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1 Bacterial/Viral Infections Affecting the Gastrointestinal Tract (Chapt. 22) 22.1. The Gastrointestinal Tract and Its Defenses A. A long tube, called a lumen, extending from mouth to anus B. Composed of eight main sections: the mouth, pharynx, esophagus, stomach, small intestine, large intestine, rectum, and anus; see Fig. 22.1 C. Four accessory organs: the salivary glands, liver, gallbladder, and pancreas D. Defenses include: 1. Mucus 2. Secretory IgA 3. Peristalsis 4. Saliva contains lysozyme and lactoferrin 5. Stomach fluid is highly acidic 6. Bile is antimicrobial 7. Gut-associated lymphoid tissue (GALT) 8. Commensals in system provides microbial antagonism towards pathogens 22.2. Normal flora of the upper respiratory tract and head A. mouth, oropharynx, nasopharynx: 1. more than 550 species occur predominantly in oral biofilms 2. in general there are 10-100 times more anaerobes than aerobes 3. the most common anaerobes are Peptostreptococcus, Veillonella, Actinomyces and Fusobacterium 4. the most common aerobic bacteria are Streptococcus, Haemophilus, and Neisseria 5. potential pathogens (most are not normal flora) include Streptococcus pyogenes, Streptococcus pneumoniae, Staphylococcus aureus, Neisseria meningitidis, Haemophilus influenzae, Moraxella catarrhalis and members of the Enterobacteriaceae 6. a number of oral flora are involved in development of biofilms (plaque) resulting in dental caries and periodontal disease 7. a group of normal flora gram-negative bacteria have been associated with acute endocarditis → → HACEK group and subacute endocarditis → viridans streptococci B. Normal flora of the stomach and intestinal tract: 1. stomach- it can be a relatively hostile environment for bacteria because of the low pH, however Helicobacter, Lactobacillus and some Streptococcus spp. are known to colonize. 2. small intestine- there are about 103 bacteria/ml in the region; most are anaerobes including Peptostreptococcus, Porphyromonas, and Prevotella; obstruction in this location can lead to blind loop syndrome which involves colonization and proliferation of bacteria from the large intestine. 3. large intestine-the colon is the major reservoir of bacteria in the body; numbers reach 1010-1011/gm of colon contents; bacteria found in highest number include Bacteroides, Bifidobacterium (probiotic bacterium), Clostridium, Eubacterium, Enterococcus and members of the Enterobacteriaceae (particularly Escherichia coli); there are many other bacteria at lower numbers. 4. altering normal flora-gut flora can be eliminated with the use of antibiotics, resulting in overgrowth by ones present in relatively low numbers, e.g. pseudomembranous colitis caused by Clostridium difficile after the use of certain antibiotics 22.3. Oral cavity diseases caused by bacteria A. dental caries - cariogenic biofilm formation and lactic acid production by primarily Streptococcus mutans can lead to dissolution of tooth enamel B. periodontal disease - 1. signs and symptoms - swelling, erythema, gum recession, bone resorption 2. pathogenesis- periodontal biofilm formation by early colonizers (predominantly gram-positive bacteria); 2 later colonization by gram-negative bacteria, e.g. Tannerella forsythus, Aggregatibacter (Actinobacillus) actinomycetemcomitans, Porphyromonas, Fusobacterium, and Treponema spp; gram-negative bacterial products including endotoxin and volatile sulfur products contribute to an inflammation response C. necrotizing ulcerative gingivitis and periodontitis 1. aka "trench mouth" and Vincent's angina 2. synergistic infections involving three pathogens: Treponema vincentii, Prevotella intermedia, and Fusobacterium nucleatum 22.3 Gastritis and gastric ulcers caused by bacteria A. Signs and symptoms 1. Gastritis: sharp or burning pain emanating from the abdomen 2. Gastric or duodenal ulcers (peptic ulcers) can be accompanied by bloody stools, vomiting, or both B. Helicobacter pylori 1. morphology - gram-negative, vibrio and spiral shaped with 6 polar-sheathed flagella (highly motile) 2. pathogenesis - urease → converts urea to ammonia; provides an alkaline microenvironment which protects the bacterium from gastric acids (especially during transit to mucosal cells); evidence indicates direct damage to tissue cells (histologic changes observed) when hydroxide ions are generated by equilibrium of ammonium with water; an inflammatory response also causes damage; urease acts as an antigen; patients with active gastritis show elevated levels of IgG and IgA - motility → for colonization (movement through mucus to the stomach lining), and helps resist the effects of peristaltic flushing - adhesins → adherence to epithelial cells; one receptor on human cells specific for the bacterium is the same molecule that confers the O blood type (higher rate of ulcers with this blood type) - LPS → contributes to inflammation - colonization of the lining of the stomach results in an inflammatory response with infiltration of mononuclear cells - may reside in stomach tissue and occasionally spread to the esophagus or other parts of the alimentary canal - lesions lead to deeper erosions and ulcers that can lead to cancer 3. Clinical manifestations - causes gastritis and gastric ulcers; it has been associated with gastric adenocarcinoma and gastric mucosa-associated lymphoid type (MALT) B-cell lymphomas. 4. epidemiology - humans are the primary reservoir (~25% carriage rate for healthy adults and 60% for adults >60 y.o.); infections are common, particularly in people in low socioeconomic class or in developing nations; thought to be primarily person-to-person transmission (oral-oral or fecal-oral); worldwide incidence is high 5. diagnosis - endoscopic exam for lesions and biopsy specimen; histologic exam of specimen is sensitive and specific; urease test is relatively sensitive and highly specific (biopsy specimen); noninvasive, urea breath test (UBT) uses labeled reagent and is sensitive and specific; blood test using ELISA is specific, but high carriage rate may require endoscopy as confirmation; fecal antigen test; see Fig. 22.9 3 6. treatment: antibiotics + acid suppressors 2.33. Acute bacterial diarrhea - Signs and symptoms associated with diarrhea may include frequent loose, watery stools, abdominal cramps, abdominal pain, fever, bleeding, and lightheadedness or dizziness from dehydration; recently in the U.S., rates are 1.2-1.9 cases/person/year; among children, rates are twice as high; in the U.S., ~30% of cases are transmitted by contaminated food; treatment is variable; most cases are self-limiting, others, e.g. shigellosis, require prompt antibiotic therapy A. Salmonella 1. general information: - member of the Enterobacteriaceae - gram-negative bacilli with flagella - more than 2,000 serotypes based on O and H antigens - the taxonomy of the genus is problematic; according to some, there are 2 species; S. enterica is the species that cause most human infections; S. enterica includes a number of variants (subspecies), variants paratyphi, hirschefeldii, and typhimurium cause most cases of salmonellosis (gastroenteritis); variant Arizona hinshawii occurs in reptiles; variant typhi causes typhoid fever 2. pathogenicity and clinical manifestations: - mechanisms - ability to grow within M cells of pyers patches and nonactivated macrophages is responsible for invasion and potential systemic spread; pathogenicity islands → for entry, adhesion, or invasion into the host; endotoxin - salmonellosis - ingestion of organisms; absorbed to epithelial cells in terminal portion of small intestine; bacteria penetrate cells and migrate to lamina propria layer (mucosa lining of the tract) of ileocecal region (last few inches of the ileum to the beginning of the cecum (large intestine)); multiply in lymphoid follicles causes reticuloendothelial hyperplasia and hypertrophy; PMNs confine infection to GI tract; inflammation mediates release of prostaglandins (prostaglandins hypothalmus inflammation and fever) which stimulates cAMP and active fluid secretion which results in diarrhea; other signs can include fever, vomiting, cramps, and blood in stool - septicemia - most often caused by variants cholerasuis and enteritidis; risk groups include children and immunocompromised individuals; bacteria are not contained within the GI tract; spread results in a prolonged disease with fever, chills, anorexia, and anemia; focal lesions can develop in any tissue, e.g. osteomyelitis, pneumonia, pulmonary abscess, or meningitis. - typhoid fever is caused by variant typhi; the first week of infection includes non-diagnostic signs of fever, lethargy, malaise, and constipation (not diarrhea); bacteria are penetrating the intestinal wall infecting the lymphatics and reticuloendothelial system; after intracellular replication, release of cells causes a prolonged bacteremia (2nd week); infection of the biliary system occurs, with a persisting bacteremia; an acute febrile illness may last 3-5 weeks; signs include fever of 38.50C, tender abdomen with perhaps rose-colored spots, diarrhea as bacteria re-infect the intestinal tract from the gallbladder; complications involve intestinal perforation, bleeding, and pneumonia. 3. epidemiology: a. salmonellosis: - one of the more common bacterial diseases in the U.S. (estimated 1.2 million infections each year; 53,800 cases reported in 2012); estimated that only 1 of every 10-20 cases are reported - contaminated food is a major source of bacteria, e.g. beef, poultry, rodents, peanut butter, eggs, 4 dairy products, and foods prepared on contaminated work surfaces - there is a large animal and rodent reservoir; cattle, chickens and rodents are major sources for the bacterium in the U.S.; also known to occur in some reptiles - a large number (106-8) of bacteria are required for development of symptomatic disease; this is the reason person-to-person transmission is not common. b. typhoid fever: see Fig. 22.10 - human carriers (gall bladder) are the only natural reservoir - contamination of water with human feces is the major mode of spread - infectious dose is low, so person-to-person spread is common - about 3% of those infected become chronic carriers; the carrier state may last weeks to years - in the U.S., 397 cases were reported in 2009; usually acquired during travel to endemic areas; it is a major health problem in developing countries. 4. diagnosis: a. for salmonellosis, isolation from fecal material (use selective media), biochemical identification, and serological tests (determine the O antigen); differentiation from Shigella includes Salmonella are motile and bile resistant, positive for H2S production and gas from fermentation b. for septicemia and typhoid fever, blood cultures during the first 2 weeks of illness; biochemical identification. 5. treatment and control: a. for salmonellosis replace fluid loss, and control pain, nausea, and vomiting; antibiotics prolong the carrier state and do not shorten the course of illness b. use antibiotics for septicemia and typhoid fever c. vaccine for poultry is used and has reduced incidence d. vaccines are available for typhoid fever and are effective, especially in children; used in locations where incidence is high e. control by reducing food and water contamination f. salmonellosis and typhoid fever are reportable diseases ________________________________________________________________ B. Shigella 1. general information: a. metabolism - characteristics which distinguish it from Salmonella are: nonmotile, no H2S, no gas during carbohydrate fermentation, and inhibited by high concentrations of bile b. member of the Enterobacteriaceae c. S. dysenteriae, S. flexneri, S. sonnei are the most well known species 2. pathogenesis and clinical manifestations: a. virulence factors: - shiga toxin (an enterotoxin) which demonstrates both cytotoxic and neurotoxic activity; it damages the mucosa and villi; local areas of erosion lead to bleeding and heavy secretion of mucus; an A-B toxin; A part binds to ribosomes and prevents protein synthesis - the ability to induce endocytosis and grow within and kill host cells. b. lesions develop in the intestinal tract in stages; bacteria penetrate the mucosal epithelial cells and eventually cause cell death; spread to adjacent epithelial cells, killing them and eroding the epithelium, resulting in ulcers; histologic changes in the tract can include mild 5 inflammatory reaction, micro-ulcers, and gross ulcers with sloughing of the epithelium; see Fig. 22.11 c. symptoms of shigellosis-bacillary dysentery (diarrhea with blood) - vary from asymptomatic infection to severe bacillary dysentery with high fever, chills, severe diarrhea (with cholera-like dehydration), abdominal cramps, blood and pus in stools, and perhaps convulsion; neutrophils in stool is indicative of an inflammation response, due to an invasive type of disease); the disease runs its course in about 10 days; bacillary dysentery is notable for high mortality among infants and aged and debilitated persons 3. epidemiology: a. humans are natural hosts b. direct fecal-oral route or mechanical vectors, e.g. fingers, feces, food, flies, and fomites; a low infective dose < 200 organisms) results in high communicability c. reservoirs are carriers; the carrier state is 1-4 weeks with some longer d. the majority of cases in the U.S. occur in children 1-10 y.o.a.; outbreaks usually occur in close groups, e.g. day-care centers, mental hospitals, nursing homes e. in the U.S. and other developed countries, S. sonnei is most common; 15,283 cases reported in U.S. in 2012; 8,965 cases in those 1-14 y.o.a. reported in 2012 4. diagnosis: a. loose stool containing mucus with bright red blood, which is unlike signs of salmonellosis or other enterotoxigenic bacteria; white cells can be observed with both shigellosis and salmonellosis b. fresh passed stool specimens for isolating the bacterium; if stored too long, acid in the feces will inhibit growth c. biochemical tests, e.g. triple-sugar-iron agar (TSI for H2S test and suger fermentations); serological tests. 5. treatment and control: a. treat dehydration and fever; all infections should be treated with antibiotics; shortens illness and decreases chances for transmission and does not prolong the carrier state like salmonellosis b. control includes a safe water supply, sewage treatment, and public information concerning proper handwashing; it is a reportable disease. 6. Case History: Shigella sonnei - The patient was a 4-year-old male who presented to the ER with a 2-h history of diarrhea, fever, irritability, and lethargy. The child had gone to sleep on the living room couch at 11 PM. His grandmother found him on the floor at 3 AM covered with feces. When she picked him up to carry him to the bathtub, she noticed he was febrile. She bathed him, and brought him to the ED. The patient's medical history was significant for his being in a group day care center. In the ED, he had 2 episodes of vomiting. His temp. was 38.90C, pulse 160 beats/min, and respiratory rate 36/min, and he was noted to be dehydrated. His stool contained bloody streaks and methylene blue stain of feces showed white blood cells. CSF examination, done because of lethargy, was within normal limits. Blood culture was negative and stool examination for ova and parasites was negative. Lab tests included cultivation on MacConkey agar, triple sugar iron (TSI), and motility medium. TSI was negative for H2S production and motility was negative. _____________________________________________________________________________________ 6 C. Escherichia 1. general information: a. member of the Enterobacteriaceae b. occur as normal flora of the intestinal tract c. cause many opportunistic and nosocomial infections d. morphology - in general, small gram-negative rods with fimbriae and flagella e. antigenicity - O, H, and K antigens are determined for epidemiological studies. 2. classification based on virulence factors (“virotyping”); 5 of the 6 known virotypes are: a. enterotoxigenic E. coli (ETEC) b. enterohemorrhagic E. coli (EHEC) c. shiga toxin producing E. coli (STEC) d. enteropathogenic E. coli (EPEC) e. enteroinvasive E. coli (EIEC) 3. pathogenesis and clinical manifestations: a. enterotoxigenic E. coli (ETEC) - infects the small intestine; 2 plasmid-mediated enterotoxins with activity similar to cholera toxin; they stimulate fluid and electrolyte loss; the primary cause of "traveler's diarrhea" (adults in areas where ETEC is endemic are at least partially immune, adults from non-endemic areas are susceptible); infant diarrhea (life-threatening) in less developed areas; watery diarrhea, cramps, nausea, low-grade fever. b. enterohemorrhagic E. coli (EHEC); aka shiga toxin-producing E. coli (STEC) - infects the large intestine; produces 2 cytotoxins = "verocytotoxins" (identical to shiga (Shigella) toxin; type III secretion system introduces bacterial products directly into gut epithelial cells; - may cause a wide spectrum of illnesses including mild-to-moderate diarrhea, hemorrhagic colitis (with severe abdominal cramps, watery diarrhea initially, followed by grossly bloody diarrhea, little or no fever), and hemolytic uremic syndrome (HUS) (most common serotype is O157:H7) - HUS → acute renal failure and thrombocytopenia; highest incidence in children < 5 years; death in 3-5% of patients; 30% of patients may experience sequelae which include renal impairment, hypertension, and CNS manifestations - foods of animal origin are probably the major sources of human infections, e.g. beef (particularly hamburger) c. enteropathogenic E. coli (EPEC) - most common in less developed countries; causes "epidemic infantile diarrhea" with fever, nausea, vomiting, and non-bloody stools; in the U.S., has caused outbreaks in hospital nurseries d. enteroinvasive E. coli (EIEC) - destroys epithelial cells lining the colon by invading (similar to Shigella, but unlike Shigella, no toxin production); causes fever, cramping, and watery diarrhea followed by development of dysentery with scant, bloody stools with mucus and PMNs; more common in less developed countries 3. epidemiology: vs. uv\-UJ*Verv^ 7 a. incidence is related to general sanitation; often occurs as traveler’s disease; often occurs as common source outbreaks; occurs in adults and as nosocomial infections in infants b. a number of O, H and K types occur; serological typing is important for epidemiological purposes; specific serotypes are associated with increased virulence, particularly for EHEC c. in the U.S., ~80,000 cases/year (travelers) of ETEC infection; route of transmission is generally not person-to-person, rather via contaminated food or water since the infectious dose is large; in developing countries an estimated 650 million infections occur most commonly in resident children d. in 2012, 6,463 cases of STEC were reported in the U.S. e. 274 U.S. cases of post-diarrheal hemolytic uremic syndrome caused by EHECwas reported in 2012; in the U.S., in addition to ground beef, transmission has included contaminated water, unpasteurized milk or fruit juices (e.g. cider made from apples contaminated with feces from cattle), uncooked vegetables, and fruits; see Fig. 22.12 4. diagnosis: a. when HUS is suspected, stool should be cultured on MacConkey-sorbitol agar; it is a selective medium (bile salts inhibit the growth of gram-positive bacteria) in which a pH indicator will reveal fermentation of sorbitol; unlike most strains of E. coli, EHEC does not ferment sorbitol; the test is used to differentiate normal flora E. coli from EHEC. b. PCR c. assay for enterotoxins or the presence of toxin genes on plasmids c. pulse-field gel electrophoresis, for epidemiology → (CDC); see Insight 22.3 5. treatment and control: a. antibiotic resistance is a problem; spread of resistance (R) factors is common among strains of the species b. for uncomplicated cases of gastroenteritis, no antibiotics are recommended; supportive therapy is recommended; antibiotics seem to prolong fecal carriage c. antibiotics should be used for long-term or chronic cases and for infants (except EHEC); also include supportive therapy d. EHEC - no antibiotics; antibiotics seem to increase the risk of developing HUS e. HUS - no antibiotics and no anti-motility agents; supportive therapy may include erythrocyte transfusions and dialysis f. prevent transmission by sanitation 6. Case: Escherichia coli O157:H7 (EHEC) - The patient was an 8-year-old male with a 2-day history of diarrhea. He presented with worsening diarrhea (14 movements that day) which had become bloody. He also complained of pain on defecation. He had vomited once. He had attended a cookout 6 days previously. He claimed that his mother made him eat a hamburger that was “pink inside” even though “he did not like it.” His physical examination was benign except for obvious dehydration. His laboratory findings were significant for a white blood cell count of 13,100/l with 9,700 neutrophils , a methylene blue stain of feces that showed abundant polymorphonuclear cells, and a positive stool guaiac. He was treated with intravenous fluids. No antibiotics or anti-motility drugs were administered. He improved and was discharged within 24 hours. Culture of his stool specimen was done using MacConkey-sorbitol agar. ___________________________________________________________________________ 8 D. Campylobacter 1. general information: a. C. jejuni is the most common cause of bacterial gastroenteritis in the U.S b. morphology: gram-negative, vibrio-like; in young cultures, may be comma-shaped, spiral, or S-shaped; pairs may appear as" wings of a seagull"; see Fig. 22.13 2. pathogenesis and clinical manifestations: a. its pathogenic mechanisms include LPS, an enterotoxin and flagella; bacteremia in some patients suggests tissue invasion; histologic damage to the mucosal surfaces of the jejunum, ileum, and colon occurs; the mucosal surface appears ulcerated, edematous and bloody and there are infiltrations of the lamina propria with neturophils, mononuclear cells, and eosinophils; inflammation is consistent with invasion of the organisms into the intestinal tissue. b. infection varies from asymptomatic to acute gastroenteritis, with fever, diarrhea (liquid, blood or both) and abdominal pain; duration is an average of 7 days; in compromised, older individuals, the disease may appear as an acute febrile bacteremia with inflammatory bowel disease and cause death. c. Guillain-Barre syndrome (GBS) - 20-40% of GBS cases are preceded by Campylobacter infections; only 0.1% of infections result in GBS; mechanism is unknown; sign includes acute paralysis 3. epidemiology: a. flora of mammals, e.g. pigs, cattle, dogs, cats, rabbits, and birds including poultry; contaminated water, milk, chicken, and other foods have caused large outbreaks, especially in developed countries b. currently, one of the leading causes of bacterial diarrhea worldwide; in the U.S., it is not a reported disease; there are estimates of 2 million infections/year in the U.S. c. individuals at risk are those exposed to large numbers of the organism and who lack gastric acids d. fecal-oral route and person-to-person also occur, but it is uncommon for the disease to be transmitted by food handlers 4. diagnosis - dark field microscopy; isolation and identification using biochemical tests; specialized media (Campy BAP), containing antibiotics to inhibit other fecal organisms is necessary; grows best at a reduced oxygen concentration and 420 C. 5. treatment and control: a. rehydration with electrolytes for mild cases; use antibiotics for more severe cases b. control by sanitation and interrupting transmission from contaminated food and water. ___________________________________________________________________ E. Yersinia - See Chapt. 20 notes, pp 3-4; 2 species, Yersinia enterocolitica and Y. pseudotuberculosis, are associated with GI tract disease; infections are notable for the high degree of abdominal pain (sometimes mistaken for appendicitis) 9 ___________________________________________________________________ F. Clostridium difficile - For general information concerning Clostridia, see Chapt. 18 notes, p.10 1. pathogenesis and clinical manifestations: a. pseudomembranous colitis is associated with the use of certain antibiotics, e.g. clindamycin, ampicillin, and cephalosporins; the strain of bacterium may or may not be resistant to the antibiotic; also the use of gastric acid inhibitors may predispose individuals to infection or over-growth by the bacterium b. other anaerobic flora is eliminated allowing overgrowth by the bacterium. c. the condition can begin within days after receiving the antibiotic or weeks after therapy is discontinued. d. 2 enterotoxins, toxins A and B, cause necrosis in the wall of the intestine e. manifestations range from diarrhea, colitis or pseudomembranous colitis, with cramps, fever, and leukocytosis; inflammation and necrosis results in release of membrane-like patches (pseudomembranes) containing fibrin and cells; continued necrosis can lead to perforation of the cecum and death can be a result; see Fig. 22.14 2. epidemiology: a. the source of the infecting strain can be either endogenous or exogenous. b. risk factors are primarily antibiotic exposure, older age, female sex, and impaired intestinal motility. c. incidence varies with the degree of hospital contamination with bacterial spores. d. recall, strains of Staphylococcus aureus have also been responsible for cases of antibiotic-associated colitis; see Chapt. 18 notes, p. 5 3. diagnosis - observing the pseudomembrane with a sigmoidoscope; identification of enterotoxins in stool specimens is indicative, but not diagnostic; isolation from stool is also indicative; use a combination of tests for a presumptive identification 4. treatment and prevention: a. untreated mortality rate for pseudomembranous colitis is high (27-44%); discontinue use of the implicated antibiotic and/or substitute other antibiotics; avoid drugs that slow intestinal motility; maintain fluid and electrolyte balance. b. donor stool transplants for treatment of recurrent C. difficile colitis; also probiotics in freeze dried capsules c. maintain hospital environments; infected individuals shed large number of spores in stool _____________________________________________________________________ G. Vibrio cholerae 1. general information - morphology is short, gram-negative, curved rods with a polar flagellum; natural habitat is marine or brackish water, it but can survive in fresh water; see Fig. 22.15 2. pathogenesis and clinical manifestations: 10 a. cholera toxin is an A-B type ADP-ribosylating toxin with 5 B subunits and 1 A subunit; intact toxin binds to GM1 gangliosides on host mucosal cells; A1 subunit is translocated into host cell cytoplasm where it ADP-ribosylates membrane protein, GS; GS regulates adenylate cyclase (controlling the amount of cAMP in the host cell); nonregulation causes cAMP levels to rise, disrupting the function of ion pumps and creating an ion imbalance that leads to diarrhea. b. the incubation period is hours to a few days; an abrupt onset with vomiting and diarrhea is characteristic; fluid loss may be 15-20 liters/day; voided fluid is watery with flecks of mucus, without odor (rice water diarrhea); shock and acidosis are consequences of fluid loss; the untreated mortality rate is greater than 60%. 3. epidemiology: a. known to cause widespread epidemics; primary route is fecal-oral; the possibility of spread to humans is increased because the bacterium survives well in fresh water as well as salt water. b. human carriers serve as reservoirs, (2 types):1. convalescent carriers shed bacteria for several months after the illness; 2. the chronic carrier is usually an older individual who carries the organism in the gallbladder and sheds it intermittently c. there is a theory of a permanent reservoir in selected estuaries and marshes in certain subtropical and tropical areas of the world, e.g. India, Bangladesh, and Gulf coast of the U.S.; the most recent pandemic which spread to South and Central America during the early 1990's and N. America during the mid-1990's has caused 1 million reported cases d. in the U.S., sporadic cases in the Gulf coast states occur; most cases involve contaminated seafood from Gulf waters; 17 cases were reported in the U.S. in 2012 For all Vibrio infections (vibriosis), 1111 cases were reported. 4. treatment and control: a. prompt replacement of fluid and electrolytes; see Insight 22.2 b. control with water purification and sewage treatment c. vaccination is effective in greater than 50% of individuals; the killed, whole cell vaccine does not confer long-lasting immunity; it may be used by travelers, but is not currently recommended (use antibiotic prophylaxis and /or appropriate hygiene) d. a reportable disease. _________________________________________________________________________ 2.33. Acute bacterial diarrhea with vomiting (food poisoning) A. Food poisoning caused by a preformed toxin B. Staphylococcus aureus - see Chapt. 18 notes p.4, V.B and p.5, IX.F; associated with eating food (custards, sauces, cream pastries, processed meats, chicken salad, ham) that have been contaminated by handling and then left unrefrigerated for a few hours; heating the food after toxin (toxin does not alter taste or smell) production may not prevent disease; symptoms include cramping, nausea, vomiting, diarrhea; recovery is rapid C. Bacillus cereus - related to Bacillus anthracis; see Chapt. 18 notes, p.11; 1. 2 clinical forms of food poisoning, mediated by 2 types of enterotoxins: 11 a. emetic form → incubation period of about 4 hours and is characterized by severe nausea and vomiting; a heat-stable enterotoxin is responsible; associated with consumption of contaminated rice (commonly fried rice) with preformed toxin (spores germinate in cooked rice and vegetative cells release enterotoxin); heating does not inactive it b. diarrheal form - the second type has an incubation period of about 16-18 hours and is characterized by abdominal cramps and diarrhea; a heat-labile enterotoxin is responsible; associated with contaminated meat or vegetables (foods kept warm for long periods); the enterotoxin is produced in situ (reason for the longer incubation period) D. Clostridium perfringens - see Chapt. 18 notes, p.10 _____________________________________________________________________ Paramyxovirus (Mumps) I. Taxonomy - Family – Paramyxoviridae; Sub Family – Paramyxovirinae; Genus – Rubulavirus; Species – Mumps virus II. Structure - Capsid: Helical; Genome: -ssRNA, linear; Enveloped: Yes III. What does this virus cause? Mumps. IV. How do I know if I have it? The mumps virus causes a benign parotitis (painful swelling of the parotid glands — one of three pairs of salivary glands, located below and in front of the ears). Onset is sudden. Fever, headache, muscle aches, tiredness, and loss of appetite is followed by swelling of salivary glands on one or both sides of the face, and pain with chewing or swallowing. However, only 30 – 40% of infections produce parotitis. 20 – 30% of infections are asymptomatic, and close to 50% of infections may show respiratory symptoms or non specific symptoms. Cell immunity controls infection & causes some of the symptoms; antibodies are NOT sufficient to control the virus because the virus spreads from cell to cell. V. Can it be dangerous? Most people with mumps recover fully. Complications may occur even if a person does not have parotitis and are more common in people who have reached puberty. 20 – 30% of postpubertal men who are infected may develop epididymo-orchitis following parotitis; sterility is only seen in 1 – 12% of these cases. 5 – 10% of mumps patients may show meningoencephalitis. 5% of adult females could develop oophoritis (inflammation of the ovaries) or mastitis (inflammation of breasts). In rare cases, mumps can lead to hearing loss, usually permanent, in one or both ears. Being infected with the mumps virus while pregnant (especially early on), can lead to miscarriage. VI. Laboratory Diagnosis cannot be done by clinical presentation (symptom based) alone since parotitis may be caused by other diseases (viral and non viral). Diagnosis is therefore done by: 1. Isolation of the virus from clinical specimens using continuous cell lines. Recommended sample is a throat swab. 2. RT-PCR for detection of mumps RNA (specimens include oral fluid, CSF, urine etc.). Recommended sample is a throat swab. 3. Analysis of paired sera to look for increase in IgG specific for the virus (paired sera are collected at least 2 to 3 weeks apart). 4. Indirect ELISA to look for specific IgM (when only 1 serum sample is available). VII. How can I give it to others? The virus is spread by inhalation of respiratory secretions / direct contact with respiratory secretions, saliva / fomites. In the absence of vaccination, infection occurs in 90% of people by the age of 15. The patient is considered non infectious and may safely return to work/school 1 week after a diagnosis of mumps. 12 VIII. When am I at risk of infection? Infection is seen worldwide and occurs predominantly in the spring. It usually affects unvaccinated 6 to 10 year olds. IX. How can I protect my family? A live, attenuated mumps vaccine (part of MMR). Do not share drinks or eating utensils with someone who has mumps. Disinfect surfaces that are frequently touched (such as toys, doorknobs, tables, counters, etc.) with soap and water or with cleaning wipes. Adequate hand hygiene will also help prevent picking up the virus from contact with other people or from contaminated surfaces. X. Is the MMR vaccine successful in preventing mumps? Mumps is limited to humans and there is only 1 serotype of this virus. However, we have seen cases of Mumps in previously vaccinated individuals. It is thought that the vaccine might elicit only a partial immune response against the WT strain. A more effective vaccine is required. X. How can I be treated? No specific antiviral drug is available for mumps. Mumps immunoglobulin does not offer protection from disease. Homework questions: Can you vaccinate a 6 month old infant about to go on a cruise? Can I get mumps more than once? ------------------------------------------------------------------------------------------------------------ Rotavirus I. Taxonomy - Family – Reoviridae; Genus – Rotavirus; Species – Rotavirus II. Structure - Capsid: Icosahedral; Genome: dsRNA, linear, segmented; Enveloped: No III. Introduction - The rotavirus is a non-enveloped virus with a triple-layered protein capsid and is resistant to detergents, drying and acidic pH. Viruses have a wheel like appearance. The genome is made of 11 segments of dsRNA. One of the proteins is a viral enterotoxin. These viruses have 7 distinct antigenic groups (A-G), of which 3 (A, B & C) are linked to human disease. Group A viruses are the major cause of rotavirus diarrhea worldwide. Group A viruses are further classified into G (Glycoprotein) and P (Protease sensitive) serotypes. Rotavirus disease can be severe in infants < 2 years. It is mostly seen in children less than 5 years of age. In the developing world, rotavirus is a major cause of death in children less than 5 years of age (~870,000 worldwide deaths annually). The disease can be asymptomatic in adults. The rotavirus is responsible for almost 50% of acute gastroenteritis illnesses both in developing countries and in the developed world. Subsequent infections are less severe. IV. What does it cause? Common agent of infant diarrhea (Human Infantile Gastroenteritis) V. How do I know if I have it? Symptoms include vomiting & watery diarrhea for 3 - 8 days. Fever & abdominal pain occur frequently. Immunity after infection is incomplete. The disease can be asymptomatic in adults. At risk of Rotavirus Type A infections are: Infants < 2 years of age: gastroenteritis with potential dehydration Older children and adults: at risk for mild diarrhea. Undernourished people: diarrhea, dehydration, death. VI. Lab Diagnosis: ELISA detection (in feces or rectal swabs) of rotavirus specific antigen, latex agglutination test for rotavirus and RT-PCR for rotavirus antigens. 13 Cell culture is not used because it is difficult to cultivate virus from clinical specimens. VII. How can I transmit virus to others? Virus is predominantly spread by the fecal-oral route. Respiratory transmission may also be possible. Asymptomatic shedding may occur. Virus can also be transmitted by fomites (it can withstand drying). Viruses may remain infectious for many months at room temperature!! VIII. When am I at risk of infection? Outbreaks in N. America occur annually during fall, winter and spring. Outbreaks in developing nations occur through the year. IX. How does the virus cause pathogenesis? The virus is relatively stable at room temperature and to detergents, a range of pH values (3.5 to 10) and even to repeated freezing and thawing. The rotavirus can survive the acidic conditions prevailing in the stomach. Infection of the columnar epithelial cells of the small intestine is followed by viral replication. As many as 1010 virions may be shed per gram of stool, during the illness. Immunity after infection can only lessen the severity of subsequent bouts of illness. Protective immunity requires presence of IgA in the gut lumen. X. How can I protect my family? The virus is inactivated by chlorine Proper hand washing will prevent transmission Cohorting infected infants for the duration of the illness important in prevention of transmission Vaccination (2 vaccines available). Two live, oral, attenuated vaccines against rotavirus infection: 1. Rotarix® (GlaxoSmithKline), FDA approved in April 2008. It shows an 85 % efficacy against severe rotavirus gastroenteritis (active against G1, 3, 4, 9). 2. RotaTeq® (Merck & Co., Inc.), licensed by USFDA in 2006. It shows a 98% efficacy against severe G1-G4 rotavirus gastroenteritis. NOTE: In March 2010, the FDA was made aware of the presence of Porcine circovirus (PCV) 1 in Rotarix and both PCV1 & PCV2 in RotaTeq. These viruses are not known to cause any infection or illness in people. The FDA has determined it is appropriate for clinicians and public health professionals in the US to use these vaccines as all available evidence supports the safety and effectiveness of both vaccines. The 1st licensed vaccine against rotavirus – Rotashield – was withdrawn in 1999 due to problems with increased intussusception. Rotarix and RotaTeq are beginning to be introduced in routine immunization programs in middle- and high- income countries. But historically, oral vaccines have been shown to perform differently in different regions of the world; unclear at this time if vaccine will have efficacy in 3rd world countries. The Lanzhou lamb rotavirus vaccine (LLR; Lanzhou Institute of Biomedical Products) is used in China only. XI. How can I be treated? No anti-viral therapy is available. Supportive therapy includes hydration and electrolyte supplementation. Fruit juices and soft drinks are not recommended due to their high glucose content, low sodium content and high osmolarity. ------------------------------------------------------------------------------------------------------------------------------ Noroviruses I. Taxonomy - Family - Caliciviridae; Genus - Norovirus; Species - Norwalk virus*** ***The noroviruses are small, round viruses and include the Norwalk virus, Norwalk-like viruses, caliciviruses, & other Small Round Structured Viruses (SRSV). 14 II. Structure - Capsid: Icosahedral; Genome: +ssRNA, linear; Enveloped: No III. Introduction - It is unclear at this time whether there is interspecies transmission of these viruses. Human noroviruses have been shown to bind to blood group antigens present in animal excretions. More data is needed before we can conclusively call this a zoonotic virus or not. Noroviruses are the most important non bacterial cause of acute gastroenteritis for all ages, worldwide. More than 80% of non bacterial gastroenteritis outbreaks and more than 50% of food-borne gastroenteritis outbreaks are due to noroviruses. Norovirus illness is also sometimes referred to as stomach flu, although not related to influenza. IV. How do I know if I have it? The symptoms of norovirus illness include nausea, sudden watery, non bloody diarrhea, with or without vomiting, and some stomach cramping. Sometimes people show additional symptoms of low- grade fever, chills, headache, muscle aches, and a general sense of tiredness. The incubation period is 24 to 48 hours. Illness often begins suddenly, and the infected person may feel very sick. In most people the illness is self-limiting with symptoms lasting for about 1 or 2 days. In general, children experience more vomiting than adults. Most people get better within 1 or 2 days, and they have no long-term health effects. Dehydration is usually only seen among the very young, the elderly, and persons with weakened immune systems. Norovirus can strike any population and outbreaks occur in households, communities, and institutions. V. How does the virus cause pathogenesis? Symptoms of norovirus illness usually begin about 1 to 2 days after ingestion of contaminated food, but they can appear as early as 12 hours after exposure. The many different strains of norovirus prevents lifelong immunity. Also, because of genetic differences, some people are more likely than others to get infected and develop more severe illness. Cruise ships are particularly vulnerable to norovirus infections because of frequent changes in the passenger population, relative crowding, & difficulty in adequate decontamination during short periods at shore. Fecal shedding can continue up to 2 – 3 weeks after resolution of symptoms. The fecal-oral route of transmission, the infectious dose (<100 viral particles), and the high environmental stability all aid the rapid spread of infection. VI. Lab Diagnosis: Clinical diagnosis Detection of viral RNA by RT-PCR (Samples: food, water, stool samples) and ELISA (serum). VII. How can I transmit the virus to others? Fecal-oral route Fomites Inhalation of infectious aerosols (created by vomit of infected person) Direct contact with an infected, symptomatic person (for example, when caring for the ill person, or sharing foods or eating utensils with the ill person). Persons working in day-care centers or nursing homes should pay special attention to children or residents who have norovirus illness. This is a highly contagious virus and can spread rapidly through these environments. The infectious dose is pretty low (<100 viral particles). VIII. When am I at risk of infection? Noroviruses are seen year round, although they are more common in the winter months (due to overcrowding indoors). IX. How can I be treated? No antiviral agents. No vaccine. X. How can I protect my family (Prevention and Control)? People infected with norovirus are contagious from the moment they begin feeling ill to at least 3 days (or 2 weeks) after recovery. 15 Good preventive steps include: Frequent hand washing Carefully wash fruits and vegetables Steam oysters before eating them. Clean and disinfect contaminated surfaces immediately after an episode of illness (using a bleach-based household cleaner) Wash contaminated clothing or linens with hot water and soap Discard any vomit and/or stool in the toilet and make sure that the surrounding area is kept clean Persons who are infected with norovirus should not prepare food while they have symptoms and for 3 days after they recover from their illness. There is no vaccine at the present time. ------------------------------------------------------------------------------------------------------------------------------- Astroviruses I. Taxonomy - Family - Astroviridae; Genus - Mamastrovirus; Species - Astrovirus II. Structure - Capsid: icosahedral (star-like morphology); Genome: +ssRNA, linear; Enveloped: No III. Introduction - Of the eight different antigenic types of astroviruses that have been identified, type 1 is the most commonly seen worldwide. IV. How do I know if I have it? Symptoms include diarrhea, vomiting, fever, malaise, and mild dehydration. Infection is frequently asymptomatic. V. When am I at risk of infection? In countries with temperate climates, the virus is seen in the winter months. Most infections occur in children under a year of age, suggesting lack of protection from maternal antibodies. Reinfections may be less severe due to cross immunity. Incidence is worldwide and primarily associated with pediatric disease. Most symptomatic infections are seen in children < 1 year old. As children get older, infections can be frequently asymptomatic. 60 – 90% of school kids have antibodies to these viruses. VI. Lab Diagnosis: Direct ELISA and RT-PCR Cell Culture VII. How can I be treated? There is no antiviral drug for treatment of this illness. There is no vaccine. Prevention and control rely on improved personal hygiene and proper disinfection of contaminated surfaces. ---------------------------------------------------------------------------------------------------------------------------------------- Non-polio enteroviruses are very common viruses, causing about 10 to 15 million infections in the US each year. Tens of thousands of people are hospitalized each year for illnesses caused by enteroviruses. I. Taxonomy - Family – Picornaviridae; Genus – Enterovirus; Species – Coxsackie virus / Echovirus / Enterovirus II. Structure - Capsid: Icosahedral; Genome: +ssRNA, linear; Enveloped: No III. Introduction – Although anyone can get infected with non-polio enteroviruses, infants, children, and teenagers are more likely to do so (because of lack of immunity from previous exposures). IV. How do I know if I have it? Most people who get infected with non-polio enteroviruses do not get sick, or, have mild illness, like the common cold. Symptoms of mild illness may include: fever runny nose, sneezing, cough 16 skin rash mouth blisters body and muscle aches Infants and immunocompromised individuals have a greater chance of having complications (see below). V. Is it dangerous? Some non-polio enterovirus infections can cause viral conjunctivitis, hand, foot, and mouth disease, viral meningitis viral encephalitis myocarditis (People who develop myocarditis may have heart failure and require long term care.) pericarditis acute, flaccid paralysis inflammatory muscle disease (slow, progressive muscle weakness). Some people who develop encephalitis or paralysis may not fully recover. Neonates infected with non-polio enterovirus may develop sepsis, but this is very rare. Non-polio enterovirus infections may also play a role in the development of type 1 diabetes in children. VI. How can I transmit virus to others? By having close contact with an infected person; by fomite transmission. Non-polio enteroviruses can be found in an infected person's feces, eyes, nose, and mouth secretions (such as saliva, nasal mucus, or sputum), or blister fluid. Non-polio enterovirus can be shed in stool for several weeks or longer after infection. The virus can be shed from patient’s respiratory tract for 1 to 3 weeks or less. Infected people can shed the virus even if they don't have symptoms. VII. Is it seasonal? In the US, people are more likely to get infected in the summer and fall. VIII. How can I protect my family? Washing your hands often with soap and water, especially after using the toilet and changing diapers, Avoiding close contact, such as touching and shaking hands, with people who are sick, and Cleaning and disinfecting frequently touched surfaces. There is no vaccine and no antiviral drugs for treatment. IX. Have we seen this in the US? Outbreaks of Various Non-Polio Enteroviruses Coxsackievirus A16 is the most common cause of hand, foot, and mouth disease (HFMD) in the US. Coxsackievirus A6 was the most commonly reported type of enterovirus in the US from 2009 to 2013, mostly due to a large outbreak in 2012 of severe hand, foot, and mouth disease. Some of the infected people developed symptoms that were more severe than usual. Coxsackievirus A24 and enterovirus 70 have been associated with outbreaks of conjunctivitis. Echoviruses 13, 18, and 30 have caused outbreaks of viral meningitis in the US. Enterovirus 71 has caused large outbreaks of HFMD worldwide, especially in children in Asia. Some infections from this virus have been associated with severe neurologic disease, such as brainstem encephalitis. Enterovirus D68 caused a nationwide outbreak in 2014 of severe respiratory illness in the US. As of August 15, Singapore reported more than 18,000 cases of HFMD in 2015. Japan reported more than 264,500 cases this year as of August 19. CDC recommends that travelers to Singapore or Japan follow recommendations for hygiene and cleanliness to avoid HFMD. ------------------------------------------------------------------------------------------------------------------------------- 17 Hepatitis A, B, C, D, and E I. Introduction - Although these viruses all target the liver, they are different in structure, mode of replication, means of transmission, and in the time course and sequelae of disease. Each of the viruses infects and damages the liver resulting in a release of liver enzymes and the development of the classic icteric symptoms: jaundice, dark urine and clay colored stools. Since clinical presentation of infection with these viruses is similar in the acute phase, differential diagnosis depends on specific tests for each virus. A B C D E Picornaviridae Hepadnaviridae Flaviviridae Viroid like Hepeviridae RNA DNA RNA RNA RNA Naked Enveloped Naked aka Infectious hepatitis Serum nonA nonB hepatitis post transfusion hepatitis Delta agent Enteric nonA nonB hepatitis Fecal-oral & sexual transmission Parenteral, sexual transmission Fecal-oral Not chronic/ carrier Chronic/ carrier Not chronic/ carrier No other diseases Primary hepatocellular carcinoma, cirrhosis Cirrhosis, fulminant hepatitis No other diseases Diagnosis by symptoms & -HAV IgM Symptoms, serum levels of Ags, - HBcIgM Symptoms, -HCV ELISA -HDV ELISA Diagnosis by symptoms & -HEV ELISA HAV is the most common cause of acute hepatitis and HCV is the most common cause of chronic hepatitis. Acute infection may range from subclinical to self-limited, symptomatic to fulminant disease. Hepatitis A & E viruses may also be called waterborne hepatitis viruses, while hepatitis B, C & D viruses may also be called blood borne hepatitis viruses. Hepatitis that persists longer than 6 months is called chronic. Liver damage is not due to cytopathic effects of the viruses, but rather due to immune mediated attack on infected hepatocytes. The liver is essential to life. If the liver fails, a person can live only a day or two. But if even as much as 75 - 80 % of it is removed or destroyed acutely in a healthy individual, the liver will grow new, healthy liver cells and continue to function. Hepatitis A Virus I. Taxonomy - Family – Picornaviridae; Genus – Hepatovirus; Species – Enterovirus 72 or Hepatitis A virus II. Structure - Capsid: Icosahedral; Genome: +ssRNA, linear; Enveloped: No There is only one serotype of HAV. III. How do I know if I have it? Clinical syndromes include Fever, Fatigue, Nausea Loss of appetite Abdominal pain Jaundice seen in 70-80% adults (only 10% kids < 6yrs) complete recovery seen 99% of the time severe hepatitis is associated with 80% mortality rate IV. Lab Diagnosis is symptom based and on ELISA detection of anti-HAV IgM. 18 V. How can I transmit virus to others? HAV is spread by the fecal-oral route. The virus is ingested and probably enters the bloodstream through the oropharynx or the intestines. Once HAV reaches Kupffer cells of the liver, it replicates there, is released into the bile and from there into the stool. Ingestion of fecal matter from the following sources can result in transmission of the virus: ingesting contaminated food or water, sharing contaminated utensils, and sexual contact with an infected person. Since sexual transmission of HAV during sexual activity probably occurs due to fecal-oral contact, using condoms does not prevent HAV transmission. Transmission is enhanced by poor personal hygiene and overcrowding. Even though viremia occurs early in infection and can persist for several weeks after onset of symptoms, transmission via blood is uncommon. HAV causes mild disease (it is not cytolytic) It is shed into stool ~10-14 days before symptoms It cannot initiate a chronic infection Antibody protection is lifelong It is NOT associated with hepatic cancer VI. When am I at fear of contracting this illness? Transmission is through the fecal-oral route. The virus is spread through contaminated water (fresh or saltwater) or food, and by dirty hands. Shellfish are easily contaminated if sewage is not treated properly. Most outbreaks in the U.S. have occurred after eating in restaurants. In about half the cases, an employee of the restaurant was known to have been infected and did not follow proper hand hygiene. The other half of the cases were due to contaminated food product being delivered to the restaurant from the distributor. At risk are people in overcrowded, unsanitary areas. Day care centers are a major source of HAV. Mild disease seen in children, while adults show abrupt-onset hepatitis. HAV is found worldwide and there is NO seasonal incidence. VII. Immunity: As with other RNA viruses, interferons limit replication of HAV as well. However, recent studies show that the HAV protease precursor cleaves an essential component of the interferon signaling pathway, thereby reducing the type I interferon response. Natural killer cells and cytotoxic T cells kill infected cells. Antibodies, antibody-dependent cell mediated toxicity and complement all facilitate viral clearance. Antibody protection is life long. VIII. How can I protect my family? There is an FDA approved killed vaccine. Since there is only 1 serotype and HAV infects only humans, this vaccine gives successful immunization. Studies show the presence of neutralizing antibodies as long as 9 years after vaccination. Studies have also shown an 80% efficacy in prevention of clinical illness if HAV vaccine is given to household members of infected individuals, within two weeks of exposure to the virus. Boiling water is an effective means of destroying HAV; chlorine and iodine are also effective. Immune serum globulin given within 2 weeks of exposure can prevent clinical illness. Recommendations for HAV vaccination: All children at age 1 year (i.e., 12–23 months) Children and adolescents ages 2–18 who live in areas of high disease incidence Persons traveling to or working in countries that have high or intermediate rates of HAV, Intravenous drug abusers, Military personnel, Male homosexuals, Persons with liver disorder, Persons with clotting disorders, and those in contact with an active case. HAV vaccines include: Havrix, Vaqta, Epaxal, Avaxim, and Healive. All hepatitis A vaccines are made from virus grown in human diploid cells; the final formulations of the vaccines differ. Havrix® (GlaxoSmithKline) and Vaqta® (Merck & Co., Inc), are currently licensed in the US. Maybe HepA clears 99% of time because it doesn't infect hepatocytes? 19 Epaxal is the only HAV vaccine that is Aluminum free. It is a virosomal vaccine where formalin inactivated HAV is adsorbed to the surface of special liposomes (virosomes), that replace aluminum hydroxide as the adjuvant. Twinrix (GlaxoSmithKline) is a combined HAV, HBV vaccine that includes Havrix (Hepatitis A Vaccine, Inactivated) and Engerix-B (recombinant Hepatitis B Vaccine). All are inactivated vaccines. IX. How can I be treated? There is no antiviral treatment. Immune serum globulin given within 2 weeks of exposure can prevent clinical illness. It is important to engage in prevention mechanisms: prevent the fecal-oral route of transmission of HAV avoid potentially contaminated food or water, hand washing is crucial chlorine treatment kills the virus --------------------------------------------------------------------------------------------------------------------------- Hepatitis B virus I. Taxonomy - Family – Hepadnaviridae; Genus – Orthohepadnavirus; Species – Hepatitis B virus II. Structure - Capsid: Icosahedral; Genome: partially dsDNA, circular; Enveloped: Yes III. Introduction - The Hepatitis B virion includes DNA, a reverse transcriptase enzyme, a core antigen and specific hepatitis B glycoproteins (HBAg). The virus uses RT and an RNA intermediate, to generate multiple copies of the DNA genome. The virus is called Dane particle after the scientist who discovered it. The virus core is surrounded by the capsid containing core antigens (c and e) and the envelope containing the HBsurface antigen (HBsAg). HBsAg is immunogenic. HBsAg in serum can bind to and block the action of neutralizing antibody, thereby preventing the host from resolving the infection. Hepatitis due to HBV may be called blood borne hepatitis, serum hepatitis or long- incubation hepatitis. There is only 1 serotype of the virus. IV. How do I know if I have it? HBV may cause asymptomatic or severe disease. This primarily depends on one’s immune response to the infection. The thought is that the progression to chronic infection is due to a weak T-cell response to viral antigens. Chronic infections may cause permanent damage to the liver. Symptoms may include fever, malaise, anorexia, nausea, vomiting, abdominal discomfort, chills, jaundice (yellowing of the skin, eyes, mucus membranes). Symptoms begin on an average of 90 days (range: 60–150 days) post exposure to HBV. V. Diagnosis is based on Symptoms, Elevated liver enzymes Serological profile of antibodies against HBsAg, HB core Ag Ground-glass hepatocyte cytopathology being a histological hallmark of chronic HBV infection. Hepatitis B Serological markers that aid in diagnosis: 1. Hepatitis B surface antigen (HBsAg): detected in high levels in serum during acute or chronic HBV infection 2. Hepatitis B surface antibody (anti-HBs): presence indicates recovery and immunity from HBV infection. Anti-HBs is also seen in a person who has been successfully vaccinated against Hepatitis B. 3. Total Hepatitis B core antibody (anti-HBc): will appear at the onset of symptoms in acute Hepatitis B and persists for life. Presence of anti-HBc indicates previous or ongoing infection with HBV in an undefined time frame. 4. IgM antibody to Hepatitis B core antigen (IgM anti-HBc): Presence indicates recent infection with HBV; presence indicates acute infection. 20 5. Hepatitis B e antigen (HBeAg): This is a secreted product of the nucleocapsid gene of HBV. It is found in serum during acute and chronic Hepatitis B. Presence indicates that the virus is replicating and the infected person has high levels of HBV. 6. Hepatitis B e antibody (anti-HBe): Produced temporarily during acute HBV infection, or consistently during or after a burst in viral replication. The spontaneous conversion from presence of e antigen to presence of e antibody (a change known as seroconversion) is a predictor of long-term clearance of HBV in patients undergoing antiviral therapy and indicates lower levels of HBV. HBsAg will be detected in an infected individual’s blood an average of 4 weeks (range: 1–9 weeks) post exposure to HBV. About 50% of the patients will be noninfectious by 7 weeks after onset of symptoms. All patients who do not remain chronically infected will be HBsAg-negative by 15 weeks after onset of symptoms. Refer to the table below for interpretation of HepB diagnostic markers: Tests Results Interpretation HBsAg anti-HBc anti-HBs Susceptible HBsAg anti-HBc anti-HBs + + Immune due to natural infection HBsAg anti-HBc anti-HBs + Immune due to Hepatitis B vaccination HBsAg anti-HBc IgM anti-HBc anti-HBs + + + Acutely infected HBsAg anti-HBc IgM anti-HBc anti-HBs + + Chronically infected HBsAg anti-HBc anti-HBs + Interpretation unclear; 4 possibilities: Resolved infection (most common) False-positive anti-HBc, thus susceptible "Low level" chronic infection due to undetectable level of HBsAg in serum Resolving acute infection (with low level of anti-HBs in serum) Table taken from the CDC Website: http://www.cdc.gov/hepatitis/HBV/HBVfaq.htm VI. How can I transmit virus to others? Neonatal from Mother’s Infected Blood Sexual Activity (50% of Cases) Intravenous Drug Use (20% of Cases) This virus is not spread via food or water, sharing eating utensils, breastfeeding, hugging, kissing, hand holding, coughing, or sneezing. At risk are people from endemic regions (China, Alaska, parts of Africa, Pacific Islands) Babies of Moms with chronic HepB IV drug users People with multiple sex partners People needing blood and blood product treatments Health care personnel 21 In the US, prevalence is higher in Asians, Native Americans, and African-Americans, with rates between 12 - 17%, while Caucasians and Mexicans have a lower prevalence rate of ~ 3% each. VII. How can I protect my family? HBV is an enveloped virus and consequently is rapidly inactivated by acids and lipid solvents. It is unique among the enveloped viruses in that it is relatively heat stable and may persist in dried blood and other biological fluids for several days. Prevention of exposure in occupational setting is based on the assumption that any person could harbor HBV, necessitating the need for strict infection control policies. Two single-antigen vaccines and three combination vaccines are currently licensed for use in the US. The single-antigen Hepatitis B vaccines include Engerix-B® (GlaxoSmithKline) and RecombivaxHB® (Merck). The combination vaccines include: Comvax®, Pediarix® and Twinrix®. Comvax®: Combined Hepatitis B-Haemophilus influenzae type b (Hib) conjugate vaccine. Pediarix®: Combined Hepatitis B, diphtheria, tetanus, acellular pertussis (DTaP), and inactivated poliovirus (IPV) vaccine. Twinrix®: Combined Hepatitis A and Hepatitis B vaccine. The vaccines are Recommended for infants, children, & people in high risk groups Given in a series of 3 injections (IM); contains HBsAg (subunit vaccine) Single serotype of HBV & limited host range ensures success of immunization Studies indicate that vaccine induced immunologic memory remains intact for at least 20 years among healthy vaccinated individuals who initiated Hepatitis B vaccination >6 months of age. VIII. How can I be treated? The goal of treatment in patients with chronic HBV is to reduce the risk of progressive chronic liver disease, transmission to others, and long-term complications from chronic HBV (cirrhosis and hepatocellular carcinoma). Approved Hepatitis B Drugs in the US: 1. Interferon-alpha (Intron A) is given by injection several times a week for 6 months to a year, or sometimes longer. The drug can cause side effects such as flu-like symptoms, depression, and headaches. Approved in 1991 and available for both children and adults. It cannot be used in patients with decompensated disease. The main role of interferon is primarily treatment of young patients with well compensated liver disease who do not wish to be on long- term treatment or who are planning to be pregnant within the next 2 – 3 years. 2. Pegylated Interferon (Pegasys) is given by injection once a week usually for 6 months to a year. It can cause side effects such as flu-like symptoms, depression and other mental health problems. Approved May 2005 for adults. 3. Lamivudine (Epivir-HBV, Zeffix, or Heptodin) is a pill that is taken once a day, with almost no side effects, for at least one year or longer. The possible development of hepatitis B virus mutants during and after treatment is a concern. Approved in 1998 and available for both children and adults. Compared to adefovir, lamivudine has more rapid and more potent suppression of hepatitis B virus, but entecavir, telbivudine, and tenofovir are superior to lamivudine in suppressing viral replication. The main disadvantage of lamivudine is its high rate of drug resistance. 4. Adefovir dipivoxil (Hepsera; nucleoside analog) is a pill taken once a day, with few side effects, for at least one year or longer. Kidney problems can occur while taking the drug and is a concern, but are reversible once the drug is stopped. Approved September 2002 for adults. Pediatric clinical trials are being planned. 22 The main advantage of adefovir is its activity against lamivudine-resistant virus and a lower rate of drug resistance compared to lamivudine. However, adefovir at high doses has been associated with nephrotoxicity. The most important role of adefovir is in the treatment of patients with lamivudine-resistant HBV. 5. Entecavir (Baraclude) is a pill taken once a day, with almost no side effects for up to one year. It is considered to be the most potent oral antiviral drug for chronic hepatitis B to date. Approved April 2005 for adults. Pediatric clinical trials may be planned for the future. The main advantages of this drug are its potent antiviral activity and a low rate of drug resistance. 6. Telbivudine (Tyzeka, Sebivo) is a pill taken once a day, with almost no side effects for up to one year. Studies have shown that it rapidly and profoundly suppresses HBV levels. Approved October 2006 for adults. The drug appears to have slightly more potent antiviral effects compared with lamivudine and adefovir but it selects for the same resistant mutants as lamivudine and is also more costly. 7. Tenofovir disoproxil fumarate (Viread, TDF) has potent in vivo and in vitro activity against both HIV and HBV. The drug has more potent antiviral activity than adefovir and is effective in suppressing wild-type as well as lamivudine-resistant HBV. It was initially licensed in 2001 for use against HIV infection, and in 2008 it received FDA approval for HBV treatment. Dosage is PO 300 mg/day. The optimal duration of therapy for chronic hepatitis B is unknown at this time. It may be used as 1st line treatment in treatment-naïve patients, and in patients with lamivudine, telbivudine or entecavir resistance, preferably as additional treatment in these patients. The goal of treatment is HBeAg seroconversion. Patients with HBeAg seroconversion and in whom serum HBV DNA has become undetectable should be treated for at least 12 more months after HBeAg seroconversion confirmation (by testing on two occasions at least two months apart) to reduce the rate of relapse. ~50% of patients enrolled in clinical trials achieve HBeAg seroconversion after five years of treatment. Most patients with HBeAg- positive chronic hepatitis will require several years of treatment. All patients are closely monitored after discontinuation of treatment as viral relapse could lead to hepatitis flares and hepatic decompensation. Treatment can be continued in patients with viral suppression but have not seroconverted as HBeAg seroconversion may occur in subsequent years. IX. Homework questions: Can it be dangerous? How can I transmit virus to others? ------------------------------------------------------------------------------------------------------------ Hepatitis D Virus / the delta virus I. Taxonomy - Viroid like satellite virus; Genus – Deltavirus; Species - Hepatitis D virus II. Structure - Capsid: No; Genome: -ssRNA, circular; Enveloped: Yes III. Introduction - HDV needs Hepatitis B virus (HBV) to cause an infection. HBV provides the envelope glycoproteins (HBsAg). Prevention of HBV will also prevent HDV infections. HDV is the smallest human pathogen known so far. The viral RNA has ribozyme activity. IV. How can I transmit virus to others? Transmission is via blood, semen, vaginal secretions. V. How do I know if I have it? The delta agent exacerbates the acute HBV infection resulting in the progression to a chronic state. HDV can also give rise to a condition of chronic hepatitis that includes hepatic encephalopathy and massive hepatic necrosis (80% fatality!). 23 VI. Diagnosis is by RT-PCR (detects HDV genome in blood) and ELISA for detection of antibodies against HDV. VII. How can I be treated? Prevention of HBV infection prevents HDV Treatments that lead to HBV resolution will also result in HDV resolution An HBV infected person can prevent infection with HDV by avoiding HDV- contaminated blood products No immunoglobulin or vaccine available against HDV, but HBV vaccine will indirectly protect against HDV ------------------------------------------------------------------------------------------------------------ Hepatitis C Virus I. Taxonomy - Family – Flaviviridae; Genus – Hepacivirus; Species – Hepatitis C virus II. Structure - Capsid: Icosahedral; Genome: +ssRNA, linear; Enveloped: Yes The virus was identified as the causative agent for non-A, non-B hepatitis in 1989. Hepatitis C virus (HCV) infection is the most common chronic bloodborne infection in the US, with ~ 3.2 million chronically infected individuals. III. How do I know if I have it? Acute infection with HCV is often asymptomatic and may go undiagnosed. Clinical symptoms when present are mild. The clinical significance of HCV infections lies in its ability to persist in the liver and set up a chronic infection predisposing the liver to cirrhosis and carcinoma. Although chronic HCV infections progress slower than chronic HBV infections, the long term consequences of HCV infections are more severe. IV. Diagnosis is by ELISA to detect antibodies against HCV and by RT-PCR to detect virus RNA. V. Can it be dangerous? Yes. HCV infects Hepatocytes and is able to remain cell associated and prevent cell death. Progression to liver disease occurs in 85% of patients. Continual liver repair predisposes to carcinoma. VI. How can I transmit virus to others? Transmission occurs via blood products and organ transplants Shared Needles Tattooing Body piercing circumcision in developing countries Less frequently sex & perinatal transmission VII. How can I be treated? Treatment has 2 goals: 1.to achieve sustained eradication of HCV [ie, a sustained virologic response (SVR*)]; 2.to prevent progression to cirrhosis, hepatocellular carcinoma, and decompensated liver disease necessitating liver transplantation. *SVR is defined as the persistent absence of HCV RNA in serum ≥6 months after completing antiviral treatment. An SVR is associated with a 97 – 100% chance of being negative for HCV RNA during long-term follow-up and can therefore be considered cure of the HCV infection. Treatment options may include: 1. Alpha-2 interferon alone, 2. Alpha-2 interferon in combination with Ribavirin. The combination is marketed in Europe as Rebetron. Patients with normal or minimal increases in ALT serum levels should be spared the interferon treatment—it may actually be harmful to the patient. Hemolytic anemia is a side-effect of Ribavirin treatment (monitor hemoglobin levels!). 3. Boceprevir (Victrelis) and Telaprevir (Incivek), Protease inhibitors, FDA approved in May 2011. 24 4. Simeprevir (Olysio), Protease Inhibitor, FDA approved in Nov 2013. Olysio is intended for adults with compensated liver disease (a diseased liver that is still functioning), including cirrhosis, who have not received treatment for their infection (treatment naïve) or for whom previous treatment has not been effective (treatment experienced). 5. Sofosbuvir (Sovaldi) is a nucleotide analog inhibitor of HCV NS5B polymerase (nucleotide analog inhibitor), FDA approved Dec 2013. 6. Harvoni (Ledipasvir-Sofosbuvir), 1st combination pill FDA approved in Oct 2014. Ledipasvir is an inhibitor of the HCV NS5A protein, which is involved in viral replication, assembly, and secretion. 7. Viekira Pak (ombitasvir, paritaprevir and ritonavir tablets co-packaged with dasabuvir tablets), FDA approved in Dec 2014. Viekira Pak contains 3 new drugs—ombitasvir, paritaprevir and dasabuvir that work together to inhibit HCV. It also contains ritonavir, a previously approved drug, which is used to increase blood levels of paritaprevir. Viekira Pak can be used with or without ribavirin, but it is not recommended for patients whose liver is unable to function properly (decompensated cirrhosis). Ombitasvir is a NS5A inhibitor, Paritaprevir is a NS3/4A protease inhibitor, and Dasabuvir 250mg is a non- nucleoside NS5B polymerase inhibitor. In the US, HCV genotype 1 is more prevalent than genotypes 2 and 3, with genotype 2 comprising ~ 15% of infections and genotype 3 representing < 10% of infections. Genotypes 2 and 3 are more common in Europe and SE Asia. The following treatment strategies are indicated in treatment-naïve or treatment experienced patients: Harvoni (ledipasvir-sofosbuvir) Viekira Pak (ombitasvir-paritaprevir-ritonavir plus dasabuvir) with or without ribavirin, and simeprevir plus sofosbuvir. The choice of drug(s) depends primarily on the potential for drug interactions and drug toxicity (eg, if the addition of ribavirin is warranted). If cost or insurance coverage is not an issue, ledipasvir-sofosbuvir is recommended, due to its favorable adverse effect profile, minimal drug interactions, and ease of administration (a single pill once daily). In patients who have failed prior treatment with a protease inhibitor-containing regimen (ie, simeprevir, telaprevir, or boceprevir plus peginterferon and ribavirin), Harvoni (ledipasvir-sofosbuvir) is recommended. If a patient has failed one protease inhibitor, treatment with another protease inhibitor (eg, paritaprevir or simeprevir) is not recommended due to likely resistance development and thus subsequent treatment failure. Patients with prior sofosbuvir-based regimen failure can be successfully retreated with a ledipasvir-sofosbuvir regimen (based on results of small studies). Patients who have failed prior sofosbuvir plus ribavirin with or without peginterferon and cannot wait for additional data (ie, in patients with advanced liver disease who are deemed to warrant imminent treatment), are retreated with ledipasvir-sofosbuvir plus ribavirin for 24 weeks. ---------------------------------------------------------------------------------------------------------------------------- Hepatitis E Virus I. Taxonomy - Family – Hepeviridae; Genus – Hepevirus; Species – Hepatitis E virus II. Structure - Capsid: Icosahedral; Genome: +ssRNA, linear; Enveloped: No III. Introduction - Hepatitis E virus (HEV) is also known as “enteric non A, non B.” Like HAV, HEV is spread via the fecal/oral route and is transmitted through contaminated water. The mortality rate is higher than that with HAV, 25 with pregnant women at a significant risk, nearly 30% in the 3rd trimester of pregnancy! This is due to a rapid onset fulminant hepatitis. It is most problematic in developing countries. Epidemics have been reported in India, Pakistan, Nepal, Burma, North Africa and Mexico. No immunoglobulins available for pre- or post-exposure prophylaxis. No FDA approved vaccine exists currently. However, there has been a reliable candidate that elicits over 95% immunological response in recipients (> 95% vaccine efficacy). The vaccine has been licensed for use in China. In rare cases, acute hepatitis E can progress to fulminant hepatitis (acute liver failure) and death. Overall population mortality due to hepatitis E range from 0.5% to 4.0%. Hepatitis E should be suspected in outbreaks of waterborne hepatitis occurring in developing countries, especially if the disease is more severe in pregnant women, or if hepatitis A has been excluded. IV. Lab Diagnosis: Infections are clinically indistinguishable from HAV and are self limiting. There has been a recent development of an ELISA for detection of HEV IgM. V. How can I transmit virus to others? mainly through fecal-oral route (drinking water) ingestion of products derived from infected animals transfusion of infected blood products, and vertical transmission from a pregnant woman to her fetus. The ingestion of raw or uncooked shellfish has also been identified as the source of sporadic cases in endemic areas. Although humans are considered the natural host for the hepatitis E virus, antibodies to this virus or closely related viruses have been detected in primates and several other animal species. The risk factors for hepatitis E are poor sanitation in large areas of the world and shedding of the virus in feces. VI. Prevention of infections is the most effective approach. VII. Is HEV a zoonotic virus? Researchers have shown a close relation between most human isolates of HEV and swine isolates detected in non-endemic countries. There have been hepatitis cases in Japan resulting from consumption of HEV-infected pig or deer meat. HEV is unique among the known hepatitis viruses, in that it has an animal reservoir. Pigs and other mammalian animal species infected by HEV generally remain asymptomatic, while chickens infected by avian HEV may develop a disease known as Hepatitis-Splenomegaly syndrome. HEV genotypes 1 and 2 are found only in humans. HEV genotypes 3 and 4 are found in humans and other mammals. Individuals with direct contact with animals are at higher risk of HEV infection. ------------------------------------------------------------------------------------------------------------------------------- 26 Disease Mumps Gastroenteritis Gastroenteritis Gastroenteritis Many (see comments below) Family Paramyxoviridae Reoviridae Caliciviridae Astroviridae Picornaviridae Subfamily Paramyxovirinae Genus Rubulavirus Rotavirus Norovirus Mamastrovirus Enterovirus Species Mumps virus Rotavirus Norwalk virus Astrovirus Capsid Helical Icosahedral Icosahedral Icosahedral Icosahedral Genome -ssRNA, linear dsRNA, linear, segmented (11 segments) +ssRNA, linear +ssRNA, linear +ssRNA, linear Envelope Yes No No No No Vaccine Yes Yes No No No Comments Complications include orchitis, or oophoritis, or mastitis etc. responsible for ~50% of acute gastroenteritis illnesses in the world. most important non bacterial cause of acute gastroenteritis for all ages, worldwide viral conjunctivitis, hand, foot, and mouth disease, viral meningitis viral encephalitis myocarditis pericarditis acute, flaccid paralysis inflammatory muscle disease severe respiratory illness (2014 outbreak in the US) by Enterovirus D68 Disease Hepatitis Family Picornaviridae Hepadnaviridae Flaviviridae Viroid like Hepeviridae Genus Hepatovirus Orthohepadnavirus Hepacivirus Deltavirus Hepevirus Species Hepatitis A virus Hepatitis B virus Hepatitis C virus Hepatitis D virus Hepatitis E virus Capsid Icosahedral Icosahedral Icosahedral No Icosahedral Genome +ssRNA, linear partially dsDNA, circular +ssRNA, linear -ssRNA, circular +ssRNA, linear Envelope No Yes Yes Yes No Vaccine Yes Yes No No Yes (not FDA approved) Comments There is only one serotype of HAV. There is only one serotype of HBV. Viral RNA has ribozyme activity. 1 Bacterial/Viral Diseases Affecting the Genitourinary System (Chapter 23) 23.1. The Genitourinary Tract and Its Defenses A. Reproductive system 1. Male reproductive system produces, maintains, and transports sperm cells; see Fig. 23.2 a. Consists of testes, epididymis, vas deferens, prostate gland, scrotum (testes), and penis b. Defenses includes the flushing action of urine 2. Female reproductive system produces eggs in a 28-day cycle; see Fig. 23.3 a. Consists of the uterus, fallopian tubes, ovaries, vagina b. Defenses include mucus, acidic pH in vagina, and secretory IgA B. Urinary tract consists of the kidneys, ureters, bladder, and urethra; see Fig. 23.1 1. Defenses include: a. Flushing action of urine b. Shedding of epithelial cells lining the urinary tract (desquamation) c. Acidity of urine d. Lysozyme and lactoferrin in urine e. Secretory IgA 23.2. Normal Biota of the Urinary Tract A. Normal biota of the male urethra and genital tract includes nonhemolytic streptococci, staphylococci, corynebacteria, and some lactobacilli B. Normal biota of the female genital tract 1. the anterior urethra and vagina are the only anatomic areas permanently colonized with bacteria; the cervix and above has no normal biota 2. vagina: a. flora depends on age, pH, and hormonal levels of the female b. the flora is greatly influenced by estrogens (which cause glycogen release) c. in utero, the vagina of the fetus is sterile d. bacteria are derived from the hands of care givers and the infant's feces e. in the first six weeks, maternal estrogens are present in the vaginal epithelium; the microbiology is similar to the adult vagina, i.e. Lactobacillus predominates f. following metabolism of estrogens/glycogen, staphylococci, streptococci and Enterobacteriaceae predominate g. after menarche, a healthy vagina is dominated by Lactobacillus and a variety of both gram-negative and gram-positive anaerobes and facultative anaerobes h. after menopause, Lactobacillus decrease in numbers 3. anterior urethra: Lactobacillus, staphylococci, and streptococci; bacteria which transiently colonize and cause urinary tract infections (UTIs) commonly include fecal bacteria such as members of the Enterobacteriaceae and Enterococcus spp. C. urine cultures: require a "clean-catch" specimen; there may be 104 bacteria/ml initially from the urethra 23.3. Urinary Tract Diseases Caused by Microorganisms A. Urinary tract infections (UTIs) See Disease Table 23.1 1. Bladder (cystitis) 2. Kidneys (pyelonephritis) 3. Urethra (urethritis) 4. Signs and symptoms: a. dysuria - burning pain with urination 2 b. urine can be cloudy due to bacteria and WBCs c. urine can be orange tinged due to RBCs (hematuria) d. fever and nausea e. back pain is an indication of kidney infection f. septicemia can occur if pyelonephritis is inadequately treated 5. Causative agents: a. Escherichia coli; strains that most commonly infect this system possess fimbriae that act as adhesins for cells lining the ureters and kidney; flagella allow movement "up" the urinary system b. Staphylococcus saprophyticus; see Chapt. 18 notes pp. 3-7 c. Proteus mirabilis: member of the Enterobacteriaceae; produces urease; infection of the kidneys can lead to formation of renal calculi (stones); flagella allow movement "up" the urinary system 6. Transmission and epidemiology a. community-acquired is usually an endogenous infection, from one organ system to another (GI to urinary system) b. incidence is higher in women than men; due to shorter length of the female urethra and because of nearness of the female urethral opening to the anus c. recurrent UTIs in some women may be due to E. coli invasion of deeper tissue of the urinary tract which allows avoidance of antibiotics d. UTIs are the most common of nosocomial infection 7. Prevention - a vaccine is in development for E. coli → fimbrial adhesion; follow basic practices e.g. empty bladder frequently, for females, wiping from front to back after a bowel movement, cranberry juice 8. Treatment- antibiotics plus Pyridium to control burning and urgency B. Leptospirosis - aka Weil's disease 1. general information: Leptospira interrogans is the agent; morphology is long, gram-negative spirochetes; ends appear to be hooked; See Fig. 23.4 2. pathogenesis and clinical manifestations: a. invasion is via mucosa and broken skin; there is no lesion at the site of entry; a generalized infection can result in a severe systemic disease with renal and hepatic failure, extensive vasculitis, myocarditis, and death; invasion of the CNS can result in meningitis b. symptoms include severe headache, chills, and fever with relapses, kidney involvement ranges from mild, transient proteinuria to severe nephritis with casts and diminished or no urinary output; jaundice occurs in severe cases; renal failure is the most common cause of death. 3. epidemiology - worldwide, zoonotic disease with a variety of hosts; rodents (particularly rats), which can shed bacteria for their entire lives, are important reservoirs; in the U.S., rats, dogs and farm animals are the major sources of human infections; bacteria are discharged in urine and transmitted to humans via infected soil, water, and food; organisms survive for months in water or wet soils; risk factors include farming, slaughterhouse work, swimming in fresh water (triathletes, kayaking), being a flood victim; person-to-person transmission has not been documented; 4. diagnosis - microscopy and culture are relatively insensitive; serodiagnosis using a microscopic agglutination test (patient's serum + live leptospires) 3 5. treatment/prevention - antibiotics; vaccines are available, but only target specific strains; vaccines are used primarily by the military 23.4. Reproductive Tract Diseases Caused by Microorganisms A. Vaginitis and vaginosis 1. Signs and symptoms - vaginal itching, burning, and sometimes a discharge 2. Causative agents - the 3 main categories of vaginitis are: protozoan (Trichomonas vaginalis) vaginitis, yeast (Candida albicans) vaginitis, and bacterial vaginosis (BV); BV was originally termed nonspecific vaginitis; vaginosis indicates increased discharge; there is evidence of vaginitis in about 33% of gynecology patients; BV is the most common (40-50% of all cases), however mixed infections routinely occur. B. Bacterial vaginosis: 1. microbiology: a. facultative anaerobes: - Gardnerella vaginalis (gm+, but appears gm-) - increased prevalence and concentration in patients indicates a role in BV, but not as a sole etiologic agent. - Lactobacillus crispatus and L. jensenii (gram-positive) - thought to maintain an acid pH by metabolism of glucose; in females with BV, Lactobacillus spp. are replaced by G. vaginalis and mixed predominately anaerobic flora. - Mycoplasma hominis (no gram reaction) - higher incidence in women with BV b. obligate anaerobes: - Mobiluncus sp. (gram-positive) - very high incidence in women with BV; used in the morphologic diagnosis of BV; there are a number of other gram-positive anaerobes - Fusobacterium sp. (gram-negative) - higher incidence in women with BV; there are a number of other gram-negative anaerobes. 2. pathogenesis: a. microbial antagonism - inhibitors produced by Lactobacillus prevent colonization or overgrowth by less desirable vaginal flora. Hydrogen peroxide is produced by some strains of Lactobacillus; most anaerobic bacteria lack catalase peroxidase and cannot eliminate toxic H2O2; a low pH caused by lactic acid production by Lactobacillus may directly inhibit anaerobes by maintaining a higher oxidation-reduction potential. b. bacterial products - amines associated with BV and malic acid produced by Mobiluncus can cause irritation of the mucous membranes; also increased endotoxin, collagenases, and proteases may play a role. c. adherence - the ability of Mobiluncus and G. vaginalis increases with increased pH d. sexual association - not thought to be transmitted, but a matter of a change in environment due to semen or saliva 3. clinical diagnosis: a. 3 of the following signs: - vaginal fluid with a pH of greater than 4.5 - homogenous adherent discharge - fishy odor on addition of 10% potassium hydroxide to discharge (odor is due primarily to 4 metabolic by-products of metabolism) - clue cells on a saline wet mount; "clue cells" = vaginal epithelial cells coated with so many coccobacilli (Gardnerella) that the cell borders are obscured; See Fig. 23.6 b. Gram-stain diagnosis - based on quantization of microbial morphotypes; large gram-positive bacilli are Lactobacillus morphotype and smaller gram-negative-appearing types are Gardnerella morphotype; others are categorized by morphology alone. 4. complications: pelvic inflammatory disease, adverse outcome of pregnancy (pre-term birth, premature rupture of membranes), postpartum endometritis, and cellulitis. 5. treatment: a. metronidazole, PO b. metronidzaole or clindamycin vaginal cream c. metronidzole in a lactate gel (contain lactic acid and growth substrates for Lactobacillus sp. d. ? probiotics B. Prostatitis 1. acute - bacterial infection; bacteria are usually from the intestinal tract; may be a consequence of UTI 2. chronic- often bacterial, sometimes not; cases that do not respond to antibiotics are thought to be mixed populations of bacteria in biofilms 3. symptoms include pain in the pelvic area, lower back, or genital area; frequent urge to urinate; blood in the urine; and/or painful ejaculation 4. treatment: antibiotics, muscle relaxers, alpha blockers C. Discharge diseases with major manifestation in the genitourinary tract 1. Gonorrhea - the etiologic agent is Neisseria gonorrhoeae: a. general information: - morphology - gram-negative cocci, usually in pairs with adjacent sides flattened; possess fimbriae and capsules; clinical specimens often reveal diplococci within PMNs - physiology and metabolism: facultative anaerobes; susceptible to adverse environmental conditions, i.e., drying, chilling, sunlight; fastidious, with complex nutritional requirements; enhanced growth at elevated CO2 concentrations; an appropriate medium is Thayer-Martin. b. pathogenesis: - virulence factors - fimbriae for adherence, phase (antigenic) variation, and promotion of endocytosis; IgA protease that cleaves IgA on mucosal surfaces; the outer membrane lipooligosaccharide (LOS) elicits inflammatory response - usually infects during sexual activity; within an hour following contact with a mucosal surface, infection is established; bacteria anchor via fimbriae to surface urethral cells - LOS elicits an inflammatory response resulting in purulent discharge; intracellular invasion of PMNs may be important in “deeper” infection and systemic spread c. phase variation and immunity - lack of immunity to the bacterium can lead to repeated infections; variations of a number of antigens are responsible. 5 d. clinical manifestations: - the primary sites of infection are the urethra in men and urethra and cervix in women; other sites in both sexes are the anorectal region, pharynx, conjunctivae, and disseminated infection - in males - incubation time is 3-7 days; onset is symptomatic and abrupt in about 75% of cases; presents with burning on urination and yellow purulent urethral discharge; it may cause fever and leukocytosis, but other systemic signs are absent; complications occur in about 1% of cases; most common is epididymitis; less common involve urethral strictures and prostatitis. - in females - incubation time is not clear, but estimated at 10 days; up to 50% are asymptomatic; presents with burning or frequency of urination, vaginal discharge, fever, and abdominal pain; spreads externally to the rectum in about 50% of cases; major complications are salpingitis and pelvic inflammatory disease (PID; these can result in sterility and/or chronic PID; inflammation of the liver (perihepatitis = Fitz-Hugh-Curtis syndrome) can occur in association with salpingitis; bacteria spread to the liver by blood or transperitoneal migration from the fallopian tubes; (Chlamydia trachomatis can also be spread by this route.); See Fig. 23.8 - in males and females - disseminated gonococcal infection (DGI )- 1-3% of infections in women (lack of treatment and much lower % in men); the most common manifestation is the arthritis-dermatitis syndrome; symptoms include fever, chills, malaise, arthritis, and skin lesions of the wrists, elbows, and ankles; patients usually have had asymptomatic genitourinary infection; meningitis and endocarditis are less common manifestations - children - gonoccoccal ophthalmia neonatorum; this is usually a result of transmission during passage through an infected birth canal; a common manifestation is purulent conjunctivitis; the rationale for mixed antibiotic prophylaxis for newborn; infection of any mucous membrane can occur, as well as disseminated disease; see Fig. 23.9; see Chapt. 18 notes e. epidemiology: - one of the most frequently reported infectious diseases in the U.S.; currently, the second most common bacterial venereal disease in the U.S. (Chlamydia is estimated to be the most common); - almost always venereally transmitted - humans are the only reservoir; primary reservoirs include asymptomatic men ~10%) and women (~50%) who are chronic carriers - worldwide problem; in the U.S., 334,826 cases reported in 2012; incidence is higher, since underreporting is common - highest rates occur in the most sexually active group (15-24 y.o.a.) - host factors contribute to incidence, e.g. number of sex partners or contraceptive practices - one of the more common causes of purulent arthritis in adults (particularly women). f. diagnosis: - gram stain of purulent materials in genital infection, anorectal infection, and arthritis (early in infection); not used for pharyngitis or disseminated infection; many PMNs with intracellular gram-negative diplococci with flattened sides will be observed; this 6 is inadequate alone for female cervical secretions - culture on Thayer-Martin medium; standard for all sites of infection; also used for antibiotic sensitivity - for females ELISA or PCR are also required for confirmation - nucleic acid amplification tests (NAATs are used for clinical specimens; sensitive, specific, and rapid (4 h); this has replaced culture in many labs; disadvantage is lack of antibiogram; combination assay for N. gonorrhoeae and Chamydia trachomatis is available. g. treatment and control: - check recommendations by the CDC (published in MMWR) - plasmid and chromosomally-mediated resistances to penicillin G (PPNG = penicillinase-producing N. gonorrhoeae), tetracycline (TRNG) and fluoroquinolones are common. - a 2-drug regimen for gonorrhea and chlamydia (if not ruled out) - infection of cervix, urethra, rectum - ceftriaxone + (anti-chlamydial) azithromycin or doxycycline or ceftriaxone + antichlamydial - report cases to the local health department - advise patients concerning sexual contacts. h. Case: Neisseria gonorrhoeae The patient was a 15-year-old heterosexual male who was brought to the emergency room by his sister. He gave a 24-hour history of dysuria and noted some “pus-like” drainage in his underwear and the tip of his penis. Urine appeared clear, and urine culture was negative although urinalysis was positive for leukocyte esterase and multiple white cells were seen on microscopic examination of urine. He gave a history of being sexually active with five or six partners in the past 6 months. He claimed that he and his partners had not had any sexually transmitted diseases. His physical exam was significant for a yellow urethral discharge and urethritis with preputial edema. A Gram stain of the discharge specimen was performed in the emergency room. He was given antimicrobial agents and scheduled for a follow-up visit one week later. He did not return. 2. Chlamydiaceae:general information - the family has been divided into 2 genera, Chlamydia and Chlamydophila; species cause human disease, Chlamydia trachomatis and Chlamydophila psittaci and Chlamydophila pneumoniae; morphology -very small, gram-negative-like, with inner and outer membrane, LPS, but little peptidoglycan, cocci; an obligate intracellular parasite of eukaryotic cells; 3 major phases occur in the developmental cycle are penetration, development within a phagosome, and maturation; see Fig. 23.12 3. Chlamydia trachomatis: a. pathogenesis: - the type of cells infected is restricted to those found on the mucous membranes of the urethra, endocervix, endometrium, fallopian tubes, anorectum, respiratory tract, and conjunctivae; clinical manifestations are due to direct destruction of cells during replication and host inflammatory response. - bacteria gain acess through small abrasions; granuloma formation is characteristic; lesions may become necrotic, attract PMNs, and cause inflammation to surrounding tissues; 7 infection does not confer long-lasting immunity; reinfection induces a vigorous inflammatory response with subsequent tissue damage; this can cause scaring with sterility and sexual dysfunction in those with genital infections. b. clinical manifestations of urogenital and rectal infections: - females - most genital tract infections are asymptomatic; manifestations include mucopurulent cervicitis, endometritis, urethritis, salpingitis, pelvic inflammatory disease, and perihepatitis; dual infection with gonorrhea is common - males - most genital infections are symptomatic, however, as many as 25% may be asymptomatic; manifestations include mucopurulent urethritis (non-gonococcal urethritis = NGU), epididymitis, and proctitis; dual infection with gonorrhea is very common - lymphogranuloma venereum (LGV) - some strains can invade the lymph system; initial manifestation is a primary lesion at the site of infection, e.g. penis, urethra, glans, scrotum, vaginal wall, cervix, vulva; the lesion is often overlooked because it is small, painless and heals rapidly; other signs include fever,headache, and myalgia; the next stage is marked by inflammation and swelling of the lymph nodes draining the site of initial infection; the inguinal nodes are most commonly involved; they can become painful buboes that enlarge and can rupture; proctitis is common in women and is a result of lymphatic spread from the cervix or vagina; in men, proctitis can develop after anal intercourse or lymphatic spread from the urethra. c. neonatal/infant infections: - neonatal conjunctivitis - exposure occurs at birth; clinically appears as swollen eyelids and large amounts of purulent discharge - infant pneumonia - exposure occurs at birth; onset is 2-3 weeks after birth, with rhinitis and a staccato cough, but no fever. d. epidemiology: - urogenital infections - the most common bacterial disease and sexually transmitted bacterial disease in the U.S.; an estimated 4 million new cases each year in the U.S.; in 2012, ~1.4 million cases were reported; 50-80% of infections in women are clinically silent; there is believed to be a high incidence of symptomless infections in men as well; highest incidence in the 15-24 y.o.a. group; commonly occurs as a co-infection with gonorrhea (the 2 infections are the most common cause of epididymitis in sexually active men) - LGV - caused by LGV serovars; the disease occurs sporadically in the U.S., Europe and Australia; prevalence is much higher in Africa, Asia, and S. America; in the U.S., 200-500 cases have been reported annually during the past decade; male homosexuals are the major reservoir of disease in the U.S.; symptomatic infection is less common in women than men - neonatal (inclusion) conjunctivitis - the eyes of newborn are infected during passage through an infected birth canal; it is the most common form of neonatal conjunctivitis in the U.S.; 25% of infants whose mothers have active genital infections develop conjunctivitis; there are estimates of ~100,000 cases/year - infant pneumonia - interstitial pneumonia develops in 10-20% of infants exposed at birth; 8 estimated to cause one-third of the cases of interstitial pneumonia in infants e. diagnosis: - microscopy - examination of giemsa-stained cell scrapings for the presence of inclusions was one of the earliest methods for diagnosis; this is relatively insensitive and not commonly employed - culture - isolation in tissue culture is one of the most specific methods for diagnosis and considered the gold standard; used to observe cytopathology (including inclusion bodies); the process depends on obtaining a clinical specimen with sufficient number of bacteria to process; it is also expensive, difficult, and time-consuming; molecular diagnosis as replaced culture in most cases - nucleic acid amplification tests (NAATs) - PCR and other amplification procedures are highly sensitive because only a few bacteria are necessary for identification; urine samples can be used successfully if purulent discharge is not available; NAATs are replacing older nucleic acid probe tests f. treatment - use agents that are taken up by host cells effectively; for cervicitis/urethritis, azithromycin or doxycycline 4. Ureaplasma urealyticum and Mycoplasma genitalium - General information: thought to cause genitourinary tract infections; lack a true cell wall; related to Mycoplasma species; stain poorly or not at all a. there are estimates that 15-25% of nongonnoccocal and nonchlamydial urethritis, in men is caused by these organisms. Estimates in women ? b. in women, known to cause chorioamnionitis and postpartum fever c. diagnosis: usually not done for either d. treatment: persistent urethritis after doxycycline treatment might be caused by doxycycline- resistant U. urealyticum or M. genitalium azithromycin D. Genital ulcer diseases: 1. Treponema pallidum: a. morphology: helically coiled, long, corkscrew-shaped, gram-negative spirochete; too thin to be observed with transmitted-light microscopy; periplasmic flagella allow corkscrew movement; outer membrane; see Fig. 23.16 and 23.17 b. physiology: microaerophile that is extremely sensitive to heat, drying, osmotic stress, and aerobic conditions; demonstrates a long generation time (24-36 hours); this contributes to a long incubation time c. pathogenesis - can infect almost every tissue of the body, which results in a wide variety of clinical manifestations ("great imitator"); syphilis is a painless, slowly evolving chronic granulomatous disease that fluctuates between short symptomatic stages and prolonged asymptomatic stages. - the surface mucoid coat - proteins act as adhesins for host cells; it impedes access to bacterial antigens and when coated with fibronectin, protects against phagocytosis. 9 - features of an infection - the incubation period is 10-90 days (the average is 3 weeks); invasion of mucous membranes or abrasions in the skin, localization, replication, and dissemination via lymphatics and blood d. clinical manifestations - progression of disease is marked by 3 clinical stages - primary disease - a papule develops into a superficial ulcer with a firm base = a hard chancre (tje chancre is filled with spirochetes); the primary lesion in women occurs on the labia, wall of the vagina, or cervix; in men, it occurs on the shaft of glans of the penis; in both, it can occur on the lips, tongue, tonsils, and anus; painless enlargement of the regional lymph nodes may occur, but there are no other systemic signs; 40-60% of patients (especially women) may pass through the 1o and 2o stages without knowing that they have the disease; the chancre heals spontaneously in 3-6 week, but the spirochetes move to circulation - secondary disease - 2-12 weeks after the 1o lesion; in 25% of cases, several alternating relapses and remission of the 2o stage occur; signs include fever, sore throat, generalized lymphadenopathy, headache, and rash (the most prominent symptom) commonly on palms and soles; moist papules (condylomata) may occur on mucous membranes; patches and draining skin lesions are highly infectious; see Fig. 23.13 - latent disease - "early latency" is the first 4 years between 2o and 3o syphilis; "late latency" is the subsequent period, up to 30-40 years. - tertiary disease - the last stage progresses slowly, but is the most destructive; gummas are painless granulomas with central coagulation necrosis, occurring in skin and bones; they cause tissue destruction, due to an enhanced immunological host reaction; neurosyphilis appears as syphilitic meningitis, general paresis, or tabes dorsalis with complications that can include paralytic dementia; cardiovascular syphilis causes 80% of the fatalities in tertiary disease; see Fig. 23.14 - congenital disease: results from transplacental infection (which is unusual for a bacterial disease) of the fetus; about 50% are stillborn or abort; early congenital manifestations are apparent at birth or up to 2 y.o.a.; late congenital patients appear normal past the age of 2 years; manifestations for both include interstitial keratitis, notched incisors, and 8th-nerve deafness (Hutchinson's triad); see Fig. 23.15 e. immunity - the bacterium stimulates a vigorous immune response, however the disease is usually not fully controlled or eradicated; characterized by persistent infection; the dense coat coated with fibronectin is thought to inhibit specific antibody attachment; persons with untreated syphilis are relatively resistant to reinfection; persons treated during early 2o or 1o stages are relatively susceptible to reinfection (apparently, living organisms are needed to maintain a high immunity) f. epidemiology: - worldwide; humans are the only natural hosts; not a highly contagious disease; perhaps a 30% chance of contracting the disease following exposure; sexual transmission is the most common route; transmission occurs at highest rates during the early stages of disease; the reservoir of untreated cases are primarily those who have progressed to latent stages - does not survive exposure to drying or disinfectants; not transmitted by fomites; occurs most frequently among the sexually active population, 15-30 y.o.a.; congenital transmission 10 can occur during bacteremic stages (as long as 8 years); the primary stage is a risk factor for HIV acquisition and transmission - in 2012, 49,903 cases for all stages of disease were reported; 15,607 cases of 10 and 20 disease were reported and 332 cases of congenital (<1 yr) disease were reported g. diagnosis: - it cannot be cultured in vitro; can be grown on tissue culture at reduced oxygen concentration - direct microscopic observation - for patients with 1o chancre and active 2o lesions and congenital infections; bacteria can be observed in lesion material using darkfield microscopy; failure to observe organisms is not certain evidence of a negative test; see Fig. 23.17 - serologic tests: * nontreponemal - measure Wassermann antibodies which are specific for cardiolipin; these lipids from damaged host cells are released during early stages of disease and present on the bacterial surfaces; reaginic antibodies (IgG and IgM) develop against these lipids; beef heart extract is used as a source of cardiolipin. The two most common tests are VDRL (Venereal Disease Research Lab) and RPR (Rapid Plasma Regin); there can be problems with false positive and negative reactions (particularly during the primary and tertiary stages) * treponemal tests - are specific antibody tests used to confirm nontreponemal tests; an example is FTA-ABS (fluorescent treponemal antibody-absorption) (an IFA test) h. treatment and control: - there is no evidence of penicillin resistance; long-acting benzathine penicillin is used for the early stages of syphilis, and penicillin G is recommended for congenital and late syphilis - effective therapy requires maintenance of a specific level for 7-10 days for the 1o disease; for 2o and 3o disease, prolonged treatment is required (because the organism grows so slowly); a Jarisch-Herxheimer reaction may follow treatment of 2o and 3o disease. - control - a reportable disease; interview patients to identify all sexual contacts; examine and treat all contacts. There is no vaccine available. i. Case: Treponema pallidum A 23-year-old male presented to the local emergency room with a low-grade fever, malaise, and headache. He was sent home with a diagnosis of influenza. He presented 7 days later with a 1-day history of worsened headache, photophobia, and stiff neck. On physical examination he appeared to be in mild distress with a temperature of 38.80 C. He had mild nuchal rigidity and a maculopapular rash on his trunk, arms, palms, and soles. There were some membranous lesions on the tongue. No focal deficits were seen on neurologic examination. He had a white blood cell count of 11,200/mm3 with an increased number of PMNs. A CT scan of the head was normal, and a lumbar puncture revealed 120 WBCs/mm3, a glucose level of 40 mg/dl (normal), and a protein level of 82 mg/dl (elevated). Blood cultures were obtained, and antimicrobial therapy was begun. The next day a serologic test of his CSF and blood revealed the diagnosis. Dark-field microscopy demonstrated motile spirochetes. Further questioning of the patient revealed that 7 weeks previously, he had a painless ulcer on his penis which healed spontaneously. 2. Haemophilus ducreyi: see Chapt. 21, small, gram-negative coccobacilli a. clinical manifestation: the cause of chancroid; trauma/abrasion needed for introduction of infection; often a painful ulcer with a ragged margin is present; usually confined to the genitalia and perianal areas; painful, suppurative inguinal buboes are characteristic in about 40% patients; it does not cause a systemic infection. 11 b. epidemiology: usually transmitted by sexual intercourse; more frequent in the tropics; In the U.S., it is considered an uncommon STD (15 reported cases in 2012) c. diagnosis: diagnosis is primarily by exclusion and clinical appearance; painful genital ulcer plus buboes; rule out syphilis by serologic test and darkfield examination and exclude herpes simplex virus by PCR test d. treatment - a number of antibiotics can be used ___________________________________________________________________________ Herpes Simplex Virus I and II I. Taxonomy - Family – Herpesviridae; Subfamily – Alphaherpesvirinae; Genus – Simplexvirus Species – Human herpesvirus 1 (Herpes Simplex Virus 1) Human herpesvirus 2 (Herpes Simplex Virus 2) II. Structure - Capsid: Icosahedral; Genome: dsDNA, linear; Enveloped: Yes III. Introduction: These viruses do not survive well on environmental surfaces. Therefore, infection usually requires direct inoculation into areas which will allow replication: mucous membranes of the mouth, Eye, Genitals, Respiratory tract, Anus etc. HSV infections can be lytic or latent. An advantage of latency is that the virus can avoid the immune system. These latent viruses may reactivate later in life. Reactivation causes the virus to replicate resulting in herpes lesions in the lips, eyes, fingers or genitalia. IV. What does it cause? Genital Herpes, with most cases being caused by HSV-2. Most individuals have no or only minimal signs or symptoms from HSV infection. Symptoms typically appear as one or more blisters on or around the genitals or rectum. These herpes blisters break, leaving tender ulcers that may take 2 – 4 weeks to heal when they occur the first time. Typically, the 1st outbreak is followed by others (typically 4 or 5; symptomatic recurrences) in the subsequent weeks or months, but these are almost always less severe and shorter than the 1st outbreak. The number of outbreaks tends to decrease over a period of years. According to CDC: 15.5 % of persons ages 14 – 49 years have HSV-2 infection. Overall prevalence of genital herpes is likely higher than 15.5 %, because an increasing number of genital herpes infections are also caused by HSV-1, which is typically acquired in childhood. Most infected persons are unaware of their infection. It is estimated that in the US, 87.4% of 14 – 49 year olds infected with HSV-2 have never received a clinical diagnosis. V. How do I know if I have it? Case study Viral Culture & Isolation is definitive, but it takes 1 - 2 weeks. The virus can be obtained from vesicles, but not crusted lesions. Rapid Tests on body fluids: 1. PCR for HSV DNA: Accurate & fast; takes 1 day. 2. ELISA for HSV antigens Tzanck Smear: look for epidermal multi-nucleated cells and eosinophilic intranuclear inclusions When symptoms occur, they typically appear as one or more vesicles on or around the genitals, rectum or mouth. The average incubation period after exposure is 4 days (range of 2 – 12). These vesicles break and leave painful ulcers that may take 2 – 4 weeks to heal. These symptoms are referred to as an outbreak / episode. Clinical manifestations of genital herpes differ between the 1st outbreak and recurrent outbreaks. The 1st outbreak is often associated with a longer duration of lesions, increased viral shedding (HSV transmission more likely) and systemic symptoms including fever, body aches, swollen lymph nodes, and headache. Recurrent outbreaks of genital herpes are common, in particular during the 1st year of infection. About half of patients who recognize 12 recurrences have prodromal symptoms, such as mild tingling or shooting pains in the legs, hips and buttocks occurring hours to days before eruption of lesions. Symptoms of recurrent outbreaks are typically shorter in duration and less severe than the 1st outbreak of genital herpes. These outbreaks do tend to decrease over time. Recurrences are much less frequent for genital HSV-1 infection than for genital HSV-2 infection. VI. Can it be dangerous? Yes, especially in newborns or immunocompromised individuals. If a woman has active genital herpes at delivery, a C section is usually performed. Infection of a baby from Mom with herpes infection is rare. Genital ulcerative disease caused by HSV makes it easier to transmit and acquire HIV infection sexually. HSV infected individuals show an estimated 2 to 4 fold increased risk of acquiring HIV, if exposed to HIV when genital herpes is present – this is because genital herpes can cause ulcers or breaks in the skin or mucous membranes, which compromises the protection normally provided by the skin and mucous membranes against infections, including HIV. Herpetic genital ulcers can bleed easily, and when they come into contact with the mouth / vagina / rectum during sex, they increase the risk of HIV transmission. CDC: “Neonatal herpes is one of the most serious complications of genital herpes. Healthcare providers should ask all pregnant women if they have a history of genital herpes. Herpes infection can be passed from mother to child during pregnancy, childbirth, or in the newborn period, resulting in a potentially fatal neonatal herpes infection. During pregnancy there is a higher risk of perinatal transmission during the first outbreak than with a recurrent outbreak, thus it is important that women avoid contracting herpes during pregnancy. Women should be counseled to abstain from intercourse during the third trimester with partners known to have or suspected of having genital herpes. A woman with genital herpes may be offered antiviral medication from 36 weeks gestation through delivery to reduce the risk of a recurrent outbreak. Routine HSV screening of pregnant women is not recommended. However, at onset of labor, all women should undergo careful examination and questioning to evaluate for presence of prodromal symptoms or herpetic lesions. If herpes symptoms are present a cesarean delivery is recommended to prevent HSV transmission to the infant.” VII. How can I transmit virus to others? Virus is transmitted orally (mostly HSV-1), sexually (mostly HSV-2) & by placement into eyes and breaks in skin. Virus also shows asymptomatic shedding, which aids in its transmission. Infection is lifelong (latency) and recurrent disease is a source of transmission (via infected lesion fluid). Genital HSV-2 infection is more common in women (~1 out of 5 women 14 to 49 years of age) than in men (~1 out of 9 men 14 to 49 years of age). Transmission from an infected male to his female partner is more likely than vice versa. VIII. How can I protect my family? Wear gloves Wash hands frequently Mothers with active lesions should not have contact with nursery babies. Active lesions should be covered (mask, gloves, bandage, etc) Active lesion patients should be cared for, away from high risk groups (neonates, immunocompromised, burn patients, severe eczema patients) Acyclovir helps prevent dissemination in the immunocompromised IX. Protective Immunity: Humoral and cellular immunity help to resolve infection. During primary infection, the production of interferon and the action of natural killer cells limit the disease—HSV rarely causes viremia in immunocompetent individuals. The production of Abs helps limit the spread of the virus. X. How can I be treated? Acyclovir (Zovirax), Famciclovir (Famvir) and Valacyclovir (Valtrex) appear to have similar efficacy for the treatment of primary genital herpes and for the suppression of recurrent infection, with the latter two drugs having greater oral bioavailability than acyclovir. Topical therapy is of marginal benefit and should not be used. Use of these therapeutic options significantly reduced pain, length of time to healing, and duration of viral shedding. 13 Suppressive therapy has been shown to decrease the frequency of genital herpes recurrences by 70 – 80% in those who show frequent recurrences. Taking regular lysine supplements seem to prevent recurrences. -------------------------------------------------------------------------------------------- Human Papillomavirus (HPV) I. Taxonomy - Family – Papovaviridae; Genus – Papillomavirus; Species – Human papilloma virus II. Structure - Capsid: Icosahedral; Genome: dsDNA, circular; Enveloped: No III. What does it cause? HPV causes warts, also known as papillomas. Warts are benign, squamous epithelial growths and may occur on skin or mucus membranes. HPV can cause cervical and other cancers including cancer of the vulva, vagina, penis, or anus. It can also cause cancer in the back of the throat, including the base of the tongue and tonsils (oropharyngeal cancer). Health problems related to HPV include genital warts and cervical cancer. Genital warts can be found in the genital and anal areas of both men and women. Although they can occur at any age, they are most common in individuals between 17 and 33 years of age. About 90% of genital warts are caused by HPV types 6 and 11 and are generally acquired through sexual contact with an infected individual. Cervical cancer is caused mostly by HPV type 16, but types 18, 31, and 45 can also be the cause. HPV DNA integrates into the host cell DNA and cell cycle control is disrupted. Genital warts rarely cause discomfort or pain. Infections with HPV 16 and 18, as well as other high-risk types, may lead to cancers of the genitals, anus, mouth and upper respiratory tract. IV. How do I know if I have it? - External warts are diagnosed visually. Hard to detect warts may be made more visible by using vinegar, which turns HPV-infected areas white. Visible warts typically do not cause cancer. Vaginal and anal Pap smears check for cancerous cells in both men (anal) and women. PAP smears can reveal koilocytotic (vacuolated cytoplasm) squamous epithelial cells. These cells are rounded and occur in clumps. If the Pap smear is inconclusive, the follow up test is an HPV DNA test. There are several FDA approved HPV DNA tests: 1. Hybrid Capture 2™ (HC2): detects a cocktail of 13 different high-risk (oncogenic) HPV types and reports the results as positive for one or more of these types, or negative for all. 2. Cervista™: detect HPV 66 in addition to the 13 HPV types detected by HC2. 3. the PCR-based Cobas 4800 test: detect HPV 66 in addition to the 13 HPV types detected by HC2. The Cobas test identifies HPV types 16 and 18, while detecting the remaining 12 types in a probe mix. The Cervista test indicates positivity for one or more types in the 14-probe mix, but also offers the option of testing for HPV 16/18 specifically. There are several possible indications for HPV DNA testing. Currently, HPV testing is used to triage women whose PAP smears show atypical squamous cells of undetermined significance (ASC-US). Biopsy of warts also help detect cancerous cells. There is consensus on how to manage Pap smears that are read as significantly abnormal (high grade squamous intraepithelial lesions or HSIL). BUT, there is uncertainty on how to treat patients whose Paps were read as either minimally abnormal (low grade squamous intrapitheal lesions or LSIL) or of uncertain importance (atypical squamous cells of undetermined significance or ASCUS). A large, multicenter clinical trial sponsored by NCI was undertaken to address these uncertainties. Prior to the development of the HPV screening test, patients with Paps that were LSIL or ASCUS were counseled to have a repeat Pap done in 3-6 months. If a woman's second Pap was abnormal, she would undergo a colposcopy and biopsy. 14 According to the NCI study: the HPV DNA test will be most helpful for further evaluating those with ASCUS Paps. The DNA test will help separate those with high risk HPV requiring more aggressive management (colposcopy and biopsies) from those with low risk HPV, which can be managed with further observation as most will resolve without further intervention. The chance of missing high-grade dysplasia is ~ 30% with conventional Paps, is 15 - 20% with liquid Paps, and is < 4% with the HPV DNA test. The test only detects cancer causing HPVs. V. Can it be dangerous? Yes, genital warts if undetected can be life threatening because of the potential towards oncogenic transformation. Almost all nongenital warts are harmless & tend to resolve themselves over time. Approximately 14,000 cases of cervical cancer are diagnosed in the US each year and over 5,000 women die of cervical cancer each year, in the US. Cervical cancers are caused by HPV infections, with HPV types 16 and 18, causing about 70 % of all cases. HPV also causes anal cancer, 85 % of which is caused by HPV-16. Almost half of all vaginal, vulvar, and penile cancers are caused by HPV types 16 and 18. Most recently, HPV infections have been found to cause cancer of the oropharynx, with, more than half of these cases in the US being linked to HPV-16. These infections have increased during the past 20 years, especially among men. It has been estimated that, by 2020, HPV infections will have caused more oropharyngeal cancers than cervical cancers in the US. Additional factors that may increase the risk of developing cancer following a high-risk HPV infection: Smoking Weakened immune system, Having many children (esp. for increased risk of cervical cancer), Long-term oral contraceptive use (esp. for increased risk of cervical cancer), Poor oral hygiene (esp. for increased risk of oropharyngeal cancer), and Chronic inflammation VI. Can I infect others with it? Yes. HPV infections are one of the most common sexually-transmitted diseases: 20 to 60% of adult women in the US are infected with one or another genotype of HPV. Asymptomatic shedding promotes transmission. Virus can be transmitted by direct contact. Warts can also be transmitted from one body part to another via autoinoculation. The viruses are fairly stable in the environment, allowing their transmission via fomites (surfaces of countertops/furniture, shower stalls, towels and medical equipment), surfaces of furniture, bathroom floors, and inadequately chlorinated swimming pools. VII. How can I transmit virus to others? Infection occurs when HPV enters your body through a tear in the outer layer of your skin. Transmission occurs by direct contact, sexual contact, by passage through infected birth canal (laryngeal papillomas). HPV infections associated with genital warts and related lesions are contracted through sexual intercourse, anal sex and other skin-to-skin contact in the genital regions. Some HPV infections that result in oral or upper respiratory lesions are contracted through oral sex. Rarely a woman with an HPV infection may transmit the virus to her infant during vaginal delivery. This exposure may cause HPV infection either in the baby's genitals or the upper respiratory system. HPV infections often go undetected because they don't always cause warts. VIII. Who is at increased risk of infection? At risk are sexually active people and children of infected women. In the US alone, there are ~ 20 million people who have HPV infections that can cause genital warts. IX. How can I protect my family? There are 3 FDA approved HPV vaccines: 2vHPV (Cervarix), 4vHPV (Gardasil) and 9vHPV (Gardasil). Minimum age is 9 years for 2vHPV (Cervarix; HPV 16 & 18), 4vHPV (Gardasil; HPV 6, 11, 16 & 18) and 9vHPV (Gardasil 9; HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58). 15 9vHPV, 4vHPV, or 2vHPV is indicated for routine vaccination of females 11 or 12 years of age and females through 26 years of age who have not been vaccinated previously or who have not completed the 3-dose series. 9vHPV or 4vHPV is indicated for routine vaccination of males 11 or 12 years of age and males through 21 years of age who have not been vaccinated previously or who have not completed the 3-dose series. 9vHPV or 4vHPV vaccination is indicated for men who have sex with men and immunocompromised men (including those with HIV infection) through age 26 years if not vaccinated previously. These vaccines target the two most common high-risk HPVs, types 16 & 18. Together, these two HPV types currently cause about 70 percent of all cervical cancers. HPV types 6 and 11, which together currently cause about 90 percent of all cases of genital warts. The vaccines elicit virus-neutralizing antibodies that prevent initial infection with the HPV types represented in the vaccine. Gardasil is given as a series of three injections over 6 months. The second and third doses should be given two and six months (respectively) after the first dose. Girls and women 13 – 26 years of age, who were previously non-vaccinated, can also receive the HPV vaccine. Gardasil does not appear to cause any serious side effects. So far, studies have found that vaccinated persons are protected for 4 to 5 years. Cervarix is recommended for girls 10 -25 years of age. Immunization with Cervarix consists of 3 doses given at 0, 1, and 6 months. The most common local adverse reactions are pain, redness, and swelling at the injection site, while the most common general adverse events are fatigue, headache, myalgia, gastrointestinal symptoms, and arthralgia. In 2009, FDA approved use of Gardasil in males between the ages 9 to 26. Adverse events following vaccination with Gardasil: The majority (92%) of adverse events were mild and included the following: pain and swelling at the injection site (the arm), fever, dizziness, nausea, and fainting. Syncope (fainting) which is common after injections and vaccinations, especially in adolescents, should be monitored by closely observing the person for 15 minutes after vaccination. The Guillain-Barré syndrome (GBS) has been reported after vaccination with Gardasil . There is no indication that Gardasil increases the rate of GBS above the rate expected in the general population, whether or not they were vaccinated. There have been some reports of blood clots in females post Gardasil vaccinations. These clots which have occurred in the heart, lungs, and legs have been seen in people with a risk of getting blood clots: individuals taking oral contraceptives (the birth control pill), smokers, obesity etc. Although deaths have been reported in individuals who vaccinated with Gardasil, there is no conclusive evidence linking the vaccine with this serious adverse event. X. How can I be treated? Warts typically regress or are removed by cryotherapy electrocautery laser surgical excision chemical means (10-25% solution of Podofilox) Interferon injected into warts, stimulates the immune response against HPV (problem with AIDS patients) Imiquimod (Aldara) applied topically also stimulates the immune response Podophilox causes tissue necrosis, destroying the wart through direct antimitotic activity on the cells Topical or intralesional cidofovir inhibits viral DNA synthesis (used in immunodeficient patients) Recurrence is common. -------------------------------------------------------------------------------------------------------------------- 16 Molluscum contagiosum (MC) I. Taxonomy - Family – Poxviridae; Genus – Molluscipoxvirus; Species – Molluscum contagiosum Virus II. Structure - Capsid: Brick shaped; Genome: dsDNA, linear; Enveloped: Yes III. How do I know if I have it? - The characteristics of MC lesions include:papules to pearly, umbilicated nodules; vary in size; central caseous plug can be expressed; most common on trunk, genitalia and proximal extremities; may appear alone or in clusters of 5 to 20; usually painless. See Chkpt. 18.8 Many, but not all, cases of molluscum contagiosum in adults are caused by sexual contact. Sexually transmitted molluscum contagiosum manifests as lesions on genitals, lower abdomen, inner upper thighs and buttocks. Genital lesions are considered a marker for sexual activity. IV. Lab Diagnosis is done by doing a case study and confirming histologically (large, eosinophilic cytoplasmic inclusions seen in epithelial cells). PCR can also be used to show presence of virus in skin lesions. VI. How can I give it to others? Transmission is by direct contact (includes sexual) or fomites. MC transmission has been associated with swimming pools and sharing baths with an infected person. However, it has not been proven how or under what circumstances swimming pools/shared baths might increase spread of the virus. It may be that the virus might spread via sharing of towels or toys. More research is needed to understand if and for how long the virus can live in swimming pool/bath water and if such water can infect swimmers. In adults, sexual transmission is the most common mode of transmission. VII. How can I be treated? - I.V. Cidofovir (antiviral); curettage: the most efficacious treatment with the lowest rate of side effects; Cantharidin used topically; Imiquimod, a potent inducer of interferons, can be used topically; topical imiquimod > effective than cantharidin but is expensive, and an optimum treatment schedule is yet to be reported; additional topical options include salicylic acid, glycolic acid, tretinoin, azortene, 5 % sodium nitrite co-applied daily with 5 percent salicylic acid topical preparations, podofilox, liquefied phenol, tretinoin, adapelene and potassium hydroxide; oral treatment of molluscum includes cimetidine; liquid nitrogen; laser therapy. No therapy is universally effective. MC lesions normally disappear within 6 to 18 months without treatment and without leaving scars, although it may persist longer with genital lesions and also in immunodeficient people. This is not a latent virus. Additional viruses that can be transmitted sexually include: JC virus, EBV, CMV, Ebola, HIV, HTLV, HepA, HepB and HepC. drome (GBS) has been reported after vaccination with Gardasil . There is no indication that Gardasil increases the rate of GBS above the rate expected in the general population, whether or not they were vaccinated. There have been some reports of blood clots in females post Gardasil vaccinations. These clots which have occurred in the heart, lungs, and legs have been seen in people with a risk of getting blood clots: individuals taking oral contraceptives (the birth control pill), smokers, obesity etc. Although deaths have been reported in individuals who vaccinated with Gardasil, there is no conclusive evidence linking the vaccine with this serious adverse event. X. How can I be treated? Warts typically regress or are removed by cryotherapy electrocautery laser surgical excision chemical means (10-25% solution of Podofilox) Interferon injected into warts, stimulates the immune response against HPV (problem with AIDS patients) Imiquimod (Aldara) applied topically also stimulates the immune response Podophilox causes tissue necrosis, destroying the wart through direct antimitotic activity on the cells Topical or intralesional cidofovir inhibits viral DNA synthesis (used in immunodeficient patients) Recurrence is common. -------------------------------------------------------------------------------------------------------------------- 16 Molluscum contagiosum (MC) I. Taxonomy - Family – Poxviridae; Genus – Molluscipoxvirus; Species – Molluscum contagiosum Virus II. Structure - Capsid: Brick shaped; Genome: dsDNA, linear; Enveloped: Yes III. How do I know if I have it? - The characteristics of MC lesions include:papules to pearly, umbilicated nodules; vary in size; central caseous plug can be expressed; most common on trunk, genitalia and proximal extremities; may appear alone or in clusters of 5 to 20; usually painless. See Chkpt. 18.8 Many, but not all, cases of molluscum contagiosum in adults are caused by sexual contact. Sexually transmitted molluscum co