1. Ch 23
Microbial Diseases of the Cardiovascular and Lymphatic Systems

2. LEARNING OBJECTIVES List the signs and symptoms of septicemia
Differentiate gram-negative sepsis, gram-positive sepsis, and puerperal sepsis.
Describe bacterial endocarditis and rheumatic fever.
Discuss the epidemiology of tularemia, brucellosis, anthrax, gas gangrene.
Describe pathogens that are transmitted by animal bites and scratches.
Compare and contrast the causative agents, vectors, reservoirs, symptoms, treatments, and preventive measures for plague, Lyme disease, and Rocky Mountain Spotted Fever.
Describe infectious mononucleosis.
Compare and contrast the causative agents, vectors, reservoirs, and symptoms for yellow fever,
Compare and contrast the causative agents, modes of transmission, reservoirs, and symptoms for Ebola hemorrhagic fever and Hantavirus pulmonary syndrome.
Compare and contrast the causative agents, modes of transmission, reservoirs, symptoms, and treatments for Chagas’ disease, toxoplasmosis, malaria, and babesiosis.
Describe Swimmer’s Itch

3. Sepsis and Septic Shock
Sepsis: SIRS caused by spread of bacteria or their toxin from a focus of infection.
Septicemia: Sepsis involving proliferation of pathogens in the blood.
Gram-negative sepsis can lead to septic shock
Antibiotic-resistant enterococci and group B streptococci cause gram-positive sepsis.
Puerperal sepsis (S. pyogenes): due to uterus infection following childbirth or abortion; can progress to peritonitis or septicemia.
Sepsis is defined as the presence of SIRS in the setting of infection. Severe sepsis is defined as sepsis with evidence of end-organ dysfunction as a result of hypoperfusion. Septic shock is defined as sepsis with persistent hypotension despite fluid resuscitation and resulting tissue hypoperfusion.

4. DIC
The lysis of gram-negative bacteria causes them to release lipopolysaccharide (LPS; endotoxin) from the outer membrane of their cell wall. The LPS binds to a LPS-binding protein circulating in the blood and this complex, in turn, binds to a receptor molecule (CD14) found on the surface of body defense cells called macrophages. This triggers the macrophages to release various defense regulatory chemicals called cytokines, including IL-1, IL-6, IL-8, TNF-alpha, and PAF. The cytokines then bind to cytokine receptors on target cells and initiate inflammation and activate both the complement pathways and the coagulation pathway. (LPS, lipopolysaccharide; IL-1, interleukin-1; IL-6, interleukin-6; IL-8, interleukin-8, TNF-alpha, tumor necrosis factor-alpha; PAF, platelet-activating factor.) This will be discussed in greater detail under Bacterial Pathogenicity.

5. Bacterial Infections of the Cardiovascular and Lymphatic Systems
Subacute Bacterial Endocarditis
Rheumatic Fever
Tularemia
Brucellosis
Anthrax
Gas Gangrene
Bite Wounds

6. Subacute Bacterial Endocarditis:
usually caused by alpha-hemolytic streptococci from mouth (dentist!)
Preexisting heart abnormalities are predisposing factors.
Signs include fever, anemia, and heart murmur.
Acute bacterial endocarditis: usually caused by S. aureus  rapid destruction of heart valves.
Pericarditis: Streptococci

7. Endocarditis
Fig 23.4

8. Rheumatic Fever
Autoimmune complication of S. pyogenes infections. Expressed as arthritis or heart inflammation. Can result in permanent heart damage.
Antibodies against group A -hemolytic streptococci react with streptococcal antigens deposited in joints or heart valves or cross-react with heart tissue.
Rheumatic fever can follow strep throat. Bacteria might not be present at time of rheumatic fever.
Prompt treatment of streptococcal infections can reduce the incidence of rheumatic fever.
Figure 23.5

9. Tularemia “Rabbit fever” caused by Francisella tularensis
Bacteria reproduce in phagocytes
Transmitted by bites and scratches of infected animals, carcass handling, tick bites (~ 200 cases/year)
Ulcer at the site of entry and enlargement of the regional lymph nodes  Ulcero-glandular form (most common, plaguelike)
Aerosol infection  pneumonic form (bio weapon!)
Francisella tularensis is a small, Gram-negative, non-motile, encapsulated, pleomorphic coccobacillus (short rod). It is a facultative intracellular parasite which grows poorly or not at all on most laboratory media and requires a special glucose cysteine blood agar for isolation. Care must be taken in handling the sample because of the low infectious dose.
Tularemia was first described as a plaguelike disease of rodents in Tularemia has since been weaponized. Prior to signing the Biological Convention the U.S. military did stockpile it for use as a biological weapon. According to a former Soviet Union biological weapons scientist, the Soviet Union continued to develop stocks of the organism that causes tularemia into the 1990’s, including developing strains of the organism engineered to be resistant to antibiotics and vaccines. The WHO has estimated that an aerosol dispersal of 50 kg of Fransicella tularensis, the organism that causes tularemia, over an urban area of 5 million people would cause 250,000 casualties and approximately 19,000 deaths. Illness would persist for several weeks and disease relapses would occur for weeks to months. The CDC estimates that the economic impact of an F. tularensis attack would be $5.4 billion for every 100,000 persons exposed.
Although F. tularensis could be used as a weapon in a number of ways, it is believed that an aerosol release would have the greatest adverse medical and public health consequences. A weapon using airborne tularemia would likely result 3 to 5 days later in an outbreak of acute, undifferentiated febrile illness with developing symptoms of pneumonia. Without treatment, the clinical course could lead to respiratory failure, shock, and death
The organism grows very slowly and hence must be incubated for several days. The identity of the organism is confirmed with specific

10. Ulceroglandular Tularemia
Post-war Kosovo 2000: infection was transmitted through contaminated food or water and that the source of infection was rodents. Environmental circumstances in war-torn Kosovo led to epizootic rodent tularemia and its spread to resettled rural populations living under circumstances of substandard housing, hygiene, and sanitation.
An outbreak of primary pneumonic tularemia on Martha's Vineyard. Feldman KA, Enscore RE, Lathrop SL, Matyas BT, McGuill M, Schriefer ME, Stiles-Enos D, Dennis DT, Petersen LR, Hayes EB. Epidemic Intelligence Service, Centers for Disease Control and Prevention, Fort Collins, Colo., USA. BACKGROUND: In the summer of 2000, an outbreak of primary pneumonic tularemia occurred on Martha's Vineyard, Massachusetts. The only previously reported outbreak of pneumonic tularemia in the United States also occurred on the island in METHODS: We conducted a case-control study of adults with pneumonic tularemia and investigated the environment to identify risk factors for primary pneumonic tularemia. Patients with confirmed cases were residents of or visitors to Martha's Vineyard who had symptoms suggestive of primary pneumonic tularemia, were ill between May 15 and October 31, 2000, and had a positive laboratory test for tularemia. Controls were adults who had spent at least 15 days on Martha's Vineyard between May 15 and September 28, RESULTS: We identified 15 patients with tularemia; 11 of these cases were primary pneumonic tularemia. Francisella tularensis type A was isolated from blood and lung tissue of the one man who died. Patients were more likely than controls to have used a lawn mower or brush cutter in the two weeks before the illness or before an interview, for controls (odds ratio, 9.2; 95 percent confidence interval, 1.6 to 68.0) and during the summer (odds ratio, undefined; 95 percent confidence interval, 1.8 to infinity). Lawn mowing and brush cutting remained significant risk factors after adjustment for other potentially confounding variables. Only one patient reported being exposed to a rabbit while cutting brush. Of 40 trapped animals, 1 striped skunk (Mephitis mephitis) and 1 Norway rat (Rattus norvegicus) were seropositive for antibodies against F. tularensis. CONCLUSIONS: Study of this outbreak of primary pneumonic tularemia implicates lawn mowing and brush cutting as risk factors for this infection.
Ulceroglandular Tularemia
Girl with ulcerating lymphadenitis colli due to tularemia, Kosovo, April 2000.

11. MV in MA

12. Brucellosis (Undulant Fever)
B. abortus (cattle, elk, bison), B. suis (swine), B. melitensis (goats,sheep, camels)
Brucella, gram-negative rods, grow in phagocytes
Undulating fever spikes to 40°C each evening
The bacteria enter through minute breaks in the mucosa or skin, reproduce in macrophages, and spread via lymphatics to liver, spleen, or bone marrow.
Contact with infected animals (slaughterhouse workers, veterinarians, farmers, dairy workers) – also via ingestion of milk or milk products cases/y; worldwide incidence ~ 500,000.
Mortality rate ~ 2 % (endocarditis)
Morphology and physiology: Brucella are Gram-negative, nonmotile, coccobacilli. They are strict aerobes and grow very slowly (fastidious) on blood agar. In the host, they live as facultative intracellular pathogens.Epidemiology, transmission and symptoms Brucellosis is primarily a disease of animals and it affects organs rich in the sugar erythritol (breast, uterus, epididymis, etc.). The organism localizes in these animal organs and cause infertility, sterility, mastitis, abortion or resides as carriage. Humans in closed contact with infected animals (slaughterhouse workers, veterinarians, farmers, dairy workers) are at risk of developing undulant fever. There are cases of brucellosis seen in the US, although the worldwide incidence is estimated at 500,000. Four different species of Brucella are known to infect humans: B. abortus (cattle), B. suis (swine), B. melitensis (goats/sheep) and B. canis (dogs). Although brucellosis has been eradicated in most developed countries through animal vaccination, it persists in many underdeveloped and developing countries.WEB RESOURCES WWW Links - Zoonoses   Brucella abortus - Gram-negative, coccobacillus prokaryote; causes bovine spontaneous abortion due to its rapid growth in the presence of erythritol (produced in the plancenta). SEM x 29,650 © Dr Dennis Kunkel, University of Hawaii. Used with permission
B. abortus and B. canis cause a mild suppurative febrile infection whereas B. suis causes a more severe suppurative infection which can lead to destruction of the lymphoreticular organs and kidney. B. melitensis is the cause of most severe prolonged recurring disease. The bacteria enter the human host through the mucous membranes of the oropharynx (ingestion/inhalation routes), through abraded skin, or through the conjunctiva. Usually infection occurs by direct contact with infected material, although it may also occur by ingestion of milk or milk products. The bacteria are engulfed by neutrophils and monocytes and localize in the regional lymph nodes, where they proliferate intracellularly. If the Brucella organisms are not destroyed or contained in the lymph nodes, the bacteria are released from the lymph nodes resulting in septicemia. The organisms migrate to other lympho-reticular organs (spleen, bone marrow, liver, testes) producing granulomas and/or micro abscesses. Symptoms include fever, chills, sweats, fatigue, myalgia, profound muscle weakness, and anorexia. Joint involvement occurs often. Brucellosis may be either acute or chronic. Fatalities (0-3%) generally are due to endocarditis.
Pathogenesis
The symptoms in brucellosis are due to the presence of the organism and appear weeks (sometimes up to 2 months) after exposure. While in the phago-lysosome, B. abortus releases 5'-guanosine and adenine which are capable of inhibiting the degranulation of peroxidase-containing granules and thus inhibit the myeloperoxidase-peroxide-halide system of bacterial killing. The intracellular persistence of bacteria results in granuloma formation in the reticuloendothelial system organs and tissue damage due to hypersensitivity reactions, mostly type-IV.
Diagnosis
Diagnosis is based on prolonged (at least a week) presence of undulating fever, myalgia, arthralgia and the history of exposure (contact with animals or consumption of unprocessed material from infected animals). Definitive diagnosis can be made by culturing blood samples on blood enriched media. The (fastidious) organisms grow very slowly (4-6 weeks in blood culture). B. abortus but not other Brucella grow better in 5% CO2 atmosphere. On blood agar, they produce white glistening colonies. Serology can be used to further confirm the diagnosis.
Prevention and treatment 
Prolonged treatment with rifampin, which penetrates cells with streptomycin or tetracyclin is used to treat human Brucella infections. The control measures include animal vaccination and avoidance of infected material.

13. Well-formed hepatic granuloma from a patient with brucellosis

14. Methylene blue stain: Cultured human macrophage infected with Brucella melitensis. coccobacillary bacteria replicate in phagolysosomes
(original magnification x 1,000). Photograph: Courtesy of Robert Crawford, Ph.D., Senior Scientist, American Registry of Pathology, Washington, DC.

15. Anthrax Zoonosis; found in soil Cattle routinely vaccinated
Bacillus anthracis G+ rod, ES, aerobic, virulence factors: capsule, 3 exotoxins
Zoonosis; found in soil
Cattle routinely vaccinated
In human
Pulmonary anthrax (woolsorter”s disease), Inhalation of endospores; 100% mortality
Cutaneous anthrax, most common, endospores enter through minor cut; 20% mortality
Gastrointestinal anthrax: Ingestion of undercooked contaminated food; 50% mortality
Treated with ciprofloxacin or doxycycline

16. Anthrax is caused by the bacteria Bacillus anthracis
Anthrax is caused by the bacteria Bacillus anthracis. While anthrax commonly affects hoofed animals such as sheep and goats, humans may get sick from anthrax, too. The most common type of anthrax infection is cutaneous anthrax, an infection of the skin. Cutaneous infections account for 95% of all anthrax cases worldwide.
Cutaneous anthrax occurs after the bacteria touches a cut or scrape on the skin. After about two weeks, an itchy sore develops, similar to an insect bite. This sore may blister and form a black ulcer, which is usually painless. It is usually surrounded by significant swelling.  A scar often develops, and then dries and falls off within two weeks. Some patients have painful lymph nodes.
In some cases, the infection can spread through the bloodstream and become fatal. However, death is extremely rare in the majority of individuals who receive prompt, appropriate treatment.
Historically, the main risk factor for acquiring cutaneous anthrax is contact with animal hides or hair, bone products, and wool, as well as contact with infected animals. Therefore, those most at risk for anthrax include farm workers, veterinarians, and tannery and wool workers.
Anthrax is a potential agent for use as a biological weapon or for bio-terrorism. In 2001, bioterrorist activities involving the U.S. Postal Service infected 22 people with anthrax; 7 survivors had confirmed cutaneous anthrax disease.While at least 17 nations are believed to have a biological weapons program, it is unknown how many nations or groups are working with anthrax. Most bio-terrorism experts have concluded that it is technologically difficult to use anthrax effectively as a weapon on a large scale.

17. Gas Gangrene (Clostridial Myonecrosis)
Gangrene: Soft tissue death from ischemia  especially susceptible to growth of anaerobic bacteria such as:
C. perfringens, G+ rod, ES, anaerobic, release of  toxin (cytotoxic), H2 and CO2
Ubiquitous in soil and dust – “war disease”
C. perfringens can invade the wall of the uterus during improperly performed abortions
Death due to toxemia
Treatment: debridement and amputation – hyperbaric chamber; antibiotics and antitoxin of limited value (why?)

18. generally occurs at wound or surgical site  painful swelling and tissue destruction. Rapidly progressive, often fatal.

19. Animal Bites and Scratches
Anaerobic bacteria infect deep animal bites
Pasteurella multocida – normal flora of oral and nasopharyngeal cavity of dogs and cats; may cause septicemia
Bartonella henselae – (rickettsia) Cat scratch disease. Relatively common (~20,000 cases in US) – mostly in young – occasionally serious
Human bites – (not in book) normal mouth flora (incl. S. aureus,  hemolytic S. viridans, H. influenza and various anaerobes)

20. Primary lesion is a papule or vesicle
Lymph node histopathology is characteristic of the disease
Cat Scratch Disease

21. Clenched Fist Bite Injury . . .
This gentleman presented with a draining sinus on the dorsal aspect of his proximal phalanx, about one month after sustaining a clenched fist bite injury.  He could not clearly recall details of his initial treatment.

22. . . .leading to Osteomyelitis
Evidence of osteomyelitis with bone erosion and subperiosteal bone formation (arrows).

23. Vector-Transmitted Diseases
Plague
Relapsing Fever
Lyme Disease
Ehrlichiosis
Typhus
Epidemic Typhus
Spotted Fevers

24. Plague Bubonic plague: Bacterial growth in blood and lymph
“Black death”: Yersinia pestis, G- rod, bipolar staining
Endemic in Southwest  sylvatic plague
Reservoir: Rats, ground squirrels, and prairie dogs
Vector: infected fleas
Bubonic plague: Bacterial growth in blood and lymph
Septicemia plague: Septic shock
Pneumonic plague: Bacteria in the lungs
Plague suits. The beak was filled with sweet smelling oils and vinegar to counteract the smell of plague victims. Although physicians in the 1300's did not know the cause of plague, the suits may have been effective to some degree in that they kept fleas off and the shiny beak may have posed an obstacle to the entry of fleas. Left From:
PLAGUEPlague is caused by  Yersinia pestis and is the disease known in the middle ages as the black death. This is because it frequently leads to gangrene and blackening of various parts of the body. Capillary fragility results in hemorrhages in the skin which also result in black patches.Morphology and physiologyYersinia pestis is a pleomorphic, Gram-negative, bipolar staining, facultatively aerobic, nonmotile, bacillus. Optimal temperature for growth is 28 degrees C. It is a facultative intracellular parasite.Epidemiology, transmission and symptoms The three documented pandemics of plague (Black Death) have been responsible for the death of hundreds of millions of people. Today, sporadic infections still occur. In the U.S., animal (sylvatic) plague occurs in a number of western states, usually in small rodents and in carnivores which feed on these rodents.Humans are infected by carrier rodent fleas or by contact with infected animals. The flea acquires the Y. pestis organisms during a blood meal from infected rodents. These organisms lose their capsule, multiply in the intestinal tract and partially block the proventriculus. During the feed on a human host the flea regurgitates some of the organisms into the wound. The bulk of non-capsular organisms are phagocytized and destroyed by neutrophils. However, few organisms are taken up by histiocytes which are unable to kill them and allow them to resynthesize their capsule and multiply. The encapsulated organisms, when they are released from histiocytes are resistant to phagocytosis and killing by neutrophils. The resulting infection spreads to the draining lymph nodes which become hot, swollen, tender and hemorrhagic giving rise to the characteristic black buboes whence the name of the disease, bubonic plague is derived. Within hours the organism spreads into the spleen, liver and lungs resulting in pneumonia. While in circulation, the organism causes diffuse intra vascular coagulation resulting in intra vascular thrombi and purpuric lesion all over the body. If untreated, the infection has a very high (unto 90%) mortality rate. The organism in exhaled in cough droplets, infect other humans in close proximity and cause pneumonic plague, which more difficult to control and has 100% mortality.PathogenesisMany pathogenic factors play direct and indirect roles in Y. pestis pathogenesis.Low calcium response (lcr) : This is a plasmid-coded gene that enables the organism to grow in a low Ca++ (intracellular) environment. It also coordinates the production of several other virulence factors, such as V, W and yops (Yersinia outer proteins).V and W proteins: These plasmid-coded proteins are associated rapid proliferation and septicemia.Yops: A group of 11 proteins, which are coded by plasmids, are essential for rodent pathogenesis and are responsible for cytotoxicity, inhibition of phagocyte migration and engulfment and platelet aggregation.Envelope (F-1) antigen: This is a protein-polysaccharide complex which is highly expressed at 37 degrees in the mammalian host but not in the flea and is anti-phagocytic.Coagulase and Plasminogen activator: Both of these are plasmid-coded proteins. Coagulase is responsible for micro thrombi formation and plasminogen activator promotes the dissemination of the organism. It also destroys C3b on the bacterial surface, thus attenuating phagocytosis.WEB BOOK Diagnosis
Diagnosis is based on appearance of buboes. The diagnosis is confirmed by culture of a lymph node aspirate. Extreme caution is warranted in handling of the specimen, as it is highly infectious.
Prevention and Treatment
Hospitalization and strict isolation are the rule. Streptomycin and tetracycline are highly effective. An effective formalin-killed vaccine is available but is recommended only for people at a high risk. The disease is internationally quarantinable and reporting of cases is mandatory. Control of urban plague is based upon flea and rodent control.
Plague suit

25. The Black Death
Fig 23.11

26. Femoral bubo: Most common site of, tender, swollen, lymph node in patients with plague
The incubation period is typically 2 to 10 days, but may be as short as a few hours for pneumonic plague.
Risk factors for plague include a recent flea bite and exposure to rodents, especially rabbits, squirrels, or prairie dogs, or scratches or bites from infected domestic cats.
Symptoms    Return to top
Bubonic Plague: Symptoms appear suddenly, usually after 2-5 days of exposure to the bacteria.
Sudden onset of high fever
The classic sign is a smooth, painful swelling of a lymph gland(s), called a buboe. The most common area is the groin, but swollen glands may also ocur in the armpits or neck. Pain may occur in the area before the swelling.
Chills
General discomfort or ill feeling (malaise )
Muscular pain
Severe headache
Seizures
Pneumonic Plague: Symptoms begin abruptly, typically 2-3 days after exposure.
Severe cough
Frothy, bloody sputum
Difficulty breathing
Septicemic Plague: This blood infection may cause death even before the signs of bubonic or pneumonic plague occur.
Fever
Low blood pressure
Blood clotting problems
Failure of several or all organ systems
Signs and tests    Return to top
These tests may indicate a plague infection:
Culture of bubo
Treatment    Return to top
Patients with the plague need immediate treatment withing 24 hours of initial symptom development, or death may be unavoidable. Treatment consists of antibiotics such as streptomycin, chloramphenicol, or tetracycline. Note: Oral tetracycline is usually not prescribed for children until after all the permanent teeth have erupted. It can permanently discolor teeth that are still forming.
Oxygen, intravenous fluids, and respiratory support are usually also prescribed.
Patients with pneumonic plague are strictly isolated from other patients. People who have had contact with anyone infected by pneumonic plague are observed closely and are given antibiotics as a preventive measure.
Expectations (prognosis)    Return to top
Half of bubonic plague victims die if not treated, and almost all victims of pneumonic plague die if not treated. Treatment reduces the death rate to 5%.
Calling your health care provider    Return to top
Call your health care provider if symptoms develop after exposure to fleas or rodents, especially if you live in or have visited an area where plague occurs.
Prevention    Return to top
Rat control and surveillance of the disease in the wild rodent population are the main measures used to control the risk of epidemics. A vaccination is available for high-risk workers, but its effectiveness is not clearly established.

27. Bipolar staining: Dark stained bipolar ends in Wright's stain (blood from plague victim)

28. Lyme Disease 3 stages with various symptoms
Zoonosis caused by Borrelia burgdorferi
Reservoir: mice, deer; Vector: Ixodes ticks
3 stages with various symptoms
Early localized stage: Bull’s eye rash = erythema (chronicum) migrans ECM; flu-like symptoms
Early disseminated stage: Heart and Nervous system symptoms; also skin and joints affected
Late stage: Chronic arthritis

29. Diagnosis
Symptoms alone: often misdiagnosis
In most cases not possible to isolate and culture B. burgdorferi  indirect serological tests (ELISA and Western blot)
PCR
Prevention
Treatment in early stages!

30. Erythema migrans

31. Ixodes scapularis / pacificus
Ixodes pacificus

33. Life Cycle of the Tick
Compare to Fig 23.13a

34. Ehrlichiosis First described in 1986
Caused by Ehrlichia species and transmitted by Ixodes ticks – diseases of animals and humans
Obligately intracellular (in white blood cells)
Monocytic Ehrlichiosis (HME)
granulocytic Ehrlichiosis (HGE)
Nonspecific symptoms (similar to other diseases)

35. HME and HGE

36. Lyme Disease and Ehrlichiosis
Ehrlichiosis is a disease caused by Ehrlichia organisms. It was first described in The two specific organisms that have been implicated are Ehrlichia chaffeensis and granulocytic Ehrlichia.
The Ehrlichia bacteria belong to the family Rickettsiae. Rickettsial organisms are responsible for a number of serious diseases with worldwide distribution such as Rocky Mountain spotted fever, typhus, murine typhus, scrub typhus, Queensland tick typhus, Boutonneuse fever, North Asian tick-borne rickettsiosis, rickettsial pox, and others. All of these diseases require an insect (tick, flea, mite) to transmit them to humans or other animals.
The infectious organism of ehrlichiosis is transmitted to humans by the bite of a tick. Rickettsiae are often associated with a specific tick. Ehrlichia inhabit the Lone Star tick (Amblyomma americanum), the American dog tick (Dermacentor variabilis), and the deer ticks (Ixodes dammini and Ixodes scapularis). (NOTE: the deer tick is also the carrier of Lyme disease.).
In the U.S., ehrlichiosis is found mainly in the southern central states and the Southeast. It has recently also been reported in the upper midwestern and Northeast.

37.
Grasp the tick as close to the skin surface as possible and pull upward with steady, even pressure. Do not twist or jerk the tick; this may cause the mouthparts to break off and remain in the skin.  (If this happens, remove mouthparts with tweezers.  Consult your healthcare provider if infection occurs.)
Do not squeeze, crush, or puncture the body of the tick because its fluids (saliva, hemolymph, gut contents) may contain infectious organisms.

38. Rocky Mountain Spotted Fever (RMSF)
Rickettsia rickettsii
Zoonosis –
Reservoir: mammals
Vector: ticks
Characteristic hemorrhagic rash – maculopapular – starts on palms and soles (unlike measles!)
Can damage vital organs

39. Rocky Mountain Wood Tick (Dermacentor andersoni)
The Rocky Mountain wood tick (Dermacentor andersoni) is one of two major vectors in the United States of Rocky Mountain spotted fever (Rickettsia rickettsii), a bacterial zoonosis transferred to humans from small rodents via a tick vector. Only members of the hard tick family Ixodidae are naturally infected with Rocky Mountain spotted fever, including the widespread American dog tick, D. variabilis, found east of the Rocky Mountains and in limited areas of the Pacific Coast.

40. Red structures indicate immunohistological staining of Rickettsia rickettsii in endothelial cells of a blood vessel from a patient with fatal RMSF

41. Spotted Fevers (Rocky Mountain Spotted Fever)
Figure 23.16

43. VIRAL DISEASES OF THE CARDIOVASCULAR AND LYMPHATIC SYSTEMS
Infectious Mononucleosis
Viral Hemorrhagic Fevers

44. Infectious Mononucleosis
“Kissing disease” – caused by Epstein-Barr virus (EBV) of Herpesviridae, also known as HHV-4
Well-established relationship between HHV-4 and oncogenesis (Burkitt’s Lymphoma etc.)
Virus multiplies in parotid glands and is present in saliva. It causes the proliferation of atypical lymphocytes (life-long infection) – Transmission via saliva
Most people (~95%) infected. Childhood infection usually asymptomatic. Adolescent infection  Mononucleosis.
Characteristic triad: fever, pharyngitis, and lymphadenopathy (+spleno- and hepatomegaly) lasting for 1 to 4 weeks.
Epstein-Barr virus, frequently referred to as EBV, is a member of the herpesvirus family and one of the most common human viruses. The virus occurs worldwide, and most people become infected with EBV sometime during their lives. In the United States, as many as 95% of adults between 35 and 40 years of age have been infected. Infants become susceptible to EBV as soon as maternal antibody protection (present at birth) disappears. Many children become infected with EBV, and these infections usually cause no symptoms or are indistinguishable from the other mild, brief illnesses of childhood. In the United States and in other developed countries, many persons are not infected with EBV in their childhood years. When infection with EBV occurs during adolescence or young adulthood, it causes infectious mononucleosis 35% to 50% of the time.
Herpes viruses contain double-stranded DNA, and they have an icosahedral capsid and a glycoprotein-containing envelope. They are relatively fragile and do not survive long outside the human host fluids.
EBV is ubiquitous. It is estimated that more than 90% of adult humans demonstrate serologic evidence of a prior infection with EBV. Most cases of IM are due to EBV, but the vast majority of EBV infections do not result in IM. In industrialized nations and among higher socioeconomic groups, infection with EBV tends to occur in adolescents and young adults. It is in this age group that the ensuing immunopathology gives rise to the characteristic clinical syndrome.

45. Triad
Swollen lymph nodes, sore throat, fatigue and headache are some of the symptoms of mononucleosis. It is generally self-limiting and most patients can recover in 4 to 6 weeks without medications.

46. Young adults present with fever, pharyngitis, lymphadenopathy, and tonsillitis.  

47. Proliferation of infected B cells results in massive activation and proliferation of Tc cells (CD8 cells)  characteristic lymphoid hyperplasia.
Transformation of B cells to immortal plasmacytoid cells  secrete a wide variety of IgMs = heterophile antibodies (Monospot test)
Commercially-available test kits are 70-92% sensitive and % specific
Following exposure, EBV infects epithelial cells of the oropharynx and salivary glands. B lymphocytes may become infected through exposure to these cells or may be directly infected in the tonsillar crypts. B-cell infection allows viral entry into the bloodstream, which systemically spreads the infection.
In the immunocompetent patient, the proliferation of infected B cells results in massive activation and proliferation of cytotoxic T lymphocytes, leading to the characteristic lymphoid hyperplasia. Clinically, this is observed as tonsillitis, lymphadenopathy, and hepatosplenomegaly.
The T-cell response is largely responsible for the rise in the absolute lymphocyte count and for the finding of atypical lymphocytes. These atypical lymphocytes (ie, Downey cells) actually are CD8 cytotoxic T cells.
B-cell infection caused by EBV leads to the transformation of the B cells to immortal plasmacytoid cells, which secrete a wide variety of immunoglobulins (eg, heterophile antibodies). Antibodies against specific EBV antigens and a number of autoantibodies also are produced.
The quantitative heterophile antibody test is considered positive with a titer of 40 or greater. This test may take up to 24 hours to perform.
A shorter version—the qualitative heterophile antibody test (Monospot)—is either positive or negative. This test takes minutes to perform, and results are known right away.
About 2 weeks after the onset of the disease, many patients are found to have IgM antibodies in their serum that react against warm red blood cells. When these antibodies are present in serial dilutions of > 1:56 (that is, after diluting the patient's serum more than 56 times and adding it to a suspension of red blood cells), infectious mononucleosis is suggested. However, other less-common diseases may produce a positive test.
About 1 week after the onset of the disease, many patients develop heterophile antibodies. The antibodies peak at weeks and may persist for several months to 1 year. However, a small number of persons with mononucleosis may never develop such antibodies.
"Downy cell“: lymphocytes infected by EBV or CMV in infectious mononucleosis. Cytoplasmic rim is intensely blue and has tendency to "stream" around adjacent red cells.

48. Pathogenesis of infectious mononucleosis
EBV also establishes a lifelong dormant infection in some cells of the body's immune system. A late event in a very few carriers of this virus is the emergence of Burkitt's lymphoma and nasopharyngeal carcinoma, two rare cancers that are not normally found in the United States. EBV appears to play an important role in these malignancies, but is probably not the sole cause of disease.
Most individuals exposed to people with infectious mononucleosis have previously been infected with EBV and are not at risk for infectious mononucleosis. In addition, transmission of EBV requires intimate contact with the saliva (found in the mouth) of an infected person. Transmission of this virus through the air or blood does not normally occur. The incubation period, or the time from infection to appearance of symptoms, ranges from 4 to 6 weeks. Persons with infectious mononucleosis may be able to spread the infection to others for a period of weeks. However, no special precautions or isolation procedures are recommended, since the virus is also found frequently in the saliva of healthy people. In fact, many healthy people can carry and spread the virus intermittently for life. These people are usually the primary reservoir for person-to-person transmission. For this reason, transmission of the virus is almost impossible to prevent.

49. Viral Hemorrhagic Fevers
Enveloped RNA viruses: Arenaviruses, filoviruses, bunyaviruses, and flaviviruses
Viruses geographically restricted to where their host species live
For some viruses, after accidental transmission from host, humans to human transmission
Human cases or outbreaks sporadic and irregular. Not easily predictable
Marburg VHF: 1967 outbreak in Marburg (D) – imported from Africa; Mortality rate 25%
Ebola HF: 1995 major outbreaks in Zaire and Sudan; Mortality rate 50 – 90%

50. Classic Viral Hemorrhagic Fevers: Yellow Fever
Caused by arbovirus (flaviviridae) transmitted by mosquitoes
Direct damage to liver and heart  jaundice, hemorrhaging, weak heart  circulatory and kidney failure
African and American tropical jungles
Diagnosis: test for presence of virus- neutralizing antibodies
No treatment Highly effective attenuated vaccine

51. Hantavirus Pulmonary Syndrome (HPS)
Korean hemorrhagic fever caused by Hantaan virus of Bunyaviridae
HPS first reported in US in spring of 1993.
Transmission through urine, droppings, or saliva of infected rodents  humans breathe in aerosolized virus. No person to person transmission in US
Sudden respiratory failure
Mortality rate > 35%

52. Hanta Virus Cases

53. PROTOZOAN DISEASES OF THE CARDIOVASCULAR AND LYMPHATIC SYSTEMS
American Trypanosomiasis (Chagas’ Disease)
Toxoplasmosis
Malaria
Babesiosis

54. American Trypanosomiasis or Chagas Disease
Trypanosoma cruzi
Reservoir: Rodents, opossums, armadillos
Vector: night feeding reduviid bugs (kissing bugs)
Symptoms in 1% of infected. Acute phase (fever etc.) to chronic phase (heart damage)
Antigenic variation  persistent evasion of immune system  Cyclic parasitemia (7-10 days)
Feeding reduviid bug. These hematophagous triatomines release parasite-laden feces during or after a blood meal. Parasites are introduced into the vertebrate host if this material contaminates the bite wound or a mucous membrane. These bugs are typically found in rural areas in South and Central America and even in the southern half of the United States.

55. Antigenic variation
As trypanosomes multiply in the blood, the host eventually mounts an effective immune response against trypanosomes with a given VSG coat.  This removes all parasites with the old VSG coat, leaving behind those that have switched to a new (and temporarily unrecognisable) VSG coat.  These new antigenic switch variants form the next wave of infection.  Antigenic variation of the surface coat allows the trypanosome to maintain a chronic infection which can last for years.
Course of trypanosome infection: emergence of variant surface glycoproteins (VSG)  - Host antibodies indicated with Y's.

56. Millions in Latin America affected
Millions in Latin America affected. No cure and little effective treatment
Romaña's sign: pathogonomic, early sign of Chagas disease. → Unilateral severe conjunctivitis, swelling of eyelid, inflammation of tear gland, swelling of regional lymph nodes.
Romaña's sign,   unilateral ophthalmia with palpebral edema, conjunctivitis, and swelling of regional lymph glands as a sign of Chagas' disease. a person's eye on one side of the face swells, usually at the bite wound or where feces were deposited or accidentally rubbed into the eye.
Yes, Chagas can cause serious illness. Many people get the infection during childhood. Usually, the early stage of infection is not considered severe. However, sometimes the disease can cause death, particularly in infants. For about one-third of the persons who get Chagas disease, chronic symptoms develop years after infection. For those who develop chronic symptoms, the average life expectancy decreases by an average of 9 years.

57. Toxoplasmosis Toxoplasma gondii
> 60 mio people infected in US (mostly asymptomatic)
Zoonosis – Transmission via undercooked meat, cat feces, drinking water. Flu-like symptoms
Can cross placenta  Congenital risk (TORCH)  brain damage or vision problems
Risk of new infection or reactivation in the immunosuppressed
T. gondii undergoes sexual reproduction in the intestinal tract of domestic cats, and oocysts are eliminated in cat feces.
Toxoplasmosis can be identified by serological tests, but interpretation of the results is uncertain.
Serology and PCR for diagnosis
If you are planning to become pregnant, your health care provider may test you for Toxoplasma. If the test is positive it means you have already been infected sometime in your life. There usually is little need to worry about passing the infection to your baby. If the test is negative, take necessary precautions to avoid infection (See below).
TORCH infectionsDefinition TORCH is an acronym for a special group of infections. These may be acquired by a woman during pregnancy. "TORCH" stands for the following infections:
toxoplasma infection, also called toxoplasmosis
other infections, such as hepatitis B, syphilis, and herpes zoster, the virus that causes chickenpox
rubella, the virus that causes German measles
cytomegalovirus, or CMV
herpes simplex virus, the cause of genital herpes
What is going on in the body? All of the TORCH infections can affect people of any age or sex. However, the term TORCH is only used when it applies to pregnant women and their unborn or newborn children. As a group, the TORCH infections represent a common cause of birth defects. They can also cause stillbirth, the delivery of a dead baby.

58. Compare to Fig. in book

59. Malaria Four species of Plasmodium: P. falciparum (malignant)
Vector: Anopheles mosquito
Worldwide million cases; ~ 1.5 – 3 million people die; ~ 1,200 cases in US
Plasmodium infects red blood cells  microscopic diagnosis
Symptoms: chills, fever, vomiting, headache; at intervals of 2 to 3 days
New drugs are being developed as the protozoa develop resistance to drugs such as chloroquine.

60. Microscopic Diagnosis
Figure 23.25

61. Malaria
Figure 23.24

62. Compare to Fig 12.19

63. Distribution of Malaria

64. Sickle cell trait provides protection!

65. Babesiosis Babesia microti Vector Ixodes tick - Zoonosis
Hemoprotozoan  rupture of RBCs  hemolytic anemia
In malaria-endemic areas misdiagnosis as Plasmodium

66. Schistosomiasis / Bilharzia(sis)
Schistosoma mansoni, S. haematobium, and S. japonicum
250 million people infected worldwide
Cercaria penetrates skin when exposed to contaminated water  worms grow inside blood vessels and produce eggs  eggs travel to liver (liver damage), intestine or bladder.
Treatment available (praziquantel)
Fig 17.2

67. The Life Cycle of the Blood Fluke, Schistosoma mansoni

68. Other Schistosomes: Swimmer’s Itch or Cercarial Dermatitis
Schistosome cercaria accidentally enters human skin (bird is definitive host for adult parasite)
Almost every state in US (Most predominant in the north). Also in more than 30 countries.
Disappears without treatment ( 7 days) – no internal organs involved
Most human schistosomiasis is caused by Schistosoma haematobium, Schistosoma mansoni, or Schistosoma japonicum. Less prevalent species such as Schistosoma mekongi and Schistosoma intercalatum also may cause systemic human disease. Less importantly, other schistosomes with avian or mammalian primary hosts can cause severe dermatitis in humans (eg, swimmer's itch secondary to Trichobilharzia ocellata).

69. Human is accidental host

70. Parasites die after entering  dermatitis in previously sensitized individuals. Sensitivity rarely disappears; usually gets worse in subsequent exposures.
Widely scattered from Michigan lakes to Alaska.

71. the end