, dogs, and cats—become infected via flea bites, they act as amplifying hosts; that is, they support increases in the numbers of bacteria and infected fleas. Infected fleas that have left their normal animal hosts can spread plague to humans, who can also become infected through direct contact with infected animals. Buboes develop 2–10 days following a flea bite (F 21.6b). ­ Pathogenesis and Epidemiology Untreated bubonic plague is fatal in 50% of cases. Even with treatment, 5% of patients die. In fatal infections, death usually occurs within a week of the onset of symptoms. Bubonic plague is not spread from person to person. Pneumonic plague, by contrast, can spread from person to person through aerosols and 21.6c) and, if left untreated, is fatal in nearly sputum (F 100% of cases. Plague is rare in the United States—only nine human cases were reported in 2015—but the disease is considered endemic in Arizona, California, Colorado, Nevada, New Mexico, and Oregon. Risk factors include occupational and environmental exposure to rodents and their fleas. ­ into the targets. Yersinia preferentially injects antiphagocytic proteins into dendritic cells, neutrophils, or macrophages, neutralizing their ability to mount an adaptive immune response or to eliminate the bacterium and thus allowing bacteremia. Endotoxin released from dead Yersinia can trigger inflammation, fever, and blood clotting. Direct contact Airborne transmission Flea bite Normal lymph nodes (a) Natural endemic reservoir hosts (rodents) Bubo (b) Bubonic plague (c) Pneumonic plague H ▲ Figure 21.6 The natural history and transmission of Yersinia pestis, the bacterium that causes plague. (a) The natural endemic cycle of Yersinia among rodents. (b, c) umans develop one of two forms of plague as the result of the bite of infected fleas or direct contact with infected hosts. Bubonic plague involves inflamed lymph nodes, often in neck, armpit, or groin. Yersinia can move from the bloodstream into the lungs to cause pneumonic plague, which can be spread between humans via the airborne transmission of the bacteria in aerosols. Why is plague so much less devastating today than it was in the Middle Ages? Figure 21.6 Urban living has reduced contact between people and flea vectors living on wildlife and farm animals; improved hygiene and the use of insecticides have reduced contact with flea vectors living on pets; and antimicrobials are effective against Y. pestis. M21_BAUM7206_05_SE_C21.indd 639 11/23/16 3:41 AM c Gl n e a eA a apt er 21    Microbial Cardiovascular and Systemic Diseases t is D e as       Ch 1. An expanding red rash, which often resembles a bull’seye, occurs at the site of infection within 3–30 days (Figure 21.7). About 80% of patients have such a rash, which lasts for several weeks. Other early signs and symptoms include malaise, headaches, dizziness, stiff neck, severe fatigue, fever, chills, muscle and joint pain, and lymphadenopathy (infected lymph nodes). 2. Neurological symptoms (for example, meningitis, encephalitis, and peripheral nerve neuropathy21) and cardiac dysfunction typify the second phase, which is seen in only 10% of patients. 3. The final phase, seen in almost 80% of patients, is characterized by severe arthritis that can last for years. The pathological conditions of the latter phases of Lyme disease are due in large part to the body’s immunological response; rarely are Lyme disease bacteria seen in the involved tissue or isolated in cultures of specimens from sites affected during this last phase. Lyme disease is rarely, if ever, fatal. 21.3 ­ Bubonic Plague and Pneumonic Plague Cause Yersinia pestis (Gram-negative coccobacillus). ­ Virulence factors Plasmids code for adhesins, type III secretion systems, capsule, and anti phagocytic proteins; endotoxin. Portal of entry Bubonic plague: transmitted by the bite of a flea from infected rodent. Pneumonic plague: travels in blood to lungs; inhaled. Plague has been called the Black Death because of the appearance of dead infected tissue. Signs and symptoms Bubonic plague: buboes (painfully inflamed lymph nodes), fever, chills, malaise, muscle pain, headache, bactermia, septicemia, low blood pressure, disseminated intravascular coagulation, and death of infected tissue, which turns black. Pneumonic plague: fever, malaise, severe cough, bloody sputum, and difficulty in breathing. Incubation period Bubonic plague: one to seven days. Pneumonic plague: one to four days, though it can be as little as a few hours. Susceptibility People who enter areas where Yersinia is endemic in animal populations, such as prairie dog “towns”; people exposed to others who have pneumonic plague. Treatment Immediate treatment with antimicrobial drugs such as streptomycin or doxycycline. Pathogen and Virulence Factors A large (0.5 mm * 3-20 mm) spirochete—Borrelia burgdorferi22 (bō-rē′lē-ă burg-dōr′fer-ē) (Figure 21.8)—causes Lyme disease. B. burgdorferi has an unusual metabolism in that it does not use iron in its enzymes or its electron transport chains. It uses manganese in place of iron, thereby circumventing one of the body’s natural defense mechanisms—the lack of free iron in human tissues and fluids. R Prevention odent control; avoidance of endemic areas; possible vaccine. Researchers are in the final phases of testing a human vaccine for regulatory approval. Disease at a Glance 21.3 summarizes the features of plague. Lyme Disease LE A R N I N G O U TC O M E S 21.14 Describe the features of the three stages of Lyme disease. 21.15 Discuss the life cycle of the Ixodes tick as it relates to Lyme disease. 21.16 Explain how the virulence factors of Borrelia allow it to evade the body’s defenses. 21.17 Elucidate the treatment and prevention of Lyme disease. ▲ Figure 21.7 Distinctive “bull’s-eye” rash of Lyme disease. Such a rash is often seen in the initial phase of the disease. ­ In 1975, epidemiologists noted that the incidence of childhood arthritis in Lyme, Connecticut, was over 100 times higher than expected. Upon further investigation, they described a tickborne zoonosis, Lyme disease. Signs and Symptoms Lyme disease mimics many other diseases, and its range of signs and symptoms is vast. The disease typically has three phases in untreated patients: M21_BAUM7206_05_SE_C21.indd 640 From Greek neuron, meaning “nerve,” and pathos, meaning “suffering.” Named for the French bacteriologist Amedee Borrel and a specialist in tick-borne diseases, Willy Burgdorfer. 21 22 11/23/16 3:41 AM       Bacterial Cardiovascular and Systemic Diseases c Clini al Case tudy Nightmare on the Island F L N O Borrelia 15 μm ▲ Figure 21.8 Borrelia burgdorferi. This Gram-negative spirochete L causes yme disease. The bacterium can change its outer membrane proteins via genetic rearrangement to emerge as antigenically different variants, making it more difficult for immune cells to recognize the pathogen and clear it from the blood. When it dies, Borrelia releases an active endotoxin (lipid A) from its outer membrane. M21_BAUM7206_05_SE_C21.indd 641 H H N 1. What bacterium infected Jacob? 2. What is a common name of the disease afflicting Jacob? 3. What do the laboratory scientists at the hospital determine about the Gram reaction of the bacterium? 4. Why didn’t the physician use penicillin instead of streptomycin? Pathogenesis Red blood cell LM keeps Jacob in bed, which isn’t difficult because his breathing becomes more labored and painful. Two days later he begins coughing up blood, and Peggy recognizes that this isn’t an ordinary summertime cold. She rushes Jacob to the local clinic, where the doctor orders immediate intravenous streptomycin and transport to a hospital on the mainland. The physician tells Peggy that Jacob is likely infected with the most virulent bacterium known. e questions her about Jacob’s activities on the island: as the boy touched any animals? Done any outdoor activities? Been bitten by a tick? “ o, no, no.” Then she recalls that Jacob helped mow the grass earlier in the week. Within days, Jacob feels better and can answer questions. e tells the doctor that the lawnmower had run over the dried body of a small dead rabbit. The physician suspects the mower had spewed bacteria into the air; Jacob had inhaled a near-fatal dose. The grassy lawn will no longer recall the fond memories of Peggy’s childhood; instead, she will remember men in biohazard suits taking samples, documenting the nightmarish time she almost lost her son. H H S Peggy loves her time on The Island each year. er parents had taken her every year to the resort destination as a girl, and now she is doing the same with her children. Their seaside home near Cape Cod, Massachusetts, is modest in comparison to some of the neighbors’, but it has been in Peggy’s family for over a hundred years, and she has fond memories from every stage of her life. ne of Peggy’s fondest memories is playing tag with her friends on the lawns of The Island’s homes. ow, she smiles as she watches her eight-year-old son, Jacob, help the older son of one of her childhood girlfriends mow the grassy expanse. “Building memories—that’s what it’s about,” she muses. ittle does she know that some memories can build nightmares. Three days later Jacob wakes up complaining of a scratchy throat, headache, and “soreness all over.” Peggy is concerned about his dry cough and 103° temperature. “A summer cold?” she wonders. She Hard ticks of the deer tick genus Ixodes23 (ik-sō′dēz) are the vectors of Lyme disease. Understanding the life cycle of the tick is essential to understanding the disease. A deer tick lives for two years, during which it passes through three stages of development: a six-legged larva, an eight-legged nymph, and an eightlegged adult. Once during each stage, it attaches to a vertebrate host for a single blood meal. After each of its three feedings, the tick drops off its host and lives in leaf litter or on brush. The different stages of Ixodes typically feed on different hosts, though all stages of all species of Ixodes may feed on humans. Transmission of Borrelia from a female tick to her offspring is rare, so larvae that hatch in the spring are usually uninfected 1 , becoming infected during their first blood meal (Figure 21.9) 2 . Over the winter, larvae digest their blood meals while Borrelia replicates in the ticks’ guts 3 . In the spring of their second year, the ticks molt into nymphs 4 and feed a second time, infecting new hosts with Borrelia via saliva 5 . (Uninfected nymphs can become infected if they feed on an infected host.) Laboratory studies have shown 23Greek, meaning “sticky.” 11/23/16 3:41 AM apt       Ch er 21    Microbial Cardiovascular and Systemic Diseases 1 Uninfected, 6-legged tick larvae hatch Spring (Year 1) from egg, crawl up vegetation, and wait to jump on passing animal. Larva Spring (Year 2) 2 Tick larvae become infected with Borrelia when they feed on small mammals or birds in the spring and summer (year 1). After feeding for 3–4 days, they drop off. 5 Infected nymphs feed on animals or humans, introducing Borrelia (year 2). Winter (Year 2) Summer (Year 2) Winter (Year 1) Nymph 4 Larvae develop into 8-legged nymphs that remain infected. 8 Female ticks lay uninfected eggs in fall (year 2). 7 Adult ticks feed on deer or other animals and mate in fall (year 2). 6 Nymphs develop into adult ticks over the summer (year 2). Summer (Year 1) 3 Borrelia multiplies in infected larvae. Fall (Year 2) Fall (Year 1) ▲ Figure 21.9 The life cycle of the deer tick Ixodes and its role as the vector of Lyme disease. Besides the nymph stage, what other stage in the tick’s life cycle can infect a human with B. burgdorferi? Figure 21.9 Adult ticks infected with B. burgdorferi can also infect humans during a blood meal. Epidemiology Even though its discovery was relatively recent, retrospective epidemiological studies have shown that Lyme disease was present in the United States for decades before its discovery. The disease is one of the more reported vector-borne diseases in the United States—over 34,000 cases in 2015. Three major events have contributed to an increase in cases of Lyme disease in the United States over the past 30 years (Figure 21.10a): M21_BAUM7206_05_SE_C21.indd 642 the human population has encroached on woodland areas, the deer population has been protected and feeds in suburban yards, and foxes that would normally reduce the mouse population have been displaced by coyotes, which rarely feed on mice. Thus, humans have been brought into closer association with ticks infected with Borrelia after feeding on mice and deer. Lyme disease occurs in most states, but cases are concentrated 21.10b). in the Northeast and the upper Midwest (F IGURE that infected ticks must remain on a host for 36–48 hours in order to transmit enough spirochetes to establish a Borrelia infection in that host. Nymphs drop off their hosts and undergo further development into adults 6 . In the fall, adult ticks feed a final time 7 , mate, lay eggs 8 , and die. Adults infected with Borrelia infect their hosts as they feed. Adult ticks are much larger than nymphs are, so humans usually see and remove adults before they can transmit Borrelia; thus, it is the nymphs that most often infect humans. Introduced by a tick’s bite, Lyme disease spirochetes move from the site of infection through the blood and lymph. They can accumulate in joints and, along with antibodies directed against them, trigger arthritis. Diagnosis, Treatment, and Prevention A diagnosis of Lyme disease, typically based on observations of its usual signs and symptoms, is rarely confirmed by detecting Borrelia itself in blood. Instead, the diagnosis is confirmed with ELISA and western blot tests to demonstrate the presence of antibodies against Borrelia. Treatment with antimicrobial drugs such as doxycycline, cefuroxime, or amoxicillin effectively cures most cases of Lyme disease in the first phase, though prolonged treatment with large doses may be required. Treatment of later phases is more difficult because later symptoms frequently result from immune responses rather than the presence of the spirochetes. Anti-inflammatory drugs act against the arthritic symptoms. 11/23/16 3:41 AM 1990 c Gl n e a a eA t is D e as 38 36 34 32 30 28 26 24 22 20 18 16 14 12 10 8 6 4 2 21.4 Lyme Disease Cause Borrelia burgdorferi (Gram-negative spirochete). Virulence factors Uses manganese in place of iron; changes outer membrane antigens frequently; endotoxin. Portal of entry Skin via bite of infected tick. Signs and symptoms “Bull’s-eye” rash, malaise, headache, dizziness, stiff neck, severe fatigue, fever, chills, muscle and joint pain, and lymphadenopathy. Three stages in the life of the deer tick, Ixodes, life size. Incubation period 7 to 14 days. Susceptibility People in highly endemic areas are particularly susceptible because of increased exposure. 1995 2000 2005 Year 2010 2015 2020 (a) Treatment Doxycycline or amoxicillin antibiotic treatment for three to four weeks if the disease is caught early. ater disease may require intravenous treatment, depending on severity. L Cases (thousands)       Bacterial Cardiovascular and Systemic Diseases L Prevention Wear light-colored, tight-fitting clothes outdoors to limit tick exposure, use tick repellent, promptly remove ticks, examine skin for ticks and bites, and avoid tick-infested areas. The yme disease vaccine for humans is no longer commercially available. Disease at a Glance 21.4 summarizes the features of Lyme disease. Ehrlichiosis and Anaplasmosis LE A R N I N G O UTC O M E S 21.18 Describe the manifestations of ehrlichiosis and anaplasmosis. 21.19 Identify the three developmental stages of Ehrlichia and 1 dot placed randomly within county of residence for each confirmed case (b) ▲ Figure 21.10 The occurrence of Lyme disease in the United States. (a) Incidence of cases, 1982–2016. (b) The geographic distribution of the disease, 2013. People hiking, picnicking, and working outdoors in areas where Lyme disease is prevalent should take precautions to reduce the chances of infection, particularly during May to July, when nymphs are feeding. People who must be in the woods should wear long-sleeved shirts and long, tight-fitting pants; should tuck the cuffs of their pants into their socks to deny ticks access to skin; and uses tick repellents. As soon as possible after leaving a tick-infested area, people should thoroughly examine their bodies for ticks or their bites and use forceps to remove attached ticks. Though researchers developed a vaccine against B. burgdor­ feri, it was not widely used because of the ready availability of other preventive measures and because the vaccine produced symptoms of Lyme disease in some patients. The manufacturer stopped supplying the vaccine in March 2002. M21_BAUM7206_05_SE_C21.indd 643 Anaplasma. 21.20 Discuss difficulties in diagnosing and treating ehrlichi- osis and anaplasmosis. Two emerging, tick-borne human diseases—human monocytic ehrlichiosis (HME) and human granulocytic anaplasmosis (HGA)— known simply as ehrlichiosis and anaplasmosis, respectively, were unknown in humans before 1987, though they were known in animals. Signs and Symptoms Ehrlichiosis and anaplasmosis manifest similarly, with flulike signs and symptoms of fever, chills, nausea, muscle aches, and headache. Leukopenia (a decrease in the number of white blood cells in the blood) and thrombocytopenia (a decrease in the number of platelets) also occur. Diarrhea, malaise, or a fine pinhead rash may be present. The symptoms are usually quite general and minimal but may be life threatening, depending on the patient’s age and general health. Pathogens and Virulence Factors Ehrlichia chaffeensis (er-lik′ē-ă chaf-ē-en′sis) causes ehrlichiosis. A related species, Anaplasma phagocytophilum (an-ă-plaz′mă 11/23/16 3:41 AM       CHAPTER 21    Microbial Cardiovascular and Systemic Diseases ­ fag-ō-sī-tō′fil-ŭm, formerly known as Ehrlichia equi), causes anaplasmosis. Both bacteria are rickettsias, which are Gramnegative, highly pleomorphic, obligate intracellular parasites of eukaryotic cells. The bacteria trigger their own endocytosis (internalization by a cell) by white blood cells—monocytes in the case of Ehrlichia and neutrophils in the case of Anaplasma— and then live inside phagosomes. These bacteria prevent fusion of lysosomes in the phagocyte with their phagosome homes by an unknown mechanism. NN NN NN NN NN NN Pathogenesis Hard-shelled ticks, including the Lone star tick (Ambylomma, am-bē-lō′ma), the deer tick (Ixodes), and the dog tick (Derma­ centor, der-mă-sen′ter), vector the bacterial agents of ehrlichiosis and anaplasmosis into humans. Once inside blood cells, the bacteria grow and reproduce within phagosomes passing through three developmental stages: an elementary body, an ini­ tial body, and a morula (FIGURE 21.11). Release of the bacteria from a morula and into the blood makes them available to feeding ticks, which become infected and pass the bacteria on to a new host. Epidemiology Epidemiologists consider ehrlichiosis and anaplasmosis to be emerging diseases because they were unknown before 1987, and the number of reported cases has increased from a few dozen per year in the 1980s to over 3700 per year now. This increase is likely due in part to improved diagnosis and reporting. Entry Elementary body in phagosome Nucleus Initial body Morula containing many rickettsias Release of rickettsias ▲ FIGURE 21.11 The growth and reproduction of Ehrlichia and Anaplasma in an infected leukocyte. If the rickettsias shown here are Ehrlichia chaffeensis, then what kind of leukocyte is being infected? Figure 21.11 Ehrlichia chaffeensis infects human monocytes to cause ehrlichiosis. M21_BAUM7206_05_SE_C21.indd 644 NN NN ▲ FIGURE 21.12 The geographical distribution of ehrlichiosis and anaplasmosis in the contiguous United States (2015). Blue indicates where ehrlichiosis (human monocytic ehrlichiosis, HME) was reported, orange indicates where anaplasmosis (human granulocytic anaplasmosis, HGA) was reported, and purple indicates where both diseases were reported. NN = not notifiable in these states. Diagnosis, Treatment, and Prevention Diagnosis of ehrlichiosis and anaplasmosis is difficult because their manifestations may be mild and they resemble other diseases. Physicians consider ehrlichiosis or anaplasmosis in any case of otherwise unexplained acute fever in patients exposed to ticks in endemic areas (FIGURE 21.12). Immunofluorescent antibodies against the bacteria inside white blood cells or polymerase chain reaction (PCR) tests can demonstrate infection, confirming a diagnosis. Doxycycline is effective against both Ehrlichia and Anaplasma. Treatment should start immediately, even before diagnosis is confirmed by serological testing, because the complications of infection and mortality rates increase when treatment is delayed. Prevention involves avoiding tick-infested areas, promptly removing ticks, wearing tight-fitting clothes, and using insect repellents. No vaccines against the two species are available. We have examined bacterial diseases of the cardiovascular system and bacterial systemic diseases. In the following section, we turn our attention to viral cardiovascular and systemic diseases. TELL ME WHY Health departments often recommend that outdoor enthusiasts wear light-colored pants while hiking in areas where Ixodes ticks are endemic. Why? Viral Cardiovascular and Systemic Diseases Many viral diseases spread through the body via the lymphatic and cardiovascular systems. When viruses infect the blood, the condition is called viremia (vī-rē′mē-ā). Here we examine 11/29/16 9:08 PM       Viral Cardiovascular and Systemic Diseases yellow fever, mononucleosis, cytomegalovirus disease, and hemorrhagic fevers. Yellow Fever LE A R N I N G O U TC O M E 21.21 Describe the signs, symptoms, cause, diagnosis, treat- ment, and prevention of yellow fever. ­ Signs and Symptoms Yellow fever develops in three stages. The early stage involves a slight fever, headache, muscle aches, and vomiting for a few days. This is followed by a period of remission in which the signs and symptoms resolve. Fifteen percent of patients proceed to the third and most severe stage, characterized by delirium, seizures, coma, and degeneration of the liver, kidneys, and heart, as well as massive hemorrhaging accompanied by high fever, nausea, nosebleed, and shock. Hemorrhaging in the intestines may result in “black vomit.” Liver damage causes jaundice, from which the disease acquires its name and its nickname, “Yellow Jack.” Pathogen and Virulence Factors Yellow fever virus (genus Flavivirus, family Flaviviridae) is an enveloped, +ssRNA virus with an icosahedral capsid. Aedes aegypti24 (ā-ē′dēz ē-jip-te′) mosquitoes carry the virus between humans (Figure 21.13). This mosquito develops in shallow water such as might be found in domestic collections of water in outdoor pots, water barrels, and old tires. Aedes feeds during daylight hours, preferentially on people. LM 4 mm ▲ Figure 21.13 Aedes aegypti, the vector of yellow fever. Would you expect more cases of yellow fever in summer or winter months? Figure 21.13 Mosquitoes, which vector the yellow fever virus, are more active in the summer than winter; therefore, this disease is more prevalent in summer. Perhaps no disease has influenced the history of the United States as much as yellow fever. Slave ships introduced yellow fever and its mosquito vector in the 1600s to the Americas. In 1793, yellow fever killed over 4000 people in Philadelphia—10% of the population of what was then the capital of the United States. Eight years later, an epidemic on the French island colony of Haiti killed 27,000 French troops, discouraging Napoleon and causing him to forfeit goals of a French empire in the West. Instead, he sold the Louisiana Territory to the young United States. More than a century later, yellow fever and malaria further discouraged the French, opening an opportunity for the United States to build the Panama Canal. During the Spanish-American War of 1898, yellow fever killed more American soldiers than did enemy bullets. Yellow fever is primarily an African disease that was transported to the Americas in the 1700s; however, with mosquito control and the development of a vaccine in the 1900s, health care workers have practically eliminated yellow fever from North America, Central America, and much of South America. Jungle monkeys act as a reservoir for yellow fever virus, making eradication difficult. The World Health Organization (WHO) estimates about 125,000 cases and 45,000 deaths still occur annually in Africa and South America combined. Laws promulgated in the 1970s to protect the environment from insecticide abuse have allowed Ae. aegypti to reestablish itself in the southeastern United States, though yellow fever virus had not been reintroduced into the United States as of 2015. Diagnosis, Treatment, and Prevention Though the signs and symptoms of severe yellow fever are obvious, definite diagnosis follows demonstration of viral antigens in the blood via ELISA or viral nucleic acids via PCR. Treatment involves providing supportive care and varies depending upon the systems affected. People should avoid mosquito bites in geographic areas where yellow fever is endemic. Precautions include use of mosquito repellents such as DEET, picaridin, or IR3535; wearing protective clothing; and using mosquito netting. Effective, live, attenuated yellow fever vaccines provide protection for 10 years or more. Disease at a Glance 21.5 on p. 650 summarizes the features of yellow fever. Pathogenesis and Epidemiology After a bite from an infected Aedes mosquito introduces yellow fever virus into the body, the virus travels to the liver, where it is replicated rapidly. Signs and symptoms develop three to six days following the mosquito bite. Mortality from severe yellow fever is 20%. Infectious Mononucleosis LE A R N I N G O UTC O M E S 21.22 Describe the cause, signs, symptoms, and diagnosis of mononucleosis. 21.23 Explain the role of the immune system in provoking 24Greek meaning “unpleasant [thing] from Egypt.” M21_BAUM7206_05_SE_C21.indd 645 diseases of Epstein-Barr virus. 11/23/16 3:41 AM c Clini al Case tudy er 21    Microbial Cardiovascular and Systemic Diseases apt       Ch A Sick Camper S An otherwise healthy 24-year-old woman goes to her doctor complaining of a sudden onset of high fever, chills, uneasiness, and a severe headache. She also shows the doctor a painful swelling she is experiencing in her groin area. The doctor asks her about recent travel. She reports that she returned two days prior from a week-long camping and hiking trip in Texas. 1. How did the woman most likely contract the disease? 2. What are the potential problems associated with diagnosing this disease, and how crucial is prompt diagnosis of this disease? 3. The doctor asks you, as a nursing student rotating through his clinic, your opinion on the disease diagnosis and causative agent. What is your response? 4. How should the patient be treated? 5. Who should be notified once the diagnosis is confirmed? Why? Infectious mononucleosis, commonly known as kissing disease or mono, is a condition resulting from interactions of a patient’s cellular immune system with infected B lymphocytes.25 Signs and Symptoms Severe sore throat and fever characterize the beginning of infectious mononucleosis. These manifestations are followed by enlarged lymph nodes (especially in the neck), splenomegaly (enlarged spleen), extreme fatigue, nausea, loss of appetite, headache, and a skin rash anywhere on the body. Fatigue and inability to concentrate may last for months. Pathogen and Virulence Factors Human herpesvirus 4 (HHV-4), which is also known as Epstein­ Barr virus (EBV) after its discoverers, causes infectious mononucleosis. This enveloped, double-stranded DNA virus with an icosahedral capsid is replicated in a host cell’s nucleus. It can become latent within cells, resulting in lifelong infection. HHV-4 suppresses apoptosis (programmed cell death) of B lymphocytes, causing infected cells to become immortal. Such infected B cells are one source of cancers. Additional factors appear to play a role in the development of such cancers. 25Lymphocytes were formerly known as mononuclear leukocytes, from which the name mononucleosis is derived. M21_BAUM7206_05_SE_C21.indd 646 For example, Burkitt’s lymphoma, a cancer of the jaw, is almost exclusively limited to young African males exposed previously to malaria parasites. Although conclusive proof is lacking, the presence of EBV and antibodies against EBV have implicated this herpesvirus as an etiological agent of chronic fatigue syndrome, B cell lympho­ mas, and oral hairy leukoplakia. The latter arises in individuals with a T cell deficiency, as occurs in malnourished children, the elderly, AIDS patients, and transplant recipients; it is a precancerous change in the tongue. Pathogenesis and Epidemiology Epstein-Barr virus usually is transmitted via saliva, often during the sharing of drinking glasses, while kissing, or from a cough or sneeze. After initially infecting epithelial cells of the throat and salivary glands, EBV enters the blood, where it invades B lymphocytes. Infectious mononucleosis results from a “civil war” in which cytotoxic T lymphocytes kill infected B lymphocytes. This “war” is responsible for the symptoms and signs of mono. Ninety-five percent of adults worldwide have been infected with EBV, most often acquired before age six. The age of the patient at the time of infection is a determining factor in the seriousness of the disease because the competence of cytotoxic T cells is in part related to age (Figure 21.14). Infection during childhood, which is more likely to occur in countries with poor sanitation and inadequate standards of hygiene, is usually asymptomatic because a child’s cellular immune system is immature and cannot cause severe tissue damage. Where living standards are higher, such as in the United States, childhood infection is less likely, and the postponement of infection until adolescence or later results in a more vigorous cellular immune response that produces the signs and symptoms of mononucleosis in 50% of patients. Diagnosis, Treatment, and Prevention Large, lobed B lymphocytes with atypical nuclei and a deficiency of neutrophils (neutropenia) are characteristic of EBV infection. Some diseases associated with EBV, such as hairy leukoplakia and Burkitt’s lymphoma, are easily diagnosed by their characteristic signs. Other EBV infections, such as infectious mononucleosis, have symptoms common to many pathogens. Fluorescent antibodies directed against anti-EBV immunoglobulin or ELISA tests provide specific diagnosis. Care of mono patients involves relief of the symptoms; most patients recover without treatment within two to four weeks, though infection is permanent when EBV becomes latent. Patients should avoid contact sports to reduce the risk of rupturing an enlarged spleen. Burkitt’s lymphoma responds well to chemotherapy, and tumors can be removed from affected jaws if surgery is available. There is no effective treatment for other EBV-induced conditions. EBV infection is almost impossible to prevent because the viruses are widespread and transmitted readily in saliva. However, only a small proportion of EBV infections result in disease because the immune system is either too immature to 11/23/16 3:41 AM       Viral Cardiovascular and Systemic Diseases Diseases of EBV Oral hairy leukoplakia* Burkitt’s lymphoma (shown) Nasopharyngeal cancer Chronic fatigue syndrome* Hodgkin’s lymphoma* Asymptomatic Infectious mononucleosis Lacking Poor Immature Vigorous State of cellular immunity * EBV implicated, not proven E E E E O E ▲ Figure 21.14 Diseases associated with Epstein-Barr virus. Which disease results from infection with BV appears to depend on the relative vigor of a host’s cellular immune response, which itself can be related to age. ral hairy leukoplakia, white lesions in the mucous membrane of the tongue, occurs in BV-infected hosts with severely depressed cellular immunity (for example, AIDS patients). Burkitt’s lymphoma occurs primarily in African boys whose immune systems have been suppressed by the malaria parasite. BV is also implicated in nasopharyngeal cancer and chronic fatigue syndrome, which are associated with impaired immune function. Asymptomatic BV infections are typical for children exposed at a young age, before the immune response has become vigorous. Infectious mononucleosis, which is characterized by enlarged B lymphocytes with lobed nuclei, results from infection with BV during adulthood, when the cellular immune response is vigorous. cause cellular damage (in children) or because cellular immunity is efficient enough to kill infected B lymphocytes. LE A R N I N G O U TC O M E s Cytomegalovirus Disease 21.24 Describe the signs, symptoms, and cause of Cytomegalo­ virus (CMV) disease. 21.25 Discuss treatment and prevention of CMV disease. Another herpesvirus that affects humans is Cytomegalovirus (CMV), so named because cells infected with this virus become enlarged. Signs and Symptoms Cytomegalovirus (CMV) disease may result from initial infections or from latent viruses. Most people infected with CMV are asymptomatic, but fetuses, newborns, and immunodeficient patients are susceptible to severe complications of CMV infection. About 10% of congenitally infected newborns develop signs of infection, including enlarged liver and spleen, jaundice, and anemia. CMV may also be teratogenic 26 (ter′ă-tō-jen-ik)— that is, cause birth defects—when the virus infects stem cells in an embryo or fetus. In the worst cases, mental retardation, hearing and visual damage, or death may result. 26From Greek teratos, meaning “monster.” M21_BAUM7206_05_SE_C21.indd 647 AIDS patients and other immunosuppressed adults, such as transplant recipients, may develop pneumonia, blindness (if the virus targets the retina), or cytomegalovirus mononucleosis, which has signs and symptoms similar to those of infectious mononucleosis caused by Epstein-Barr virus. Pathogen and Virulence Factors Cytomegalovirus is an enveloped, double-stranded DNA virus with an icosahedral capsid. Like other herpesviruses, CMV typically infects humans early in their lives but remains in a latent state until the immune system is compromised. The major exception is prenatal infection across the placenta from mother to child. Pathogenesis and Epidemiology Bodily secretions, including saliva, mucus, milk, urine, feces, semen, and cervical secretions, carry CMV. Individual viruses are not highly contagious, so transmission requires intimate contact involving a large exchange of secretion. Transmission usually occurs via sexual intercourse but can result from in utero exposure, vaginal birth, blood transfusions, and organ transplants. Cytomegalovirus infection is one of the more common infections of humans. Studies have shown that CMV infects about 50% of the adult population of the United States; in some other countries, 100% of the population tests positive for antibodies against CMV. Like other herpesviruses, CMV becomes latent in various cells, and infection by CMV typically lasts for life. 11/23/16 3:41 AM apt       Ch er 21    Microbial Cardiovascular and Systemic Diseases Diagnosis, Treatment, and Prevention ­ Diagnosis of CMV-induced diseases is dependent on laboratory procedures that reveal the presence of abnormally enlarged cells and inclusions within the nuclei of infected cells (Figure 21.15). Viruses and antibodies against them can be detected by ELISA tests and DNA probes. Treatment for fetuses and newborns with complications of CMV infection is difficult because in most cases the damage is done before the infection is discovered. Treatment of adults is also frustrating. Interferon, antiCMV gammaglobulin, and nucleotide analogs, such as ganciclovir, slow the release of CMV from adults but do not affect the course of disease. Eye doctors inject fomivirsen into the eye to inhibit the replication of CMV in retinal cells. Fomivirsen, which is the first antisense RNA drug, is RNA complementary to CMV mRNA. It binds to CMV mRNA and stops translation of two proteins critical for CMV replication. This stops the replication and spread of CMV but does not cure the disease. Abstinence, mutual monogamy, and use of condoms reduce the chance of infection by CMV. Organs harvested for transplantation can be made safe by treatment with monoclonal antibodies against CMV, which passively reduces the CMV load before the organs are transplanted. There is no approved vaccine against CMV, though several vaccines are in clinical trials. Dengue Fever and Dengue Hemorrhagic Fever Historically, scientists have identified four antigenically distinct, though related, viruses that cause dengue (den′gā) fever. These viruses, in the genus Flavivirus, are known as dengue viruses 1, 2, 3, and 4, respectively. In 2013, a fifth strain was discovered. Signs and Symptoms Dengue fever usually occurs in two phases separated by 24 hours of remission. First, a patient suffers from fever, weakness, edema (swelling) of the extremities, and severe pain in the head and muscles. The common name for the disease, breakbone fever, indicates the severity of this pain. The second phase involves a return of the fever and a bright red rash. Dengue fever is self-limiting and lasts six or seven days. Dengue hemorrhagic fever (DHF) is a serious hyperimmune response following reinfection with the dengue virus (Figure 21.16) in which activated memory T cells release inflammatory lymphokines that trigger rupture of blood vessels, internal bleeding, shock, and possibly death. Pathogens and Virulence Factors Dengue viruses are enveloped, +ssRNA viruses with icosahedral capsids about 40–50 nm in diameter. Aedes mosquitoes are the vectors for all four strains of dengue viruses. Aedes lays eggs in water collected in domestic containers and trash and preferentially feeds on humans. Pathogenesis and Epidemiology LE A R N I N G O U TC O M E S 21.26 Describe the signs, symptoms, and cause of dengue fever. 21.27 Explain the role of adaptive immunity in causing dengue hemorrhagic fever. ”Owl’s eye” cell Usually dengue fever is a mild disease despite the severe pain that can be involved. Lifelong immunity follows recovery; however, since there are four strains of dengue virus, a patient can have dengue fever four times—one case with each serotype. Reinfection with a previously encountered strain does not produce dengue fever, but it can trigger fatal dengue hemorrhagic fever as a result of a hyperimmune response. Health care workers dramatically reduced the number of cases of dengue virus diseases following World War II, but because of lax mosquito control and an increase in world travel, the geographic distribution of dengue diseases is wider than when eradication began in the 1950s. Dengue fever is now the most common mosquito-borne viral disease of humans. Almost 3 billion people live in areas where Ae. aegypti and dengue virus are endemic; DHF is a leading cause of hospitalization and death among children in Southeast Asia. Fifty to 100 million cases of dengue fever and 500,000 cases of dengue hemorrhagic fever occur each year worldwide, killing about 25,000 annually. Diagnosis, Treatment, and Prevention LM 100 μm ▲ Figure 21.15 An abnormally enlarged “owl’s eye” cell indicates Cytomegalovirus (CMV) infection. The cell’s enlarged nucleus contains sites of viral assembly called inclusion bodies, which are diagnostic for CMV infection. M21_BAUM7206_05_SE_C21.indd 648 Physicians base diagnosis on signs and symptoms in patients who have traveled in endemic areas. Laboratory tests confirm the presence of antigens of a strain of dengue virus in a patient’s blood. No specific treatment is available for dengue diseases, but researchers have tested a safe vaccine against the four historically known strains. Recognition of the fifth strain of dengue further complicates development of a universal dengue vaccine. 11/23/16 3:41 AM       Viral Cardiovascular and Systemic Diseases ◀ Figure 21.16 Pathogenesis of dengue hemorrhagic fever (DHF). D is a severe hyperimmune response to a second infection HF Initial infection with dengue virus. Antibodies from the first infection form complexes with the reintroduced virus. Antigen-presenting cells (APCs) phagocytize the complexes and then activate T memory cells. These release an abundance of lymphokines that induce hemorrhaging and shock. Dengue virus infects monocyte. Dengue fever Recovery, resulting in antibody to dengue virus in blood Prevention depends upon control of mosquitoes, a difficult task because the most effective insecticides may harm the environment. Beneficial Microbes: Eliminating Dengue on p. 651 describes a pesticide-free alternative. African Viral Hemorrhagic Fevers LE A R N I N G O UTC O M E 21.28 Compare the signs, symptoms, cause, diagnosis, treat- ment, and prevention of Ebola and Marburg hemorrhagic fevers. Antibodies in blood complex with viruses. Reinfection Ebola hemorrhagic fever and Marburg hemorrhagic fever, named for the sites where they were first discovered, are two emerging viral diseases that are of concern to physicians, epidemiologists, and governments. Signs and Symptoms Virus-antibody complexes are phagocytized by APC. Both types of African hemorrhagic fevers begin with fever, fatigue, dizziness, muscle pain, and exhaustion, followed by minor petechiae. This progresses to severe internal hemorrhaging as well as bleeding from other body orifices, including mouth, eyes, and ears. Death results from shock, seizures, or kidney failure. Pathogens and Virulence Factors Activation of memory T cells Increased production of inflammatory lymphokines Dengue hemorrhagic fever, severe illness, shock, hemorrhage, death (10–50%) M21_BAUM7206_05_SE_C21.indd 649 The viruses that cause African hemorrhagic fever are unsegmented, -ssRNA viruses (as discussed in Chapter 13). -ssRNA viruses must be converted into mRNA (+ssRNA) before an infected cell can transcribe viral polypeptides. Taxonomists assign them to the family Filoviridae in two known genera: Ebo­ lavirus and Marburgvirus. These enveloped viruses have long filamentous capsids, which sometimes curve back upon themselves (Figure 21.17). Pathogenesis and Epidemiology African hemorrhagic fevers are acute diseases—there aren’t any asymptomatic carriers. Signs and symptoms first appear 2–21 days after infection with Ebolavirus and within 5–10 days in the case of Marburgvirus infections. Hemorrhaging is due to a malfunction of the blood-clotting system, in which infected macrophages trigger localized blood clotting that depletes the serum of clotting proteins, making the body susceptible to massive bleeding. Viral hemorrhagic fevers occur primarily in Africa, presumably where the natural hosts of the viruses—probably bats—dwell (Figure 21.18). Hemorrhagic fever viruses probably initially infect humans via contact with a host, which is 11/23/16 3:41 AM c Gl n e a a eA t as is D e er 21    Microbial Cardiovascular and Systemic Diseases apt       Ch 21.5 A Incubation period Three to six days. Susceptibility Travelers to endemic regions of South America and Africa. Virulence factors Intracellular replication cycle; adhesins. Portal of entry Injected by the mosquito Aedes aegypti; travels in blood to liver. Signs and symptoms Slight fever, muscle ache, headache, nausea, and vomiting for three to four days; about 20% of patients subsequently develop delirium, seizures, hemorrhaging, nosebleed, shock, and pronounced jaundice and severe fever, which give the disease its name. Treatment N Cause Flavivirus yellow fever virus (enveloped, positive, single-stranded arbovirus with an icosahedral capsid). RN Yellow Fever o specific treatment; supportive nursing care. Prevention Avoid travel to endemic areas, or obtain immunization with live attenuated virus, effective for 10 years or more, and avoid mosquito bites by wearing protective clothing, using an insect repellent, and using mosquito netting. Areas of yellow fever Range of Aedes Wolbachia (stained red) inside host cells. Marburg Ebola 250 nm ▲ Figure 21.18 Sites in which known locally acquired cases of Marburg and Ebola viruses have occurred. In the United States, an bola outbreak in Virginia only involved disease in monkeys in a research facility. ther cases, in Texas, involved transmission to health care workers from a patient who had traveled from iberia, Africa. from an infected cell. M21_BAUM7206_05_SE_C21.indd 650 L ▲ Figure 21.17 Filamentous Ebolavirus (orange) budding O E TEM 11/23/16 3:41 AM b ic l M ro e icia Benef s       Viral Cardiovascular and Systemic Diseases Eliminating Dengue N O N O E thought to be bats, or the host’s bodily fluids or wastes. Humans can transmit filoviruses among themselves via contact with bodily fluid, especially blood. Though transmission of filoviruses through the air has been demonstrated in laboratories, such transmission has not been shown in natural settings, hospitals, or mortuaries. Ebolavirus is fatal in up to 90% of patients, whereas Marburgvirus is fatal 25% of the time. Diagnosis, Treatment, and Prevention Physicians diagnose African hemorrhagic fevers based upon symptoms and demonstration of filoviruses in the blood via ELISA or PCR. Treatment includes supportive care involving fluid and electrolyte replacement. Some physicians treat patients with anticoagulants to stem the initial harmful blood ­ F clots. Such treatment has proven efficacious in monkeys, saving the lives of 30% of infected animals. There are no effective antiviral drugs to treat hemorrhagic fevers. Health care workers treat the African hemorrhagic fevers by replacing lost fluids and electrolytes, maintaining blood oxygenation and pressure, replacing lost blood, and treating any secondary infections or complications. Researchers have developed vaccines that protect monkeys from Ebola hemorrhagic fever and are studying their effectiveness in humans. For now, prevention involves proper procedures in hospitals and morgues to prevent the spread of the viruses. Disease in Depth: Ebola on pp. 652–653 examines Ebola in more detail, and Table 21.1 summarizes features of viral hemorrhagic fevers. 21.1 Characteristics of Some Viral Hemorrhagic Fevers Geographic Distribution umans, monkeys Aede saegypti mosquito Africa, South America Dengue, dengue hemorrhagic fever Flavivirus (Flaviviridae) umans, monkeys Aede saegypti mosquito Worldwide, especially tropics bola hemorrhagic fever Ebolavirus (Filoviridae) Probably bats Marburg hemorrhagic fever Marburgvirus (Filoviridae) Probably bats one Central Africa, research facility in the United States, medical facility in Texas one Central Africa, research facility in urope E Flavivirus (Flaviviridae) H Vector N Yellow fever M21_BAUM7206_05_SE_C21.indd 651 Natural Host(s) H Viral Genus (Family) E Disease N able T exception. When male mosquitoes infected with wMel mate with Wolbachia-infected females, the females lay eggs normally, but all the offspring will be infected with Wolbachia, which they get from their mother. urther, when an infected male mates with an uninfected female, all her eggs are sterile. Thus, only Wolbachia-infected offspring are produced; Wolbachia ensures its own reproductive success while limiting mosquito reproduction. It gets better! It turns out that dengue virus cannot live in infected mosquitoes for some reason. So, as the wMel strain of Wolbachia spreads through the Aedes mosquito population generation by generation, the success of Wolbachia is the demise of the virus. ’ eill and his collaborators have released thousands of infected mosquitoes in northern Australia and have successfully altered the mosquito population in the area so that they are unable to transmit dengue. The team has also released of infected mosquitoes in Vietnam, Indonesia, and Brazil with the goal of spreading Wolbachia pipientis strain wMel throughout the world. They hope that this will eliminate the scourge of dengue forever. N 25 µm O Aedes aegypti has distinctive stripes and a fierce bite. Unlike many mosquitoes, these aggressive bloodsuckers bite during the day. They prefer to live in urban Wolbachia (stained red) areas, resting in the shade of houses and laying inside host cells. their eggs in modern containers holding a small amount of water, such as tires, cans, and water gutters. Almost 3 billion people share their neighborhoods with Aedes. Worst of all, these mosquitoes carry viruses that cause human diseases such as dengue and yellow fever. There is no vaccine and no treatment for dengue, so prevention involves controlling the mosquitoes, which has had limited success, especially in developing countries. nter Australian scientist Scott ’ eill and a novel beneficial microbe—a special strain of Wolbachia pipientis. Wolbachia is a Gram-negative, intracellular bacterium that infects about 70% of all insect species, including Aedes mosquitoes. Strains of Wolbachia often change the biology of their insect hosts, and Dr. ’ eill’s special strain of Wolbachia—strain wMel—is no SEM 11/23/16 3:41 AM DISEASE IN DEPTH PATHOGENESIS EBOLA Ebolavirus spreads via direct contact with the bodily fluids, including semen, and wastes of its victims. Initial infections likely occur from contact with an animal reservoir, which may be bats, though this is not proven. Infected macrophages trigger localized blood clotting, which depletes the serum of clotting proteins to such an extent that there is massive uncontrolled bleeding. Ebola can be fatal in up to 90% of patients. Ebolavirus E bolavirus, named for the Ebola River in Africa where it was discovered, is of concern to healthcare workers, epidemiologists, and governments. CONTAINMENT While working with Ebola patients, healthcare workers must be sure that none of their own skin is exposed. The U.S. Centers for Disease Control and Prevention (CDC) guidelines emphasize the importance of: • Training: Prior to working with Ebola patients, workers must have received repeated training. • Practice: Workers must practice putting on and removing personal protective equipment (PPE). • Competency: Workers must demonstrate competency in performing all Ebola-related infection control practices and procedures, particularly PPE. • Observation: A trained observer must supervise each step by every worker to ensure proper completion of established PPE protocols. Guidelines include these measures: • Isolation of Ebola patients in rooms with a private bathroom. • To limit the number of people exposed to patients, doctors and nurses should disinfect patient care areas, equipment, and their own PPE immediately after use. • Trained observers should monitor workers from a separate location to ensure proper procedures are being followed. Researchers studying Ebolavirus follow Biosafety Level 4 (BSL-4) protocols, which include a disinfecting shower and decontamination of all materials prior to leaving the facility. Workers must wear an air-supplied, full-body “space” suit that maintains positive air pressure within the suit. This ensures that contaminating Ebola viruses are forcibly expelled by escaping air if there is a break in the suit. Scan this QR code to watch Dr. Bauman's Video Tutor explore Ebola hemorrhagic fever. Then go to MasteringMicrobiology to investigate further and record your research findings on the following question: Why is it difficult to diagnose Ebola hemorrhagic fever in its early stage? Medical worker in protective gear during Ebola protocol training EPIDEMIOLOGY World's worst Ebola epidemic began in 2013 in the west African nation of Guinea and spread into neighboring countries. A total of 28,616 cases with 11,310 deaths as of May 2016. 1500 Number of cases INVESTIGATE IT! Two CDC lab microbiologists suiting up before entering a Biosafety Level 4 (BSL-4) laboratory Ebola pandemic of 2014–2015 1000 500 M21_BAUM7206_05_SE_C21.indd 652 15 20 20 1 4 0 11/23/16 3:41 AM       PATHOGEN & VIRULENCE FACTORS There are at least five strains of Ebolaviruses. These enveloped, filamentous viruses in the family Filoviridae are 80 nm in diameter and vary in length up to 14,000 nm, often curving back on themselves. They have a surface glycoprotein that binds to neutrophils, inhibiting early and effective immune responses. Another surface protein binds to cells lining blood vessels, allowing the virus to enter and destroy the cells, resulting in severe hemorrhaging. TEM 400 nm TEM 250 nm SIGNS & SYMPTOMS The disease progression can vary. The illustration below shows a typical progression of symptoms. EaRLY SYMptOMS Signs and symptoms initially appear 2–21 days after infection with Ebolavirus. Ebola first presents with headache, fever, fatigue, dizziness, sore throat, and muscle pain, followed by minor red and purple blood spots under the skin (petechiae). MIddLE StaGE High fever, massive bloody vomiting, and diarrhea. LatE SYMptOMS Damage to blood vessels causes severe internal hemorrhaging as well as bleeding from other body orifices, including mouth, eyes, and ears, and organ damage. Many survivors have long-lasting, severe joint pain and eye complications ranging from vision changes to inflammation leading to blindness. Headache, dizziness, fatigue Brain swelling Sore throat Red eyes Muscle pain Bumpy rash on head, neck, and torso Bleeding from eyes, ears, and mouth Vomiting blood Severe nausea and vomiting Abdominal pain Petechiae Diarrhea DIAGNOSIS, TREATMENT, & PREVENTION Left: Medical team cares for Ebola patient in Sierra Leone Right: Screening for Ebola with an infrared thermometer M21_BAUM7206_05_SE_C21.indd 653 Physicians diagnose Ebola based on symptoms and demonstration of filoviruses in the blood via ELISA or PCR. Treatment includes supportive care involving fluid and electrolyte replacement. Antibodies against Ebolavirus (called ZMapp) are a potential therapy. Some physicians treat patients with anticoagulants to stem the initial harmful blood clots. There are no effective antiviral drugs to treat Ebola. Prevention involves quarantine, screening, and vaccination. 11/23/16 3:41 AM Malaria LE A R N I N G O UTC O M E S c A Tired Freshman 21.29 Describe the life cycle of Plasmodium, and relate malarial malaria. Malaria is a life-threatening disease caused by at least four species of the single-celled parasite Plasmodium, which is carried between people by infected Anopheles mosquitoes. Over 3 billion people are at risk because they live in areas where both the mosquito and Plasmodium are endemic. The life cycle of Plasmodium is complex; the parasite goes through many different stages in humans and in mosquitoes. Plasmodium is an apicomplexan (ap-i-kom-plek′san), which is a type of protozoan characterized by a form of asexual reproduction called schizogony. In schizogony, the nucleus of a cell undergoes successive mitoses without cytoplasmic division, forming multinucleate cells called schizonts. Eventually, a schizont divides to simultaneously form several offspring, each with a single nucleus (see Figure 12.3). Besides schiz onts, Plasmodium has at least six other stages, including gametocytes, which are infective to Anopheles. Virulence factors of Plasmodium include the following: ­ • The reproductive cycle occurs within red blood cells, which hides the parasite from the immune surveillance since red blood cells do not present antigen in conjunction with major histocompatibility protein. • A special protein assemblage called the malaria secretome injects toxins and enzymes into host cells. M Why e ell T malaria. 21.31 Describe Plasmodium virulence factors. 21.32 Describe four genetic traits that confer resistance to ­ 1. What disease should the doctor suspect? What is the infectious agent? 2. How did the student most likely contract the disease? 3. What other symptoms might the student develop? 4. What causes the symptoms of the disease? Why does the student’s girlfriend not display the same symptoms? 5. How should the student be treated? signs and symptoms to stages in the life cycle. 21.30 Describe the diagnosis, treatment, and prevention of ­ H H H S An 18-year-old college freshman reports to the campus health clinic. e states that he has felt very fatigued and generally ill for about a week and developed sore throat, fever, and headache the day before. e has been sleeping more than usual and has virtually no appetite. e says his girlfriend, who attends college in a different state and whom he saw last month, has also been feeling very fatigued for the last two weeks or so, but she displays none of the student’s other symptoms. ­ Clini al Case tudy er 21    Microbial Cardiovascular and Systemic Diseases apt       Ch Whereas many doctors are convinced that Epstein-Barr virus causes chronic fatigue syndrome (CFS), others deny the association between EBV and CFS. Why is the etiology of the syndrome debated even though Epstein-Barr virus is present in CFS patients? H Protozoan and elminthic Cardiovascular and Systemic Diseases To this point, we have considered bacterial and viral diseases of the cardiovascular system and several representative systemic diseases. In this section, we examine cardiovascular and systemic diseases caused by protozoa and by a parasitic helminth. We begin with the most prevalent of the protozoan infectious diseases, malaria. M21_BAUM7206_05_SE_C21.indd 654 • Adhesins enable infected red blood cells to adhere to certain body tissues such as brain tissue and the linings of blood vessels, which allows the parasite to avoid clearance by the spleen. • Merozoites form within vesicles of liver cells that are secreted directly into blood vessels, thereby avoiding immune cells of the liver. • The gametocytes of at least one strain (P. falciparum) trigger changes in human body chemistry, presumably breath or body odor, such that Anopheles mosquitoes are more attracted; thus Plasmodium induces a “bite me” signal in humans carrying the very stage ready to be picked up by a mosquito. Malaria patients suffer jaundice, severe recurrent fever and chills, headache, vomiting, and diarrhea. Historically, physicians prescribe antimalarial drugs, but strains of Plasmodium have developed resistance to many of these drugs. 11/23/16 3:41 AM eS       tudy eC as as is g er n D e gi Em H Protozoan and elminthic Cardiovascular and Systemic Diseases Babesiosis People living in endemic areas, and their descendants throughout the world, commonly have one or more of the following genetic traits that increase their resistance to malaria: ­ • Sickle­cell trait. Individuals with a sickle-cell gene produce an abnormal type of hemoglobin called hemoglobin S (hemoglobin A is normal). Hemoglobin S causes erythrocytes to become sickle shaped and makes erythrocytes resist Plasmodium. • Hemoglobin C. Humans with two genes for hemoglobin C are invulnerable to malaria. The mechanism by which this mutation provides protection is unknown. • Genetic deficiency of glucose­6­phosphate dehydrogenase. In order to synthesize DNA, trophozoites must acquire this enzyme from their human host; thus, inherited enzyme deficiency inhibits Plasmodium replication. • Lack of so­called Duffy antigens on erythrocytes. Because P. vivax attaches to Duffy antigens to infect erythrocytes, Duffy-negative individuals are resistant to P. vivax. Antifever medication and blood transfusions may be required as supportive measures. Treatment is usually effective except in severe cases of falciparum malaria. Draining wetlands and removing standing water reduces the rate at which mosquitoes breed, but such major environmental changes must be balanced against the impact on other M21_BAUM7206_05_SE_C21.indd 655 L L next. eslie was utterly miserable, but with intensive medical care, including the use of the antimicrobials atovaquone, azithromycin, clindamycin, and quinine, she pulled through. In the past decade, the number of reported cases of babesiosis has quadrupled. Perhaps this emerging disease is spreading because its tick vector has an expanded range resulting from climate change. Perhaps physicians are more aware of a disease whose incidence has been constant. Whatever the reason for our increased awareness of babesiosis, eslie was grateful that she was diagnosed and treated effectively so that her nightmare could finally end. 1. What aspect of the infection caused Leslie to suffer anemia, jaundice, and fatigue? 2. Why doesn’t penicillin work for treating babesiosis? 3. How many legs does the adult vector of babesiosis have? wetland-dwelling plants and animals. Personal use of insect repellents containing DEET, picaridin, or IR3535; use of mosquito netting; and protective clothing reduce mosquito bites. Researchers are developing and testing several malaria vaccines and alternate antimalarial drugs. One of the better vaccines, called RTS,S, protects 31% of infants and 56% of older babies and toddlers against Plasmodium falciparum. Disease in Depth: Malaria (pp. 656–657) examines features of malaria in more detail. Toxoplasmosis LE A R N I N G O UTC O M E 21.33 Describe toxoplasmosis, including its cause, signs, symptoms, pathogenesis, epidemiology, diagnosis, treatment, and prevention. ­ L L L L eslie hated being sick, but here she was on a fine summer day with a headache, muscle pains, and sore joints. It was just as well she didn’t know that the worst was yet to come. A small deer tick (Ixodes scapularis) had taken a blood meal from eslie’s leg six weeks before. The tick was so small and the bite so painless that eslie was unaware of the attack. She was equally unaware that the tick had infected her with an apicomplexan parasite, Babesia microti, normally found in mice. The protozoan was eating her red blood cells from the inside out. eslie became anemic, jaundiced, fatigued, and depressed, and she was losing weight. As she became weaker, she had trouble catching her breath, and within the week, her kidneys began to fail. Intermittent fever, shaking chills, drenching sweat, nausea, and anorexia came Toxoplasmosis (tok′sō-plaz-mō′sis), commonly referred to as toxo, is a major disease seen in AIDS patients. Unborn children are also at risk. Signs and Symptoms Over 80% of infected patients have no symptoms and no obvious permanent damage, and their infection may resolve spontaneously within a few months to a year. Only patients with 11/23/16 3:41 AM DISEASE IN DEPTH SIGNS AND SYMPTOMS MALARIA Many of malaria’s symptoms are associated with immune response against the parasites, cellular debris, and toxins following the synchronous cycles of the parasite’s life within erythrocytes. Two weeks after the cycle begins, enough parasites exist to cause fever, chills, diarrhea, headache, and (occasionally) pulmonary or cardiac dysfunction. Anemia, weakness, and fatigue gradually set in, and patients may become jaundiced, as seen in this malaria patient from Vietnam. Plasmodium falciparum sporozoites M Erythrocytic cycle (in human) 4–8 alaria is the most prevalent and infamous of the protozoan infections. The life cycle of Plasmodium, the causative agent of malaria, has three prominent stages: the liver phase, the erythrocytic cycle, and the sporogonic phase. PLASMODIUM LIFE CYCLE 5 A merozoite becomes a trophozoite, shown in its ring state below. 6 Trophozoites undergo schizogony to produce merozoites, which are released when the erythrocytes break open. This occurs simultaneously and cyclically every 48 to 72 hours depending on the species of Plasmodium. The damaged liver cannot effectively process the amount of hemoglobin released, leading to jaundice. 7 Some merozoites develop into male and female gametocytes within erythrocytes. 4 Free merozoites penetrate erythrocytes. Liver phase (exoerythrocytic phase) (in human) 1–3 3 Generally, two weeks 2 Sporozoites travel through the bloodstream, invade liver cells, and undergo schizogony. later, the liver cells rupture and release 30,000 to 40,000 merozoites into the blood. The liver is damaged. TEM 25 μm Colorized TEM of erythrocytes at various stages of malarial infection. (Plasmodium colored blue.) 1 A female Anopheles mosquito injects sporozoites into the human during a blood meal. INVESTIGATE IT! Scan this QR code to watch Dr. Bauman's Video Tutor explore malaria. Then to go to MasteringMicrobiology to investigate further and record your research findings on the following question: Should scientists and government agencies focus more on controlling mosquitoes or developing a malaria vaccine? M21_BAUM7206_05_SE_C21.indd 656 8 Released merozoites adhere to and then infect new erythrocytes. TEM 2.5 μm Colorized TEM of merozoites multiplying inside liver cell EPIDEMIOLOGY Malaria is endemic in over 100 countries in the tropics and subtropics, where the parasite’s mosquito vector, Anopheles, breeds. As many as 300 million people are infected with Plasmodium, and an estimated 1.2 million (usually children) die annually. Malaria was prevalent in the United States until mosquito eradication programs eliminated the disease decades ago. About 1200 to 1500 cases seen each year in the United States involve immigrants or travelers from endemic areas. Confirmed malaria cases per 1000 population, 2013 Not applicable Non-endemic 0–0.1 0.1–1 1–10 50–100 >100 10–50 11/23/16 3:41 AM       PATHOGEN AND PATHOGENESIS Four species of Plasmodium cause most cases of malaria in humans: P. falciparum, P. vivax, P. ovale, and P. malariae. Disease severity depends upon the species: P. ovale causes mild disease, P. vivax results in chronic malaria, and P. malariae and P. falciparum (left) cause more serious malaria, known as blackwater fever because hemoglobin from damaged red blood cells is excreted in the urine. LM P. falciparum causes fever, erythrocyte lysis, renal failure, and dark urine. Protozoan proteins on the surfaces of erythrocytes cause erythrocytes to adhere to capillary lining, blocking blood flow and leading to small hemorrhages and ultimately tissue death. Children, such as this infant with malaria in South Sudan, are among the most vulnerable. 7 μm 9 The Anopheles mosquito ingests erythrocytes containing gametocytes during a blood meal. Sporogonic phase (in mosquito) 9–13 10 Gametocytes leave the erythrocyte and turn into gametes. These fuse to form a zygote. Gamete 11 The zygote differentiates into an ookinete and attaches to the gut wall. 12 The ookinete becomes an oocyst in the gut wall. Sporozoites form within the oocyst. 13 Sporozoites exit the oocyst and migrate to the mosquito’s salivary glands. Zygote Ookinete Oocyst emerging from mosquito gut Malarial vector, female Anopheles mosquito, during blood meal 14 Sporozoites are injected into a human during a blood meal. The life cycle begins again. TEM 25 μm Colorized TEM of oocysts filled with sporozoites TEM 8 μm Colorized TEM of sporozoites emerging from oocyst DIAGNOSIS AND TREATMENT Diagnosis of malaria is commonly based on identification of trophozoites and other stages of Plasmodium in blood smears. Standard antimalarial drugs include chloroquine and, in areas where Plasmodium is resistant, pyrimethamine with an artemisinin drug such as artesunate. M21_BAUM7206_05_SE_C21.indd 657 PREVENTION Control of malaria involves limiting contact with mosquitoes carrying Plasmodium. Widespread use of insecticides, drainage of wetlands, and removal of standing water can reduce mosquito breeding rates. WHO recommends DDTimpregnated netting, personal use of insect repellents, and protective clothing, such as long-sleeved shirts and long pants, to reduce mosquito bites. Travelers to endemic areas can take atovaquone and proguanil several days before and for one week after travel. Several malaria vaccines are currently under development. 11/23/16 3:41 AM apt       Ch er 21    Microbial Cardiovascular and Systemic Diseases poor immunity develop toxoplasmosis, which manifests with fever, malaise, and inflammation of the lungs, liver, and heart. Headache, confusion, spastic paralysis, blindness, myocarditis, encephalitis, and death are also common. Transplacental transfer from mother to fetus is most dangerous in the first trimester of pregnancy; it can result in epilepsy, mental retardation, microcephaly (abnormally small head), inflammation of the retina, blindness, anemia, jaundice, or spontaneous abortion or stillbirth. Ocular infections may remain dormant in children for years, at which time blindness develops. Pathogen and Virulence Factors 1 Sexual reproduction of parasite occurs in cat’s digestive system, and immature oocysts are shed in cat feces. 4a Sporozoites invade tissue, developing into bradyzoites within cells. Masses of bradyzoites become pseudocysts. 2 Oocyst produces internal sporozoites. ­ Toxoplasma gondii (tok-sō-plaz′mă gon′dē-ē)—the cause of toxoplasmosis—is an apicomplexan protozoan that lives in the nucleated cells of wild and domestic mammals and birds; cats are its definitive host. In the life cycle of Toxoplasma (Figure 21.19), male and female gametes in the cat’s digestive tract fuse to form zygotes, which develop into immature oocysts that are shed in the feces 1 . An infected cat shows no signs of infection and is not harmed. Each day the cat can excrete up to 10 million oocysts, which can survive in moist soil for several months. Vegetation growing in soil containing the parasites becomes contaminated with oocysts. As each oocyst matures, it produces internal sporozoites 2 . When rodents, livestock, or humans ingest mature oocysts on vegetation 3 , digestion releases the sporozoites, which invade the host’s heart, tongue, and diaphragm cells and proliferate asexually to produce pseudocysts containing numerous bradyzoites 4 . Pseudocysts remain dormant in the tissues of livestock or rodents until humans or cats, respectively, consume these hosts 5 . Virulence factors include the ability of oocysts and of pseudocysts to parasitize a wide variety of hosts, the ability of Toxoplasma to infect many different cells within a host, and the ability of the parasite to survive intracellularly. 5a Pseudocysts are ingested by cat in wild prey or undercooked meat. M21_BAUM7206_05_SE_C21.indd 658 5b Pseudocysts are ingested by humans in undercooked meat. 4b Sporozoites invade tissue, developing into bradyzoites and forming pseudocysts. ▲ Figure 21.19 The life cycle of Toxoplasma gondii. Which two groups of humans are at greatest risk from toxoplasmosis? the release of cytokines, and reduction in the release of glutamate neurotransmitter in the brain are involved. People with healthy immune systems are able to minimize damage and keep T. gondii from spreading beyond the pseudocysts. Toxoplasma gondii is one of the world’s most widely distributed protozoan parasites of humans. The CDC estimates that up to 40% of the U.S. population carry this obligate intracellular parasite. In AIDS patients with a CD4+ cell count under 200, symptoms are thought to result when Toxoplasma, resident in the body from a previous infection, reactivates as the immune system fails.  ­ Humans typically become infected by ingesting undercooked meat containing the parasite. Over 2.4 billion people are infected; at greatest risk are butchers, hunters, and anyone who tastes food while preparing it. Ingesting or inhaling contaminated soil can also be a source of infection. The protozoan can also cross a human placenta to infect the fetus. Interestingly, the parasite attacks female fetuses more than males, though scientists do not know why or how Toxoplasma selects a fetus by gender. Historically, contact with infected cats and their feces was proposed as a major risk for infection, but recent studies have shown that cats are not the major source of infection for humans because cats shed Toxoplasma only briefly. Nevertheless, doctors typically caution pregnant women and immunocompromised people to avoid emptying litter boxes. Researchers are uncertain of the specific way in which T. gondii causes disease. It appears that cellular destruction, 3b livestock or human consumes them, becoming accidental hosts. Figure 21.19 AIDS patients and first-trimester fetuses are at greatest risk from toxoplasmosis. Pathogenesis and Epidemiology 3a Rodent or bird ingests sporulated oocysts, or 11/23/16 3:41 AM c Gl n e a a eA t is D e as American Trypanosomiasis (Chagas’ Disease) 21.6 Toxoplasmosis Cause Toxoplasma gondii (apicomplexans protozoan). LE A R N I N G O UTC O M E Toxoplasma 21.34 Describe the signs, symptoms, causes, diagnosis, treat- ment, and prevention of American trypanosomiasis. Virulence factors Ability to survive inside many different types of cells in many different hosts. Portal of entry Ingestion in meat or inhalation of contaminated soil or cat litter. Signs and symptoms Most patients have no manifestations. In immunocompromised patients: fever; malaise; inflammation of lungs, liver, and heart; headache; confusion; spastic paralysis; blindness; myocarditis; encephalitis. Transplacental transfer to a fetus can cause epilepsy, mental retardation, microcephaly, inflammation of the retina and blindness, anemia, jaundice, or spontaneous abortion or stillbirth. Incubation period 10 to 23 days. Susceptibility Immunocompromised and unborn babies. Treatment Pyrimethamine and sulfonamides. Prevention Avoid contact with contaminated soil (cat litter); wash all fruits and vegetables; thoroughly cook; freeze, or smoke meat. Diagnosis, Treatment, and Prevention  ­ Physicians diagnose T. gondii infection by serological detection of organisms in tissues, by microscopic identification of parasites in biopsies, or by molecular identification of T. gondii genes or proteins in specimens using PCR, Southern blot, or DNA probes. Serology is the most common diagnostic method. Molecular techniques are most useful for congenital toxoplasmosis. In healthy adults, toxoplasmosis normally resolves without treatment. Treatment for AIDS patients, pregnant women, and newborns is pyrimethamine and sulfonamides, administered together for three to four weeks. Clindamycin can substitute for sulfonamides in patients who are allergic to sulfa. Treatment of pregnant women prevents most transplacental infections but is controversial because the medications are toxic. More aggressive treatment may be needed in AIDS patients, including the addition of steroids to reduce inflammation. Controlling the incidence of infection is difficult because so many hosts harbor the T. gondii. A vaccine for cats is currently under development to reduce the chance of pet-to-owner transmission. The best prevention is to avoid contact with contaminated soil, particularly soil contaminated with cat feces; wash all fruits and vegetables before consumption; and thoroughly cook meat until it reaches an internal temperature of 66°C (150°F); in other words, until a steak is no longer pink in the middle. Smoked meats and meats frozen overnight are considered safe. Disease at a Glance 21.6 summarizes the characteristics of toxoplasmosis. M21_BAUM7206_05_SE_C21.indd 659       H Protozoan and elminthic Cardiovascular and Systemic Diseases Charles Darwin (1809–1882) wrote in The Voyage of the Beagle, “At night I experienced an attack (for it deserves no less a name) of . . . the great black bug of the Pampas [Argentina]. It is most disgusting to feel soft wingless insects, about an inch long, crawling over one’s body. Before sucking they are quite thin but afterwards they become round and bloated with blood.” Following his return to England, Darwin suffered from almost continual ill health and died years later of heart failure. Some researchers hypothesize that Darwin suffered from American trypanosomiasis. This disease, also named Chagas’ disease for Brazilian doctor Carlos Chagas (1879–1934), produces manifestations similar to those experienced by Darwin. A parasitic trypanosome, which is transmitted via the bite of the mentioned bug, causes Chagas’ disease. Signs and Symptoms The initial sign of Chagas’ disease is a swelling at the site of infection, followed by general signs and symptoms—fatigue, fever, malaise, and swelling of lymph nodes that drain the site of infection—for four to eight weeks. These initial manifestations occur in only 1% of patients. The disease then enters an intermediate asymptomatic stage for 10–20 years. Patients may develop difficulty in swallowing, severe constipation, an irregular heartbeat, and fatal congestive heart. Not every patient develops chronic manifestations of Chagas’ disease. Pathogen and Virulence Factors Trypanosoma cruzi (tri-pan′ō-sō-mă kroo′zē) is the flagellated protozoan that causes American trypanosomiasis. The disease is endemic throughout Central and South America. Opossums and armadillos are the primary reservoirs for T. cruzi, but most mammals, including humans, can harbor the organism. Transmission occurs through the bite of insects—true bugs in the genus Triatoma (trī-a-tō′mă). These bloodsucking bugs feed preferentially from blood vessels in the lips, giving the bugs their common name—kissing bugs. T. cruzi matures in the hindgut of a kissing bug and enters a mammalian host when the bug’s feces are rubbed into the bite wound. T. cruzi circulates in the blood and has an intracellular stage, infecting macrophages and heart muscle cells. T. cruzi evades the immune system in part by living inside host cells. Further, the pathogen has the ability to switch its surface antigens, and it produces a protein that acts to suppress immune cytokines. 11/23/16 3:41 AM apt       Ch er 21    Microbial Cardiovascular and Systemic Diseases Figure 21.20 illustrates details of the life cycle of T. cruzi. Within the hindgut of a kissing bug, T. cruzi becomes infective 1 and is shed in the bug’s feces while the bug feeds on a mammalian host 2 , usually at night. When the host scratches the itchy wound created by the bug’s bite, infective trypanosomes deposited in the feces enter the nearby wounds 3 . Alternatively, trypanosomes can enter the body through an open cut, the eyes, or mouth, and infected mothers can pass the parasite to their children in the womb or while breast-feeding. The bloodstream carries the parasites throughout the body, where they penetrate cells, especially macrophages and heart muscle cells, and transform into small, nonflagellated forms 4 . Nonflagellated trypanosomes multiply by binary fission 5 , and then each develops a flagellum attached to the cell down its length with an undulating membrane 6 . These flagellated forms cannot multiply. The host cell bursts, releasing flagellated trypanosomes that either infect other cells 7 or circulate in the bloodstream. Trypanosomes in the blood can be ingested by a kissing bug when it takes a blood meal 8 . Within the midgut of the kissing bug, the flagellated cells produce another reproductive form that multiplies by binary fission 9 . 9 Flagellated parasites develop in the midgut of the bug into a different flagellated form that multiplies Triatoma by binary fission. (kissing bug, life size) 8 Flagellated trypanosomes in the blood are ingested by kissing bug while it feeds. 1. The site of the bug’s bite swells. 2. The generalized stage is characterized by fever, swollen lymph nodes, myocarditis (inflammation of the heart muscle), splenomegaly, and enlargement of the esophagus and colon. 3. The chronic stage is asymptomatic and can last for years. 4. A final symptomatic stage is characterized primarily by congestive heart failure following the formation of pseudocysts, which are clusters of parasites in heart muscle tissue. An estimated 8–10 million people have American trypanosomiasis, and about 10,000 die from it each year. In some South American communities, 40% of the residents are infected with T. cruzi. Pediatricians in Latin America are concerned about heart failure in children resulting from Chagas’ disease. 2 Infective trypanosomes are deposited in feces of kissing bug at bite wound site. 3 Scratching introduces infective trypanosomes into blood. Pathogenesis and Epidemiology Infection follows the bite from infected Triatoma, blood transfusion with infected blood, or organ transplantation from an infected donor. American trypanosomiasis progresses over the course of several months through four stages: 1 Trypanosomes become infective in hindgut of kissing bug. 7 Some flagellated cells infect other body cells, becoming nonflagellated in the process. 6 Nonflagellated trypanosomes transform, each developing a flagellum attached to the parasite’s body with an undulating membrane; these flagellated forms burst out of infected cells into the blood. These trypanosomes cannot multiply in the blood. 4 Trypanosomes travel in blood, penetrate cells, and transform into a nonflagellated form. 5 Nonflagellated trypanosome multiplies by binary fission inside cells. ▲ Figure 21.20 The life cycle of Trypanosoma cruzi in a South American. Diagnosis, Treatment, and Prevention Microscopic identification of trypanosomes (see Disease at a Glance 21.7) or their antigens in blood, lymph, spinal fluid, or a tissue biopsy is diagnostic for American trypanosomiasis. ELISA can demonstrate past infection with T. cruzi. Historically, physicians have used a simple and practical diagnostic method called xenodiagnosis. In this procedure, the physician allows an uninfected kissing bug to feed on the patient suspected of having a T. cruzi infection. Four weeks later, the physician dissects the bug; the presence of parasites within the hindgut of the bug indicates that the patient is infected. M21_BAUM7206_05_SE_C21.indd 660 Physicians treat the earliest stages of American trypanosomiasis with benznidazole or nifurtimox; however, recall that only 1% of patients develop early manifestations of the disease and thereby know that they have been infected. Therefore, most patients do not take antitrypanosome drugs soon enough—late stages of Chagas’ disease cannot be treated. Preventing American trypanosomiasis involves replacing thatch and mud building materials, which provide homes for the bugs, with concrete and brick. Alternatively, an insecticide-laden paint applied to the walls may provide significant 11/23/16 3:41 AM 21.7 c a Gl n e a t eA as is D e American Trypanosomiasis (Chagas’ Disease) Cause Trypanosoma cruzi (flagellated protozoan). Red blood cell       H Protozoan and elminthic Cardiovascular and Systemic Diseases the world. Schistosomiasis (skis′tō-sō-mī′ă-sis) is a potentially fatal disease and one of the major public health problems in the world. Signs and Symptoms T. cruzi Virulence factors Intracellular life, antigen switching, synthesis of protein that inhibits immunity. Portal of entry Bite of infected Triatoma (kissing) bug. F Signs and symptoms LM Swelling at site of bite, 10 µm fever, swollen lymph Blood smear containing trypomastigote nodes, myocarditis, of Trypanosoma cruzi. splenomegaly, and enlarged esophagus and colon. ollowing these symptoms, a chronic, asymptomatic stage may last for years before congestive heart failure occurs. Incubation period A few days to a few weeks. Congestive heart failure generally occurs 10–20 years following infection. Susceptibility People visiting or living in endemic areas, especially in poorly constructed dwellings in South and Central America. L E Treatment arly stages may be treated with benznidazole or nifurtimox. ate stages of American trypanosomiasis cannot be treated. Prevention Avoid sleeping in mud, thatched, or adobe houses in endemic areas, and use insect repellent. A transient dermatitis called swimmer’s itch may occur in the area where infective larvae burrow into the skin. They then migrate throughout the body via the vascular system; such migration produces no signs or symptoms. However, when the worms mature and mate, infections become dangerous as eggs lodge in the liver, lungs, brain, kidneys, and other organs. Trapped eggs die and calcify, leading to renal failure, splenomegaly, increased blood pressure in the pulmonary circulation, or heart failure. Death can result. In some infections, movement of eggs into the bladder and ureters (tubes draining the kidneys into the bladder) causes bladder obstruction and bloody urine and has been tied to fatal bladder cancer. Pathogens and Virulence Factors Three geographically limited species of Schistosoma infect humans to cause schistosomiasis: • S. mansoni (man-sō′nē) is common in the Caribbean, Venezuela, Brazil, Arabia, and large areas of Africa. • S. haematobium (hē′mă-tō′bē-ŭm) is found only in Africa and India. • S. japonicum (jă-pon′i-kŭm) occurs in China, Taiwan, the Philippines, and Japan, although infections in Japan are relatively rare. The freshwater larvae of these worms, called cercariae, can burrow through human skin to enter the blood. benefit. Tourists staying in well-constructed hotels and resorts are not at risk. The use of insecticides, both personally and in the home, and sleeping under insecticide-impregnated netting can prevent insect feeding. No vaccine exists for American trypanosomiasis. D i s ea s e at a Gl a nce 21 .7 su m ma r i z es A mer ic a n trypanosomiasis. We have considered protozoan cardiovascular diseases— malaria, toxoplasmosis, and American trypanosomiasis. Next, we consider a representative blood disease of a parasitic worm, schistosomiasis. Schistosomiasis LE A R N I N G O U TC O M E 21.35 Describe the signs, symptoms, causes, diagnosis, treat- ment, and prevention of schistosomiasis. Parasitic blood flukes of the genus Schistosoma (skis-tō-sō′mă) are one of the more common parasitic helminths of humans in M21_BAUM7206_05_SE_C21.indd 661 Pathogenesis and Epidemiology Humans are the principal definitive host for most species of Schistosoma, though S. japonicum infects other mammals. Figure 21.21 illustrates the life cycle of Schistosoma: The free-swimming, infective larval stage burrows through human skin 1 that is in contact with contaminated water. Humans become infected while washing clothes or utensils, bathing, swimming, or drinking. Infective larvae enter the vascular system of the liver or bladder (depending on species), where they feed on blood, mature, and mate 2 . Females daily lay hundreds of eggs, which have distinctive spines (see Disease at a Glance 21.8), in the walls of the blood vessels. The eggs work their way to the lumen of the intestine (S. mansoni and S. japon­ icum) or lumens of the urinary bladder and ureters (S. haemato­ bium) to be eliminated into the environment 3 . In freshwater, the eggs hatch, releasing free-swimming larvae 4 . Larvae penetrate freshwater snails 5 , where they reproduce asexually and develop into another, infective, larval form 6 . These larvae escape from the snail to complete the cycle by burrowing into human skin. The World Health Organization estimates there are about 240 million people infected worldwide with Schistosoma, and 11/23/16 3:41 AM er 21    Microbial Cardiovascular and Systemic Diseases Diagnosis, Treatment, and Prevention 6 Larvae reproduce asexually in snail, forming a different larval form. 1 The free-swimming larvae are infective and can penetrate human skin. 5 Larvae penetrate freshwater snail. T M Why Why can people who avoid cats get infected by Toxoplasma anyway? Clini al Case tudy 3 Eggs are passed into the environment in feces or urine. ­ M21_BAUM7206_05_SE_C21.indd 662 A 43-year-old man, infected with IV eight years previously, is brought to the hospital because of mental confusion and disorientation, headache, fever, and general discomfort. urther examination also indicates an enlarged liver. F ▲ Figure 21.21 The life cycle of Schistosoma, a blood fluke. 700 million are at risk. More than 200,000 people die each year in Africa alone. Most cases of schistosomiasis occur in sub-Saharan Africa, but Schistosoma is endemic in Asia, South America, and Africa. Schistosomiasis is not found in the United States. The number of cases of schistosomiasis has increased over the past few decades because of economic stability, improved irrigation systems, and an increase in the number of water reservoirs, which provide more habitats for the schistosomes’ intermediate host—snails. An Opportunistic Infection H 4 In water, eggs hatch into free-swimming larvae. S c 2 Larvae lose their tails and develop into adults in blood vessels of the liver or bladder; the adults mate. Diagnosis is most effectively made by microscopic identification of spiny eggs in either stool (S. mansoni and S. japonicum) or urine (S. haematobium) samples. The species of blood fluke causing a given infection can be ascertained based on the shape of the egg and the location of its spine. Immunological assays are used to identify antigen when laboratory technicians cannot find eggs in urine or stool samples but infection is suspected. The drug of choice for treating schistosomiasis is praziquantel. Prevention of infection depends on improved sanitation, particularly sewage treatment, and avoiding contact with contaminated water. A vaccine against S. haematobium and another against S. mansoni are currently in clinical trials. Disease at a Glance 21.8 summarizes the features of schistosomiasis. e These different larvae escape from the snail host and swim in the water. ell apt       Ch 2. 3. 4. 5. 1. W  hat tests might the doctor run to diagnose the disease? What opportunistic infection is likely to be the cause of the man’s symptoms? The doctor performs a CD4 + cell count. What is the patient’s maximum count most likely to be? How did the patient most likely become infected? What is the probable outcome for a non-immunocompromised patient infected with the same parasite? 11/23/16 3:41 AM eS as eC as is g gi Em er n D e       tudy H Protozoan and elminthic Cardiovascular and Systemic Diseases Snail Fever in China c a e A A Gl n e t is D e as H N known in rural China as “snail fever,” is reemerging. early 900,000 people are infected in China, and an estimated 30 million people are at risk. Why? In the 1950s, the government regularly swept lakes of snails, nearly eradicating schistosomiasis, but with the waning of such control measures today—coupled with frequent floods—snail fever is reemerging in the countryside and even encroaching into cities. ortunately for Jinhai and his family and neighbors, the drug praziquantel taken for one to two days can kill the worm in their bodies. Coupled with good sewage treatment and snail suppression, schistosomiasis can be conquered. F H The Year of the Snake was an awful year for Jinhai: a year of too much rain, a year of stress and disturbances in his rural village, and a year that seemed to be filled with nothing but illnesses. is whole family of fishermen and farmers had had fever and chills, coughing, and muscle aches for months. Jinhai and his brothers had had severe rashes that itched mercilessly. is children and nieces and nephews were anemic, tired all the time, and having difficulty learning even the basics of their school lessons. And now, Jinhai had this hugely disfiguring swollen stomach! Yes, the Year of the Snake was a bad one. Jinhai’s family was not alone. Schistosomiasis, 1. Why is schistosomiasis called “snail fever”? 2. Why does good sewage treatment help control schistosomiasis? 3. Why is the initial symptom itching skin? 21.8 Schistosomiasis Spine Cause Parasitic helminth: Schistosoma mansoni (Caribbean, South America, and Africa), S. haematobium (Africa and India), and S. japonicum (Asia). Virulence factors Can burrow through human skin. L Portal of entry arvae burrow through skin. Signs and symptoms Swimmer’s itch may occur at site of infection. There are no signs or symptoms as larvae travel the vascular system, but once the worms mature and mate, fever, chills, cough, and muscle aches occur. As trapped eggs die and calcify, renal failure, splenomegaly, increased blood pressure, bladder obstruction, distended abdomen, and heart failure may occur. Incubation period A few days for transient dermatitis; one to two months for acute symptoms. Susceptibility Individuals coming into contact with freshwater (lakes, rivers, or canals) in endemic areas are at risk. Treatment Praziquantel. F Prevention In endemic areas, avoid swimming and wading in freshwater, boil water for one minute before drinking, and heat bath water to 150° for five minutes before bathing. M21_BAUM7206_05_SE_C21.indd 663 LM 20 µm Egg of Schistosoma mansoni, from a stool sample. Distinctive spines characterize the eggs of blood flukes. 11/23/16 3:41 AM er 21    Microbial Cardiovascular and Systemic Diseases H 2. Although Sam had to suffer through the unpleasant side effects of treatment, he could have developed cardiac disease if he had not been so quickly diagnosed. ow does infection with T. cruzi lead to heart disease? r 1. The main arteries—vessels that carry blood away from the heart—are the pulmonary arteries (to the lungs) and the aorta (to the rest of the body). Arteries connect via capillaries to veins, which carry blood back to the heart. The main veins are the pulmonary veins (from the lungs) and the superior vena cava and inferior vena cava (from the rest of the body except the heart). 2. Blood consists of plasma—the liquid part of blood—and formed elements (blood cells and platelets). When clotting proteins are removed from plasma, serum remains. 3. Each of the paired atria and ventricles of the heart are separated by valves. These prevent backflow of blood into the atria when the ventricles contract. 4. The wall of the heart is composed of an outer, fibrous pericardium, a muscular myocardium, and an inner endocardium. 5. The blood flows through the cardiovascular system in this sequence: venae cavae, right atrium, right atrioventricular (tricuspid) valve, right ventricle, pulmonary semilunar valve, pulmonary arteries, lungs, pulmonary veins, left atrium, left atrioventricular (mitral) valve, left ventricle, aortic semilunar valve, aorta, arteries, capillaries, veins, venae cavae. Bacterial Cardiovascular and Systemic Diseases (pp. 630–644) 1. Septicemia is the presence of pathogens in the blood. When septicemia causes the lymphatic vessels to become inflamed, lymphangitis results. Bacteremia refers specifically to bacterial septicemia, though physicians often use bacteremia and septicemia interchangeably. 2. Toxemia occurs when bacteria at a fixed site of infection release toxins. Living microbes release exotoxins, which can cause host cells to die or fail to function. Endotoxin (the lipid A portion of lipopolysaccharide, LPS) is released from most dying Gramnegative bacteria. Lipid A triggers fever, shock, inflammation, diarrhea, hemorrhaging, and widespread, potentially fatal blood clotting—disseminated intravascular coagulation (DIC). ­ Structures of the Cardiovascular System (p. 630) M21_BAUM7206_05_SE_C21.indd 664 1. Describe two of the virulence mechanisms that T. cruzi uses to cause disease. y rS umma C hapte H At his initial examination, Dr. Stephens doesn’t note anything remarkable about Sam’s condition. is lymph nodes are swollen, but his temperature, pulse, respiration rate, and blood pressure are all normal. Dr. Stephens draws blood and collects a urine sample for further analysis. The results should be back the next day. Dr. Stephens tells Sam to get as much rest as possible and to make a follow-up appointment for tomorrow. At the follow-up appointment, Dr. Stephens reports that both the blood and urine analysis are normal. Sam is surprised that all of the tests have come back normal—even though he doesn’t feel extremely sick, he knows that there is something wrong with him. Dr. Stephens agrees—he has been Sam’s primary care physician for years and knows that if Sam says something is wrong with him, something probably is. After talking more with Sam about his recent activities, including his trip to Mexico, Dr. Stephens orders a microscopic analysis of Sam’s blood. The microscopy reveals the presence of a parasite, Trypanosoma cruzi, in Sam’s blood. A definitive diagnosis requires two additional serological tests; both return positive for T. cruzi. Trypanosomiasis is rare in the United States, and the drugs to treat the acute stage of the disease are available only from the Centers for Disease Control and Prevention (CDC). The treatment protocol uses two antiparasitic drugs that must be taken for 90 days. The downside of treatment is that side effects are common. ver the course of treatment, Sam experiences weight loss, headaches, vertigo (dizziness), and nausea; however, at the end, there is no detectable parasite in Sam’s blood. The side effects disappear after treatment ends. F More Than Stress? O apt       Ch 3. Septicemia can progress to a potentially fatal condition called septic shock. Bacterial septicemia can trigger petechiae—skin lesions—and osteomyelitis, which is inflammation of bones. 11/23/16 3:41 AM       Chapter Summary Streptococcal toxic shock syndrome (TSS) is a life-threatening toxemia. 4. Normal members of the microbiome can become pathogenic opportunists, particularly in health care situations. 5. Endotoxin can also trigger macrophages to release potent cytokines—including tumor necrosis factor (TNF), interleukins (ILs), and platelet activating factor (PAF)—which are defensive in localized infections but life threatening in septicemia. 6. In the majority of patients, the exact cause of septicemia is hidden, a condition named occult septicemia. 7. Inflammation of the endocardium is called endocarditis. Platelets and clotting proteins surround infecting bacteria and form aggregations called vegetations, which resist the body’s defenses. Fragments of vegetations and blood clots, each called an embolus, can lodge in small blood vessels, stopping the flow of blood and causing damage such as a stroke. 8. Physicians use sound waves to visualize vegetations in an echocardiogram. 9. Acute endocarditis develops quickly, whereas subacute endocarditis develops slowly. 10. When blood and lymph carry pathogens throughout the body, systemic diseases can develop. 11. Brucellosis (undulant fever, Bang’s disease) is a zoonosis caused by the bacterium Brucella and characterized by fever that spikes each afternoon. 12. Tularemia is a zoonotic disease caused by Francisella spp. 13. Plague (“Black Death,” or bubonic plague) is caused by Yersinia pestis and is characterized by buboes (inflamed lymph nodes), subcutaneous hemorrhaging, and blackened gangrenous tissues. Yersinia carries virulence plasmids that code for adhesins and type III secretion systems. The bacterium uses the latter to inject toxins to neutralize macrophages. Pneumonic plague occurs when plague bacilli spread from the blood to the lungs and in respiratory aerosols among people. 14. Lyme disease, characterized by a “bull’s-eye” rash, malaise, neurological symptoms, and arthritis, is caused by Borrelia burgdorferi, which is vectored by Ixodes ticks. 15. Ehrlichiosis and anaplasmosis are tick-borne diseases affecting monocytes and neutrophils, respectively, and characterized by fever, chills, headache, and other flulike manifestations. Ehrlichia chaffeensis and a related rickettsial species, Anaplasma phagocytoph­ ilum, cause the diseases. Viral Cardiovascular and Systemic Diseases (pp. 644–654) 1. Viremia is the condition in which viruses infect the blood. 2. Yellow fever, caused by the virus Flavivirus and carried by Aedes mosquitoes, develops in three stages ending in jaundice. The disease is significant in U.S. history. M21_BAUM7206_05_SE_C21.indd 665 3. Infectious mononucleosis (kissing disease) is caused by EpsteinBarr virus (EBV, HHV-4), which suppresses the programmed cell death (apoptosis) of infected B lymphocytes. Infected cells produce cancers such as Burkitt’s lymphoma when certain additional factors are present. 4. EBV is usually transmitted in saliva. Viruses invade B lymphocytes and trigger long-term immune responses, which could possibly be the cause of chronic fatigue syndrome. 5. Cytomegalovirus (CMV) disease affects fetuses, newborns, and immunodeficient patients and is transmitted via bodily secretions. 6. Dengue fever (breakbone fever) is characterized by fever, severe pain, weakness, and rash. Dengue hemorrhagic fever (DHF) involves a hyperimmune response to reinfection with dengue virus, resulting in internal bleeding, shock, and possibly death. Dengue viruses are carried by Aedes mosquitoes and affect millions of people each year. 7. Ebola hemorrhagic fever caused by Ebolavirus and Marburg hemorrhagic fever caused by Marburgvirus are endemic to Africa. The diseases have common features, including progression to severe internal bleeding; bleeding from the mouth, eyes, and ears; and death from shock, seizures, or kidney failure. Protozoan and Helminthic Cardiovascular and Systemic Diseases (pp. 654–663) 1. Malaria is caused by apicomplexans of the genus Plasmodium, which infect the liver and erythrocytes, causing recurrent fever and chills, anemia, weakness, fatigue, and jaundice. 2. The life cycle of Plasmodium has three stages: The liver phase (exoerythrocytic phase) involves Plasmodium sporozoites, injected by a female Anopheles mosquito, infecting the liver. The erythrocytic cycle involves trophozoites cyclically infecting erythrocytes and the development of gametocytes. The sporogonic phase involves the development and sexual union of Plasmodium in the mosquito. 3. Toxoplasmosis, caused by the apicomplexan protozoan Toxo­ plasma gondii, affects AIDS patients and unborn children. 4. American trypanosomiasis (Chagas’ disease), characterized by a swelling at the site of infection, is caused by Trypanosoma cruzi. This flagellated protozoan matures in the hindgut of a kissing bug (Triatoma) and enters a host when the bug’s feces are rubbed into the bite wound. It circulates in the blood and has an intracellular stage, infecting macrophages and heart muscle cells, and can cause fatal heart damage. 5. American trypanosomiasis can be diagnosed by a xenodiagnosis, a procedure in which a physician allows an uninfected bug to feed on a person suspected of having the disease and then seeks the trypanosome in the bug. 6. Cercariae larvae of the blood fluke Schistosoma spp. burrow into the skin, causing swimmer’s itch, and migrate through the vascular system. Adults feed on blood, lodge in the organs, and cause schistosomiasis, a potentially fatal disease. Snails are the intermediate host. 11/23/16 3:41 AM vi R on for e e w apt er 21    Microbial Cardiovascular and Systemic Diseases s u Q e sti       Ch Answers to the Questions for Review (except Short Answer questions) begin on p. A-1. Multiple Choice 2. Endotoxin is . a. another name for lipid A b. a poison in the intestinal tract c. a type of toxemia d. a component of bacterial peptidoglycan 12. Which of the following is important in developing dengue hemorrhagic fever? a. dengue virus c. previous infection b. immunological memory d. all of the above                                 4. Toxemia refers to . a. pathogens in the blood that cause illness b. blood poisoning due to toxins c. relatively harmless bacteria in the blood d. inflammation of the lymphatic vessels due to pathogens in the blood 5. Which of the following are minute hemorrhagic skin lesions? a. petechiae c. vegetations b. interleukins d. emboli                 6. Toxin released from cell walls of dying Gram-negative bacteria is . a. tetanus toxin, for example b. botulism toxin, for example c. called endotoxin d. an opportunistic toxin 7. Which are more commonly associated with septicemia? a. Gram-negative bacteria c. viruses b. Gram-positive bacteria d. protozoa 8. How is septicemia introduced into the body? a. food b. sexual contact c. direct inoculation into the blood d. respiratory droplets . c. yellow fever. d. camel fever. 14. Which is spread from person to person? a. tularemia c. bubonic plague b. pneumonic plague d. Lyme disease 15. Which of the following statements is false? a. A kissing bug transmits Trypanosoma cruzi as it feeds. b. Trypanosoma cruzi is expelled on the skin of the host in the feces of the kissing bug. c. Trypanosoma cruzi enters the bloodstream when the host scratches the wound. d. Trypanosoma cruzi causes Chagas’ disease. 16. The presence of lipid A in the outer membranes of Gram-negative bacteria . a. coagulates blood in the host b. causes these bacteria to be oxidase positive c. triggers the secretion of a protease enzyme to cleave IgA in mucus d. enables enteric bacteria to ferment glucose anaerobically 17. Following a backpacking trip in Vermont, a hiker experienced flulike symptoms and noticed a round, red rash on her thigh. What is the likely cause of her illness? a. Brucella melitensis b. Borrelia burgdorferi c. Francisella tularensis d. Yersinia pestis 18. In malaria, which portion of the life cycle occurs in the mosquito? a. liver phase b. erythrocytic cycle c. sporogonic phase d. amastigote phase                 9. The type of endocarditis that develops slowly over a period of weeks or months is described as . a. vegetative endocarditis b. tachycardia endocarditis c. acute endocarditis d. subacute endocarditis 13. Tularemia is also known as a. rabbit fever. b. mosquito fever.                                 3. Vegetations are . a. a type of septicemia b. masses of blood clots and platelets that surround bacterial infections in the heart c. fragments of blood clots that break off, travel in the blood, and lodge in small blood vessels in a body’s organs d. a diagnostic tool used with echocardiograms                 11. A cardiologist examines a patient with history of drug abuse and a recent tooth extraction and notes darkening under the fingernails. What should the diagnosis be? a. bacteremia c. black plague b. malaria d. endocarditis                 1. Septicemia refers specifically to . a. bacteria in the blood b. poison in the blood c. infected lymphatic vessels d. dangerous microbial infection in the blood 10. What are vegetations of endocarditis called when released into the blood? a. stroke c. ischemia b. emboli d. necrosis M21_BAUM7206_05_SE_C21.indd 666                 19. The definitive host for Toxoplasma gondii is . a. humans c. birds b. cats d. mosquitoes 20. Which of the following is not a high risk for endocarditis? a. transplant recipient b. cat owner c. patient with intravenous catheter d. IV drug user 11/23/16 3:41 AM 21. A horror movie portrays victims of biological warfare with uncontrolled bleeding from the eyes, mouth, nose, ears, and anus. What actual virus causes these symptoms? a. Ebolavirus b. dengue virus c. Cytomegalovirus d. human immunodeficiency virus 22. The intermediate host for the blood fluke Schistosoma is the . a. flea c. snail b. mosquito d. rodent       R Questions for eview Fill in the Blanks 1. A swollen, inflamed lymph node is known as a _______________. 2. Bang’s disease, Malta fever, rock fever of Gibraltar, fever of Crete, and undulant fever are all alternate names for _______________. 3. The infective stage of Plasmodium in humans is the _______________.                 4. _______________ is the widespread coagulation of blood caused by endotoxin. 5. A patient exhibits fever that spikes daily around 4 p.m. The doctor suspects a systemic disease called _______________.                 23. Streptococcal toxic shock syndrome . a. results from a hyperimmune response b. is a toxemia c. results from strep throat d. is typically associated with tampon usage 6. The three parts of the life cycle of Plasmodium are the _______________ cycle, the _______________ phase, and the _______________ phase. 7. Toxoplasmosis is caused by the protozoan _______________. 8. Trypanosoma cruzi causes _______________ disease. 9. The vector for bubonic plague is the _______________. Matching Match the disease with the pathogen. 1. _____ Bacterial endocarditis A. Brucella 2. _____ American trypanosomiasis B. Yersinia 3. _____ Bang’s disease C. Epstein-Barr virus 4. _____ Tularemia D. Trypanosoma 5. _____ Bubonic plague E. Flavivirus 6. _____ Lyme disease F. Borrelia 7. _____ Infectious mononucleosis G. Francisella 8. _____ Yellow fever H. Filovirus 9. _____ Ebola hemorrhagic fever I. Plasmodium 10. _____ Malaria 1. _____ “Bull’s-eye” rash A. Lyme disease 2. _____ Bubo B. Yellow fever 3. _____ “Black vomit” C. Ebola hemorrhagic fever 5. _____ Swimmer’s itch t z I ! 1. On the figure of the life cycle of Plasmodium, label the three phases (A through C) and the name of the parasite at each stage (a through d). a. __________ A. __________ b. __________ d. __________ B. __________ C. __________ D. Black plague E. Schistosomiasis M21_BAUM7206_05_SE_C21.indd 667 V J. Streptococcus Match the distinguishing sign or symptom with the disease. 4. _____ Bleeding from eyes, mouth, nose 10. Small cutaneous hemorrhagic skin lesions are called _______________. e . isuali 25. A leading cause of heart failure in South America is a. attack by bloodsucking bats b. nifurtimox c. American trypanosomiasis (Chagas’ disease) d. malaria                 24. Which of the following is used to treat cases of malaria? a. Duffy antigen c. DEET b. mosquito netting d. artemisinin c. __________ 11/23/16 3:41 AM apt       Ch er 21    Microbial Cardiovascular and Systemic Diseases 2. In the drawing of the life cycle of Ixodes and its role in Lyme disease, circle the organisms that might be infected with Borrelia. 6-legged tick larvae hatch from egg, crawl up vegetation, and wait to jump on passing animal. Spring (Year 1) Larvae Larvae feed on small mammals or birds. After feeding, they drop off. Eggs Spring (Year 2) Larvae develop into 8-legged nymphs. Nymphs feed on animals or humans. Nymph Winter Adult ticks feed on deer and mate. Female ticks lay eggs. Nymphs develop into adult ticks. Summer Fall Short Answer 1. List the three layers of the heart in order from the outside. 2. Explain how Brucella evades antibodies and some antibacterial drugs. 3. Contrast septicemia, bacteremia, and toxemia. 4. Why is it rare for healthy people with normal immune systems to have bacterial blood infections? 5. Define occult septicemia. 6. How do vegetations prolong endocarditis? 7. Explain the situation in which the body’s defensive cytokines (specifically tumor necrosis factor, interleukins, and platelet activating factor) can be life threatening. 8. After Tony had been very ill with cardiac problems, his hospital chart listed the cause as “culture negative” endocarditis. What does that mean? 9. Considering that CMV infects 50% of the adult population in the United States and 100% of the population in many other M21_BAUM7206_05_SE_C21.indd 668 countries, why is there so little Cytomegalovirus disease in the world? 10. If 1–3 million people die annually from malaria, how do populations survive in endemic areas? 11. Most of the world’s people have been infected with Epstein-Barr virus by age one and show no ill effects, even where medical care is poor. In contrast, individuals in industrialized countries are ordinarily infected after puberty, and these older patients tend to have more severe reactions to infection despite better health and medical care. Explain this paradox. 12. Explain how dead eggs of Schistosoma can cause damage in a human. 13. Contrast the severity of malaria caused by each of four species of Plasmodium. 14. Why do geneticists say there is a single species of Brucella, yet many veterinarians say there are four species? 15. Explain why poor hygiene actually protects against teenage mononucleosis. 11/23/16 3:42 AM 1. A blood bank refused to accept blood from a potential donor who had just had his teeth cleaned by a dental hygienist. Why did they refuse the blood? ­ 2. An epidemiologist notices a statistical difference in the fatality rates between cases of Gram-positive bacteremia treated with antimicrobial drugs and treated cases of Gram-negative bacteremia—that is, patients with Gram-positive bacteremia are much more likely to respond to treatment and survive. Explain one reason why this might be so. 3. Why is it more difficult to rid a community of a disease transmitted by arthropods (for example, Lyme disease or malaria) than a disease transmitted via contaminated drinking water (for example, cholera)? 4. Compare and contrast the life cycles of Trypanosoma brucei (Chapter 20) and T. cruzi. 5. Explain how each of the following could lead to the reemergence of malaria in the United States: (a) global warming, (b) increased travel of individuals from endemic regions to the United States, (c) increased immigration of individuals from endemic regions to the United States, and (d) laws protecting wetlands. 6. Discuss why sickle-cell trait is advantageous to people living in malaria endemic areas but is not advantageous in malaria-free areas. 7. Why are dengue, yellow fever, and malaria reemerging in areas where they have long been eradicated? 8. Why are ehrlichiosis and anaplasmosis considered emerging diseases given that they have been known for decades? M21_BAUM7206_05_SE_C21.indd 669       g i l Th nk n i Cr itica R Questions for eview 9. Why do physicians substitute trimethoprim and sulfamethoxazole for tetracycline when treating children and pregnant women infected with Brucella? 10. Most cases of tularemia in the United States occur in the late spring and summer months; very few cases ever occur in January. Why might this be so? 11. In 1861, yellow fever struck the Mississippi Valley, hitting Memphis, Tennessee, most forcefully. Half the citizens fled the city, and one-quarter of the remaining population died. Historical records indicate that the epidemic ceased only after winter frosts arrived. Why did frost stop the epidemic? Could yellow fever epidemics reappear in the United States? 12. Suppose scientists developed a vaccine for dengue that induced the production of memory T cells. After reviewing the characteristics of infection and reinfection, would you argue for or against the use of such a vaccine? Why? 13. Ebola hemorrhagic fever belongs to a group of diseases called “emerging diseases”—diseases that were previously unidentified or had never been identified in human populations. Emerging diseases are often first seen in developing countries such as the Democratic Republic of the Congo. What factors may explain the emergence of new diseases in these countries? 14. Propose some methods in addition to those in the text that public health officials could take to prevent transmission of Schistosoma to humans. 11/23/16 3:42 AM       Chapter 21    Microbial Cardiovascular and Systemic Diseases c Con ept Mapping Using the following terms, fill in this concept map that describes Lyme disease. ELISA Mild flulike symptoms Neurological symptoms Reservoirs Bull’s-eye rash Cardiac symptoms Deer Deer ticks 75–80% of patients Antimicrobials Arthritis Borrelia burgdorferi Symptoms Vectors Lyme disease is caused by is transmitted by is maintained in 1 2 4 which is a belong to including Spirochete Genus: Ixodes Field mice which are the typically has three phases is diagnosed by is treated with 14 12 13 used to detect Antibodies against Borrelia burgdorferi 5 3 First phase Second phase characterized by 6 characterized by 7 9 Third phase characterized by 11 experienced by 8 M21_BAUM7206_05_SE_C21.indd 670 10 3/6/18 4:43 PM