1. STDs/STIs M. Kent Froberg, MD 2009

2. Purpose Learn for the most common/important STIs: The classification and characteristics of each etiologic agent, epidemiology, prevalence, spectrum of clinical disease, diagnosis, pathology, treatment (pharmacology lectures) and prevention.

3. Organisms 1. Viruses 1.Herpes simplex viruses: HSV-1 & HSV-2 2.Human papilloma viruses: HPV 3.Human Immunodeficiency Virus: HIV (covered elsewhere) 4.Hepatitis B Virus: HBV (covered elsewhere)

4. Organisms 2. Protozoa 1.Trichomonas vaginalis

5. Organisms 3. Bacteria 1.Chlamydia trachomatis 2.Neisseria gonorrhoeae 3.Treponema pallidum 4.Haemophilus ducreyi

6. Important Concepts Many STIs asymptomatic/subclinical Are 5 of the 10 most common infections reported by CDC Rates of STIs probably underestimated Concurrent infections common Nearly all STIs  risk of HIV infection

7. More Concepts > 15 million STIs per year in US Rates in US double those of England, Canada, Germany, Sweden While syphilis & gonorrhea have declined recently, chlamydia, HPV & HSV have all  Physicians may not include an adequate sexual Hx and genital exam as part of routine H & P www.cdc.gov/std/

8. Frequency/Impact HPV: ~ 20 million infected in US, 5.5 million new infections per year HSV-2: ~ 45 million infected in US Chlamydia*: > 3 million new infections per year in US Trichomoniasis: ~ 5.5 million infected Gonorrhea*: ~ 360,000 cases reported in 2001 Syphilis*: ~ 6,000 cases reported in 2001, 440 congenital * Reportable in Minnesota

9. HSV 1 & 2 Enveloped DNA viruses causing cold sores & genital herpes Genital herpes mostly HSV-2, but HSV-1 increasing (up to 40% in some populations) Facial herpes mostly HSV-1 (5% HSV-2) Antibodies to one somewhat inhibitory to the other Genomes show 50-70% homology between HSV- 1 & HSV-2 Man only natural host

10. Clinical Disease Localized vs disseminated (  in immunosuppressed) 1. Herpes Labialis : cold sores 2.Ocular Herpes: keratoconjunctivitis 3. Herpes Genitalis 4. Cutaneous lesions: herpetic whitlow 5. Meningitis 6. Encephalitis: temporal lobe 7. Neonatal herpes

11. Herpesvirus Particle HSV-2 virus particle. Note that all herpesviruses have identical morphology and cannot be distinguished from each other by electron microscopy.

12. Herpes HSV is spread by contact, virus is shed in saliva, tears, genital and other secretions. Most common form of infection results from a kiss given to a child or adult from a person shedding the virus. HSV-1 1  infection is usually trivial or subclinical in most individuals. There are 2 peaks of incidence, the first at 0 - 5 years and the second in the late teens, when sexual activity commences. About 10% of the population acquires HSV infection through the genital route and the risk is concentrated in young adulthood.

13. Herpes Pathology Latency in craniospinal ganglia Reactivation: 45% for facial, 60% for genital More likely if immunosuppressed Triggers: stress, menstruation, infection, fever Genital recurrence: 1.6 episodes/yr,  with time Asymptomatic shedding highest in 1st six months following 1  infection

14. Genital herpes — Initial visits to physicians’ offices: United States, 1966–2002

15. Herpes simplex virus type 2 infections — Percent seroprevalence according to age in NHANES II (1976-1980) and NHANES III (1988-1994)

16. Genital Herpes Causes latent & recurrent infections Transmission: direct contact (genital/genital or oral/genital) Most transmission when there are no active lesions – important for pts to know/understand 1  infection often more severe than recurrences 60% of pts have recurrent disease

17. Genital Herpes Pathology Infection by direct contact with mucocutaneous tissue breaks Prodrome of tingling, burning, pain Papule  vesicle (clear fluid filled)  ulcer Intra-nuclear inclusions (Cowdry A & B), multinucleated giant cells at base of vesicle Ulcer  2  infection (Staph, Strep, Candida)

18. Neonatal Herpes HSV spread to neonate during vaginal delivery (doesn’t cross placenta) Mostly from asymptomatic mothers Incidence: 1/4000 LBs in US Transmission more common with 1  vs recurrent infection (33 vs 3% in one series) Earlier gestational delivery  risk Caesarian section  risk

19. Neonatal Herpes 80% due to HSV-2 50% mortality CS x within first 10 days of life Pathology: foci of necrosis in multiple organs (liver, adrenal, lung, brain) Long-term CNS deficits/blindness in 25- 30%

20. Early papules & vesicles of genital herpes

21. Confluent vesicles of Herpes

22. Polykaryon from HSV-2

23. Multiple papules of Herpes

24. Subcorneal vesicle of HSV-1

25. Polykaryons with intranuclear inclusions at base of vesicle

26. Crusted ulcers from facial herpes

27. Papules & confluent vesicles of HSV

28. Dewdrop-like vesicles of genital herpes

29. Cowdry A inclusions of HSV

30. Fatal hepatitis from HSV-1 in immunocompromised patient

31. Geographic necrosis from fulminant HSV hepatitis

32. Intranuclear inclusions within hepatocytes

33. HSV-1 encephalitis with focal necrosis of temporal lobe

34. HSV encephalitis destroying unilateral inferior temporal lobe

35. Laboratory Diagnosis Virus Isolation –HSV-1 and HSV-2 are among the easiest viruses to cultivate. It usually takes only 1 - 5 days for a result to be available. Is gold standard. Direct Detection –Tzanck smear of vesicle base –Immunofluorescence of skin scrapings - can distinguish between HSV and VZV –PCR - now used routinely for the diagnosis of herpes simplex encephalitis Serology –Not that clinically useful.

36. Cell Culture Cytopathic Effect of HSV in cell culture: Note the ballooning of cells.

38. Herpes Treatment Antiviral chemotherapy indicated where the primary infection is especially severe, dissemination, sight is threatened, and herpes simplex encephalitis. Acyclovir – this is the drug of choice for most situations. I.V. (HSV infection in normal and immunocompromised patients) Oral (treatment and long term suppression of mucocutaneous herpes and prophylaxis of HSV in immunocompromised patients) Cream (HSV infection of the skin and mucous membranes) Ophthalmic ointment Famciclovir and valacyclovir – oral only, more expensive than acyclovir.

39. Acyclovir Converted to acyclovir monophosphate by viral thymidine kinase Then to acyclovir triphosphate by cellular kinases  inhibits viral DNA polymerase  early termination of viral DNA ~1% of HSV lack thymidine kinase  resistant to acyclovir

40. Human Papilloma Virus Naked dsDNA virus of papovavirus family Produce latent & chronic infections HPV replicates in epithelial cells of skin, vagina, cervix, larynx, etc. Transmitted by direct contact Tumorogenic: causes warts, anogenital condylomas and dysplasia

41. HPV 60-100 different types described, 30-40 infect human genitalia Classified by genotyping Small virus (55 nm), circular DNA with 10 ORFs (E1-8, L1 & L2) New type defined as having < 50% homology with known HPV types

42. Clinical Disease Common warts: verruca vulgaris Most common types: 1, 2, 4 Predilection for keratinized epithelium/do not cause genital lesions (except HPV 2) Laryngeal warts: HPV 11 (~congenital)

43. Tumorogenic Types Anogenital warts (condyloma accuminatum): HPV 6, 10, 11, 40-45 (episomal viral DNA) Types 6 & 11 ~ 70% Cervical cancer: HPV 16, 18, 33, 45, 46 70% HPV 16 or 18 (integrated viral DNA) HPV 16 most common type (50%) overall HPV genomes found in >95% of all cervical cancer specimens (squamous cell & adenocarcinomas) 270,000 deaths from cervical cancer worldwide

44. Pathology Infected epithelial cells  koilocytes Koilocytes: cells with  nuclear size,  N/C, irregular nuclear contours (raisinoid), nuclear hyperchromasia, perinuclear halo Can transform cells in culture E6 binds p53 (early degradation blocks apoptosis) E7 binds Rb gene (unrestrained cell proliferation)

45. E7 from HPV replaces E2F at binding site with pRb. This allows transcriptional activation and cell proliferation.

46. Epidemiology Incidence and prevalence unknown 65% of sexual contacts of partners with condylomas displayed genital warts within 6 weeks Multiple HPV types in ~ 25% of infections Most infections spontaneously regress within 2 yrs Most common in young adults, decline with age Only a small minority of women with HPV DNA by molecular techniques have gross or microscopic abnormalities HPV infection  4x if HIV +

47. HPV Pathology & Rx: refer to lecture on cervix HPV 16 vaccine clinical trials: Females age 16-23 got HPV-16 virus- like-particle vaccine (x3) or placebo, followed and tested for HPV-16 infection for ~17 months 768 got vaccine with 0 HPV-16 infections 765 got placebo with 41 HPV-16 (3.8%/100 women-years) infections (NEJM 2002;347:1645- 51)

48. Vaccine Gardasil  recombinant virus-like particles (VLPs) from L1 protein (major capsid protein) –Lack viral DNA – reasure pts they can’t get virus from vaccine –Prevents infection from types 6, 11, 16 & 18 –6 & 11 cause ~90% of genital warts –FDA approved June 2006

49. Condyloma accuminatum

51. Koilocyte with nuclear enlargement, hyperchromasia,  N/C ratio, irregular nuclear contour & perinuclear halo

52. Trichomonas vaginalis Ubiquitous flagellated protozoan, most common non-viral STD per WHO Lives in lumen of vagina, urethra, prostatic ducts, under foreskin of uncircumcised males Does not invade tissues 170 million cases worldwide Causes trichomoniasis Humans only natural host

53. T. vaginalis Fastidious, anaerobe Iron from menses may facilitate overgrowth Not reportable in US (~3-6 million new cases/yr) Prevalence in STD clinics may approach 40% Much less frequent in men (~5% of urethritis) Peak incidence 16-35 yrs of age  risk if African-American, multiple sexual partners

54. Trichomoniasis and other vaginal infections — Initial visits to physicians’ offices: United States, 1966–2002

55. Trichomoniasis Transmission via sexual intercourse Rate of infectivity estimated at 70-80% Rates higher from men to women than women to men Incubation period 4-28 days Not spread by fomites

56. Clinical Disease Acute or chronic vaginitis Yellow-green, frothy or bubbly, purulent discharge, pruritis and dysuria Discharge in < 50% of women Exacerbated by menses (pH 5-5.5) Urethritis more common in men White, milky urethral discharge

57. Pathology Gross: discharge, multiple, punctate hemorrhages and/or areas of capillary dilitation on cervix (“strawberry cervix”) Organism may adhere to squamous epithelium Acute inflammation

58. Diagnosis & Treatment Wet mount of scrapings of vaginal fornices Can see motile organisms under phase contrast microscope Others: Giemsa stain of scrapings, PAP smear, ELISA on vaginal secretions Rx: metronidazole  82-100% cure rates Should Rx sexual partners

59. Chlamydia trachomatis Small Gram negative bacterium Obligate intracellular pathogens Biphasic developmental cycle Infectious form is elementary body (EB) 0.3-0.4  m EB is metabolically inert EB taken up by epithelial cells  reticulate body (RB)

60. Chlamydia trachomatis RB metabolically active Utilizes host cell ATP for energy Multiples by binary fission within endosome (inclusion body with 100-500 progeny) Result  host cell ruptures or expels inclusion body Infect columnar epithelium Chlamydia inhibit fusion of endosome with lysosomes (resist intracellular killing)

61. C. trachomatis Multiple biovars D-K cause nongonococcal urethritis in men; urethritis, cervicitis, salpingitis and pelvic inflammatory disease (PID) in women Can cause inclusion conjunctivitis in neonates L1-3 cause lymphogranuloma venereum (LGV rare in US- <600/yr)

62. Epidemiology Most common bacterial STD in developed world Rate in STD clinics 15-19% Leading cause of ectopic pregnancy (secondary to PID b/c inflammation and scarring of fallopian tubes) Risk factors: < 25 yrs, African-American race, multiple sexual partners. Concurrent infection with GC Majority of infections subclinical Incubation period ~ 3 weeks

63. Diagnosis Cell culture (takes 3-7 days) of vigorous swab of mucous membranes: use dacron or rayon swabs-submit in viral/chlamydial transport medium at 4  C Endocervix preferred site (urethra from men) DFA, gene probes, EIA

64. Clinical Disease Ophthalmia neonatorum ( inclusion conjunctivitis) acquired during passage through birth canal May develop pneumonitis Adults may get from autoinoculation from genital tract (trachoma)

65. Clinical Disease Males: 75% symptomatic  urethritis, dysuria & pyuria, proctitis Females: 80% asymptomatic, some cervicitis, urethritis, salpingitis 40% of untreated females  pelvic inflammatory disease (PID) Leads to tubal pregnancy, infertility Tubal pregnancy = leading cause of 1st trimester pregnancy-related deaths Females with chlamydia 3-5 fold  risk of HIV

66. More Clinical Disease Reiter’s Syndrome: conjunctivitis, polyarthritis & genital infection  most HLA-B27 + Lymphogranuloma venereum (L biovars): painful “buboes” = enlarged draining lymph nodes, may develop elephantiasis, ulcers or fistulas

67. Treatment Tetracycline or erythromycin No vaccines Penicillin ineffective Important since gonococcus co-infections may occur

68. PAP smear with chlamydial inclusion body

69. Trachoma: conjunctivitis from Chlamydia infection

70. Lymphogranuloma venereum: unilateral inguinal swelling

71. Necrotic lymph node of lymphogranuloma venereum

72. Triple zone of stellate abscess of lymphogranuloma venereum

73. Gonorrhea Neisseria gonorrhoeae Gram negative diplococci, gonococcus (GC) Frequently found intracellularly in PMNs Is oxidase positive: cytochrome C oxidase phenylenediamine black color

74. Gonorrhea Have pili  attach to mucosal surfaces Pili show antigenic variation Protein II (opacity)  clumping (aggregation) IgA proteases  may degrade host IgA LPS May bind to sperm, rbcs, non-ciliated fallopian tube epithelium May invade  dissemination

75. Epidemiology Incidence declining May be under diagnosed in females Still 500-700,000 cases per year in US Highly contagious: 50% transmission rate Chlamydia coexists in 45-50% of pts with gonorrhea

76. Gonorrhea — Rates: United States, 1970–2002

77. Gonorrhea — Rates by state: United States and outlying areas, 2002

78. Gonorrhea — Rates by race and ethnicity: United States, 1981–2002

79. Clinical Disease Incubation 2-7 days Males: urethritis, dysuria, pyuria (copius urethral discharge), epididymitis, proctitis, orchitis Conjunctivitis in newborns exposed to infected secretions in birth canal 50% of women asymptomatic Cervicitis, adenitis, proctitis, salpingitis, ovaritis, PID in 15%

80. More Clinical Disease Disseminated : more common during pregnancy (endocytosis of GC) seen in 0.3 - 3% of pts Dermatitis  papules & pustules with hemorrhagic component Arthritis  knees, elbows, tenosynovitis Rarely  endocarditis, meningitis, Waterhouse-Friderichsen syndrome (hemorrhagic destruction of adrenal gland)

81. Diagnosis Culture on Thayer-Martin media in high CO 2 (oxidase + colonies) Gram negative cocci in pairs GC don’t ferment maltose, meningococci do Gene Probe

82. Treatment Penicillin resistance 15-19% Tetracycline resistance 17-23% Emerging fluoroquinolone resistance No resistance to 3rd generation cephalosporins Disseminated: 7-14 days after infection

83. Gonorrhea: purulent discharge from urethral meatus

84. PMNs containing diplococci

85. Pustule of disseminated gonorrhea

86. Syphilis Treponema pallidum Spirochete with axial filament (motile) Gram negative but too thin to see by light microscopy (0.2 by 6-15  m) Man only natural host (grows in rabbit skin/testes) Never cultured in vitro Transmission by direct sexual contact

87. Syphilis Periods of latency and clinical disease Infection may last decades Since arrival of penicillin in 1940’s, rate has  Produces no known toxins Pathology likely from humoral and cellular immune responses Syphilis  risk of HIV (HIV  risk of neurosyphilis)

88. Primary and secondary syphilis — Rates: United States, 1970–2002 and the Healthy People 2010 objective

89. Congenital syphilis — Rates for infants <1 year of age: United States, 1981–2002 and the Healthy People 2010 objective

90. Primary and secondary syphilis — Age- and sex-specific rates: United States, 2002

91. Clinical Disease “Great Imposter” Three stages: each involve lesser numbers with more severe CS x 1  syphilis  chancre (hard, clean, painless, shallow ulcer) occurs ~ 3weeks after exposure Chancre: male  70% on penis or scrotum, female  50% on vulva or cervix, rest  lips, oral cavity, finger, base is teeming with treponema

92. Clinical Disease Chancre resolves in 3-8 weeks  Rx May have fever, lymphadenopathy 2  stage  2-10 weeks after  1 2   dissemination of spirochetes: diffuse macular rash including soles & palms, lymphadenopathy, erosions on mucous membranes, condyloma lata

93. Clinical Disease 3  stage  latency may last decades Three categories of tertiary syphilis: 1.Cardiovascular  aortitis, aortic aneurysm, aortic insufficiency (80% of mortality) 2.Neurosyphilis  general paresis, meningovasculitis, tabes dorsalis (loss of posterior columns), psychiatric disease 3.Benign tertiary syphilis  gummas = necrotizing granulomas  skin, bones, subQ

94. Syphilitic chancre

95. Chancre: base contains treponema that can be visualized by dark field microscopy

96. Spirochetes

97. Maculopapular rash of secondary syphilis

98. Rash involves palms & soles

99. Condyloma lata of secondary syphilis Trepenomes are not readily found within lesions

100. Perivascular plasma cells are characteristic of syphilis

101. Obliterative endarteritis with plasma cell infiltrate

102. Gumma: rubbery focus of necrosis

103. Destructive gummas

105. Saddle nose

106. Opened syphilitic aortic aneurysm with adherent thrombus

107. CT scan of aortic aneurysm

108. Charcot joint

109. Saber shin

110. Congenital Syphilis Treponemes cross placenta after 5th month of gestation (more common if early syphilis) Causes stillbirth, spontaneous abortion (50% mortality), early or late congenital syphilis Early congenital: desquamating skin lesions,vesicles on mucous membranes, osteochondritis, pulmonary fibrosis, hepatosplenomegaly Late congenital: interstitial keratitis, gummas, saddle nose, saber shin (> 2 yrs), Charcot joints Classic triad: interstitial keratitis, notched incisors, eighth-nerve deafness

112. Hutchinson (notched) incisors

113. Hepatic fibrosis from congenital syphilis

114. Periostitis

115. Pathology Treponemes adhere to endothelium  obliterative endarteritis Two major types of lesions: 1.perivascular plasma cells ( also lymphocytes, macrophages) 2.Gummas  necrotizing granulomas 2  to delayed type hypersensitivity

116. Diagnosis Screening serology via non-treponemal tests: 1.VDRL (Venereal Disease Research Laboratory) 2.RPR (Rapid Plasma Reagin) These test for anti-cardiolipin antibodies (are  in syphilis & many other diseases, ie Lupus) Are sensitive but non-specific

117. Diagnosis If chancre present  dark field microscopy of material from base of lesion May be seen in silver stains or DFA staining of condylomas and skin lesions (less reliable) Confirmatory Tests for 2  & 3  syphilis : more specific and expensive 1.FTA-ABS most widely used, remains + after Rx (TOC) 2.Microhemagglutination-TP also used

118. Treatment Penicillin - no known resistance Single dose for active, multiple doses for latent May see Jarisch-Herxheimer reaction following Rx of 2  or 3  syphilis (hypersensitivity) Like other STIs  condoms may not entirely prevent

119. Chancroid Haemophilus ducreyi Gram negative rod Now uncommon in US, common in Africa & SE Asia Causes soft chancre: painful genital ulcer Can be confused with syphilis, herpes, LGV

120. Chancroid Male:female ratio 9:1 Predisposes to HIV Characterized by single or multiple ulcers and inguinal adenopathy Grows on chocolate agar  gram negative coccobacilli Presumably make cytotoxin and endotoxin

121. Rx and Prevention Some resistance to ampicillin and penicillin Condoms may prevent

122. Vaginitis Yeast vaginitis  80-90% Candida albicans Are NL flora  overgrowth (birth control pills, antibiotics, diabetes) May be sexually transmitted (usually not) Dx: KOH wet mount for yeast, pseudohyphae & hyphae Dysuria, creamy discharge Rx: nystatin, imidazoles

123. Bacterial Vaginitis Gardnerella vaginalis Gram negative anaerobe NL flora Mild signs/increased odor (fishy) Dx: clue cells-epithelial cells covered with bacteria Rx: alter microenvironment