Sexually Transmitted Pathogens • Bacteria Neisseria gonorrhoeae Chlamydia trachomatis Mycoplasma hominis Ureaplasma urealyticum Treponema pallidum Gardnerella vaginalis Hemophilus ducreyi Calymmatobacterium granulomatis Shigella spp. Salmonella spp. Campylobacter spp. Streptococcus agalactiae • Viruses Herpes simplex Hepatitis A, B, C Cytomegalovirus Papillomavirus Adenovirus Molluscum contagiosum HIV • Fungi Candida albicans • Protozoa Trichomonas vaginalis Entamoeba histolytica Giardia lamblia • Ectoparasites Phthirus pubis Sarcoptes scabei Average Risk per Episode from Known Positive Source Percut Blood Mucocutan Blood Recept Anal Recept Vag Insertive Vag Fellator HIV HCV HBV eAg+ HBV eAg - 0.3% 1.8% 40% 1.5-10% .09% 0.1-5% 0.1-0.2% 0.03-0.14% .06% ?; low ?; low ?; low ?; low “Safe”r Sex • Condoms – effective only when used all the time; otherwise, failure rate is in 10% range – effective for HIV prevention, but unproven in HSV prevention • Nonoxynol-9 – may increase risk of HIV transmission when used alone as contraceptive gel – unknown if any increased risk when used as condom lubricant Contraception Failure Rates Method Actual Rate Chance Spermacide Periodic Abstinence Coitus interruptus Cervical cap Diaphragm Condom 85% 21% 20% 18% 18% 18% 12% Theoretical Rate 85% 3% 2-9% 4% 6% 6% 2% -adapted from Trussel, et al., Obstet Gynecol 76:558-67, 1990. STD’s Transmissible without Intromission • • • • • • • • • Syphilis Herpes Chancroid Lymphogranuloma venereum Human papillomavirus Bacterial vaginosis Molluscum contagiosum Phthiris pubis Sarcoptes scabei 1 Sexually Transmitted Diseases Prevention: Abstinence Neisseria gonorrheae Virulence Factors • • • • • IgA protease Pilins Opa (PII) PI LipoOligoSaccharide •Antigenic variation makes immunity difficult •Attachment proteins can be varied to be most suited to the tissue being colonized Asymptomatic Infection urethra, endocervix, rectum, pharynx Symptomatic Infection urethritis, cervicitis, proctitis, pharyngitis, bartholinitis, conjunctivitis Local Complications salpingitis, epididymitis, Bartholin’s abscess, lymphangitis, penile edema, periurethral abscess, prostatitis DGI Neisseria gonorrheae Clinical • Males – incubation 2-6 days – purulent discharge, dysuria - 90% symptomatic • 10% never develop Sx – these may be responsible for the spread of disease – homosexual males: anal, pharyngeal infection • pharyngeal seen in 20% of fellators of men with GC • fellator’s partner = irrumator • “The Clap” - gonococcal urethritis – O.F. clapoir - bubo, an illness of debauchery; – first use in English 1587 meaning gonorrhea 2 Neisseria gonorrheae Clinical • Females – dysuria, urinary frequency, exudative cervicitis – ASx infection - endocervix, urethra, anal, pharynx • high prevalence - screening Cx in active female – extension to Fallopian tubes in 15-20% causing acute salpingitis – misdiagnosed as UTI; Sx may resolve with suboptimal Rx • Children – ophthalmic infection via birth canal – infancy through puberty: vulvovaginitis = child abuse Ophthalmia neonatorum gonococcal chlamydial Neisseria gonorrheae Clinical • Disseminated GC - 3% – tends to disseminate during menses – resistant to C’-mediated ‘cidal activity of serum – patients deficient in C’6-C’8 have increased susceptibility to disseminated gonococcal and meningococcal infection – Sx: fever, polyarthralgia, skin lesions (distal extremities) • tenosynovitis - wrists-ankles-knees • Sx may resolve spontaneously or proceed to purulent arthritis • Diagnosis: – Gram’s stain, culture, rapid antigen tests Neisseria gonorrheae Treatment N.B.: 50% have co-infection with chlamydia • ceftriaxone 125 mg IM plus azithromycin 1 gm PO • ceftriaxone 125 mg IM plus doxycycline 100 BID x 7 days • cefixime 400 md PO plus azithro or doxy • ciprofloxacin 500 mg PO plus azithro or doxy • levofloxacin 500 mg PO plus azithro or doxy Disseminated GC • ceftriaxone 1 gm IM/IV until ASx, then F/U with PO -orcefixime or a FQ • spectinomycin 2 gm IM q 12h 3 Comparison of N. gonorrheae and C. trachomatis Genital Infections Site Men urethra epididymidis rectum conjunctiva systemic N. gonorrheae C. trachomatis urethritis epididymitis proctitis conjunctivitis DGI NGU, PGU epididymitis proctitis conjunctivitis Acute Urethral bartholinitis conjunctivitis perihepatitis DGI - arthritis/dermatitis Syndrome bartholinitis conjunctivitis perihepatitis Women urethra Bartholin’s gland conjunctiva liver capsule systemic Chlamydia trachomatis • Obligate intracellular parasite that can be grown on artificial media • Life Cycle – Elementary Body- endocytosed into a phagosome; inhibits phagosomal-lysosomal fusion – Reticulate body-metabolically active (8 hour incubation) • reproduces by binary fission within phagosome – ruptures and releases infectious elementary bodies • cell-to-cell infection ensues 4 Chlamydia trachomatisClinical • Serotypes D-K • Males - 30% NGU in men – fewer Asx (5-10%) than GC – Dx: PCR (urine, swab), culture – serology unreliable except for LGV • Women – cervix - mucopurulent discharge – salpingitis(major cause), TOA (with other flora) • major cause of infertility and ectopic pregnancies – urethritis – Dx: PCR (urine, swab), culture • Reiter’s Syndrome - 70% follow chlamydial infection Chlamydia trachomatis - LGV • Lymphogranuloma venereum - L serotypes • Primary – painful genital lesion - papule - 3-30 days after exposure • Secondary (days to weeks) – multilocular suppurative adenopathy • “groove sign”: division of inguinal nodes by Poupart’s ligament – proctocolitis if primary site was anal canal • Late (months to years) – draining sinus tracts, urethral/rectal strictures, lymphatic obstruction 5 Chlamydia trachomatis Treatment NGU, cervicitis, urethritis, etc. NB: Chlamydia 50%, M. hominis, U. urealyticum • • • • azithromycin 1 gm PO (98% effective) doxycycline 100 mg PO bid x 7 days levofloxacin 500 PO qd x 7 days erythromycin base 500 mg po QID x 7 days (in pregnancy) LGV • doxycycline 100 mg PO bid x 21 days • erythromycin base 500 mg PO bid x 21 days Herpes Simplex • Icosahedral DS DNA virus • replication in nucleus • Primary Infection – – – – break in mucous membranes epithelial cell invasion to sensory nerves to ganglia also may spread from primary site to nodes to blood mild primary infection may be due to cross-reacting HSV I immunity • Only a relatively small percentage of people with HSV II Ab’s report a memorable primary infection, so ASx infection may be fairly common • Reactivation – ganglia to axon to skin Comparison of HSV1 and HSV2 Characteristics urogenital infections nongenital infections labialis keratitis whitlow encephalitis (adult) meningitis neonatal primary transmission mode genital physical properties 40o sensitive heparin sensitive plaques HSV1 - (10-30%) +(80-90%) + + + + - (~30%) nongenital HSV2 + (70-90%) - (10-20%) + + + (~70%) + + small large 6 Comparison of HSV1 and HSV2 Clinical Characteristics Primary Infection Usual Site pharyngitis gingivostomatitis keratoconjunctivitis encephalitis vulvovaginitis neonatal herpes meningitis Recurrent Infection Usual Site labialis keratitis encephalitis vulvovaginitis HSV1 HSV2 + + + + - + + + + + + - + Herpes Simplex - Clinical • Females – painful vulvovaginitis, cervicitis (80%), urethritis • Males – balanitis - painful • Duration of primary stage is 21 days • 75% have at least 1 recurrence • Complications – congenital (primary only) – meningoencephalitis Pathogenesis of Reactivated Genital HSV Infection Primary HSV Infection Clinical Course VIRAL SHEDDING VESICLE WET ULCER HEALING ULCER CRUST Symptoms PUSTULE Systemic Sx Local Sx -6 -4 -2 SEXUAL CONTACT 0 2 LESIONS NOTED 4 6 8 10 12 14 16 18 20 Days M.D. MORE LESIONS HEALING Sx GONE BEGINS HEALED Recurrence Rates of Genital HSV Infection 1. Reactivated HSV in ganglionic nerve cells produces recurrent disease via peripheral migration along axons to skin and mucous membranes 2. Reactivation results in recurrent mucocutaneous lesions and potential for transmission. Clinical Course of Recurrent Genital HSV 7 Herpes simplex • Diagnosis – – – – Tzanck preparation Direct immunofluorescence Viral culture - cells and fluid Serology • older generation ELISA unreliable because of multiple cross-reacting antigens, making differentiation between HSV1 and HSV2 difficult • new immunodot assays and antigen capture ELISA based on gG1 and gG2 highly sensitive and specific 8 Tzanck Smear: multinucleate giant cell Herpes simplex - Treatment Primary genital • acyclovir 400 mg PO tid x 10 days • famciclovir 250-500 mg PO tid x 10 days • valacyclovir 1000 mg PO bid x 10 days Recurrent genital • acyclovir 400 mg PO bid x 5 days • famciclovir 125 mg PO bid x 5 days • valacyclovir 500 mg PO bid x 5 days Suppression • acyclovir 200-600 mg PO qd • famciclovir 125-500 mg PO qd • valacyclovir 500 mg PO qd Treponema pallidum - Syphilis Old World vs. New World Hypothesis • “Great Pox” arrived/ravaged Europe at the time of Columbus’ return – sailors had disease immediately on their return in 1493 – it seems to have been a very virulent disease as compared with today’s disease - Was this the same disease? • John Hunter self-inoculated with both GC and syphilis, thus muddied the waters for years longer Treponema pallidum - Syphilis • • • • • • Slender spirochaete 5-15 µm long with regular spirals Trilaminer cytoplasmic membrane Peptidoglycan layer Lipopolysaccharide layer Fibrils at each end Not able to be cultivated . • mercurials were used from medieval times on - this is a marker for the existence of syphilis 9 Primary Syphilis • Chancre: single, indurated, non-tender – 10-90 days post contact (average 14-21 days) – painless regional adenopathy – spontaneous healing in 3 weeks • Site – Males: coronal sulcus – Females: labia – anal intercourse: anus/anal canal 10 Secondary Syphilis • • • • 2-6 weeks after primary chancre Flu-like illness - headache, malaise, adenopathy Rash - salmon-colored; palms and soles Mucous patches • Condylomata lata 11 Tertiary Syphilis • Neurosyphilis: – – – – Meningovascular (early) Parenchymatous (later) Tabes dorsalis General Paresis of the Insane • Asymptomatic neurological (+ CSF) • Cardiovascular: – aneurysms, aortic insufficiency • Late Benign: – gumma (bone, soft tissue, liver, etc) Benign Tertiary Syphilis gummatous 12 Congenital Syphilis • • • • • • • Skin rash Rhinitis (“snuffles”) Periostitis Spontaneous fractures VIII deafness Optic atrophy Skeletal deformities - saddle nose, saber shins, Hutchinson’s incisors, mulberry molars • Juvenile paresis . Syphilis and HIV Infection • HIV transmision is enhanced by genital ulcer disease • Syphilis in HIV infection may be more protracted and more severe – – – – enhanced constitutional Sx more organ involvement more severe rashes predisposition to neurosyphilis and uveitis • Syphilis in HIV infection may require more vigorous treatment, and bacteriostatic drugs (e.d. doxyctcline) should be avoided in favor of bactericidal agents Syphilis - Diagnosis • Serologic testing is the mainstay of diagnosis – 2 types of serology • non-specific reagins directed against cardiolipin-type antigens, e.g. RPR, VDRL, ART, STS, Hinton, Wasserman – often reverts to negative with effective treatment, making it a good screening test and useful for tracking therapy » however, those treated in late stages may be “sero-fast”, I.e., retaining low-titer positivity after Rx • specific anti-treponemal antibodies – FTA, FTAabs, MHA-TP, HATS – remains positive for life, making it a poor screening test for new disease, or for tracking therapy, but its specificity makes it a good confirmatory test – positive in 85% of primary syphilis and 95-99% in later forms 13 Syphilis - Diagnosis • False negative reagin-based tests – too soon after sexual exposure – treated or untreated late syphilis – AIDS • False-positive reagin-based tests – infections (mono, measles, hepatitis, leprosy) – immunizations (smallpox) – sarcoid, SLE, etc • False-positive treponemal tests – Lyme Disease – non-syphilitic treponematoses (yaws, pinta, bejel) Syphilis - Treatment Early: primary, secondary, late latent < 1 year • benzathine PCN G (LA Bicillin) 2.4 x 106 U IM - or • doxycycline 100 mg PO bid x 14 days -or• ceftriaxone 125 mg IM qd x 10 days or 250 mg IM qod x 5 doses -or- 1000 mg IM qod x 4 doses Late: latent > 1 year, cardiac • benzathine PCN G (LA Bicillin) 2.4 x 106 U IM q week x 3 -or• doxycycline 100 mg PO bid x 28 days Neurological • Aq PCN G 12-24 x 106 U IV qd x 10-14 days -or• ceftriaxone 1 gm IV or IM qd x 14 days REPEAT SEROLOGIC TESTS AFTER TREATMENT! There was a young man from Back Bay Who thought syphilis just went away He believed that a chancre Was only a canker That healed in a week and a day. But now he has "acne vulgaris"(Or whatever they call it in Paris); On his skin it has spread From his feet to his head, And his friends want to know his hair is. There's more to his terrible plight: His pupils won't close in the light His heart is cavorting, His wife is aborting, And he squints through his gun-barrel sight. Arthralgia cuts into his slumber; His aorta is in need of a plumber; But now he has tabes, And saber-shinned babies, While of gummas he has quite a number. He's been treated in every known way, But his spirochaetes grow day by day; He's developed paresis, Has long talks with Jesus, And thinks he's the Queen of the May. -Anonymous, ca. 1920 Infectious Vaginitis • • • • Bacterial vaginosis (40-50%) Vulvovaginal candidiasis (20-25%) Trichomoniasis (15-20%) uncommon causes – – – – group A streptococcal ulcerative TSS-related (S. aureus) atrophic vaginitis with 2o bacterial infection FB vaginitis with 2o bacterial infection Sobel, JD, NEJM 237(26):1896-1903, 1997. 14 Bacterial Vaginosis • change in bacterial flora – reduction of H2O2-positive lactobacilli – increase of Gardnerella vaginalis, Mycoplasma hominis, Mobiuncus spp, Prevotella spp, Bacteroides spp, Peptostreptococcus spp • bacteria possibly sexually transmitted • other factors – non-white race, IUD, prior pregnancy • “fishy-smelling”, thin, off-white discharge • pruritus, inflammation absent: frequently asymptomatic • Dx: wet mount, gram’s stain : “clue cells” (epithelial cells with adherent bacteria) – release of aromatic amines after treatment of secretions with 10%20% KOH Sobel, JD, NEJM 237(26):1896-1903, 1997. Candida Vulvovaginitis • Candida albicans 80-90% • Candida glabrata increasing in frequency – thinner discharge • not really an STD, but ping-pong effect may occur • Dx: wet mount, KOH preparation • Rx: topicals, single-dose fluconazole – may need prolonged therapy, other agents if C. glabrata Trichomoniasis • Trichomonas vaginalis may be present in 30-40% of male sexual partners • associated with other STD’s • may facilitate HIV transmission • ASx carrier severe, acute inflammation • Dx: smears (wet mounts, PAP); culture possible • Rx: metronidazole (single 2-gm dose vs 500 bid X 7) 15 Human Papilloma Virus • Major risk factors in women – – – – earlier age at onset of sexual activity higher lifetime number of sexual partners younger age other STIs such as HIV or HSV-2 • Most are infected at a young age, soon after becoming sexually active • Most infections are transient (90% resolve in 5 years) • Multiple sequential/concurrent infections with different oncogenic strains common in sexually active women • Vertical transmission (respiratory papillomatosis of the newborn (especially types 6, 11) HPV • Causes a variety of lesions of the skin and mucous membranes – – – – – common warts of the skin plantar warts genital warts (or condyloma acuminatum) squamous intraepithelial lesions invasive anogenital carcinoma including cervical, vaginal, vulvar, perineal, penile and anal cancers (especially in anal revceptive intercourse) www.hafmc.org/ resources/hpv.html HPV HPV • >100 types of HPV – ~30 infect the anogenital area • spread principally through skin-skin contact • high-risk* (associated with anogenital malignancies):16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, 82 • “probably carcinogenic”*: 26, 53, 66 • low-risk (associated with condyloma only) Most HPV infections are subclinical, and can be either transient or persistent All photos copyright 1998-2000 David Reznik,DDS *Munoz, N, et al., Epidemiologic Classification of Human Papillomavirus Types Associated with Cervical Cancer. NEJM 2003; 348(6): 518-527. 16 HPV - Diagnosis HPV- Natural History • Papanicolaou (cervical or anal) • Molecular screening for HPV DNA in positives highly reliable to predict women with high risk of progressing to high-grade lesions* – molecular screening can be overdone especially in young women, who may be only transiently infected with oncogenic strains • misclassification, anxiety, overtreatment *Wright, TC, et al., 2001 Consensus Guidelines for the Management of Women with Cervical Cytological Abnormalities. JAMA 2002; 287:2120-9. HPV - Treatment • Imiquimod cream • 20 % podophyllin antimitotic solution • 0.5 % podofilox solution • 5 % 5-fluorouracil cream • Trichloroacetic acid (TCA) • cryosurgery • electrocautery • laser treatment • Investigational Vaccine Wright TC and Schiffman M, NEJM 348(6):489-490, 2003 Granuloma Inguinale (Donovanosis) • Calymmatobacterium granulomatis (donovani) – a gram-negative rod related to Klebsiella • begins as a small subcutaneos nodule in the genital area that breaks through to the surface • uncommon in USA • Diagnosis: – smear – histopathology: mononuclear cells, PMN, no giant cells, Donovan bodies • Treatment: – doxycycline 100 mg PO bid until lesions heal – TMP-SMX I DS PO bid until lesions heal 17 Hemophilus ducreyi - Chancroid • common in Africa, uncommon in USA – major risk for acquisition of HIV • most cases in males • small friable papule develops in 2-5 days – penis, vagina, anus • later, development of regional lymphadenopathy – buboes, draining sinuses – Dx: “boxcars” on touch prep – fastidious (chocolate agar or fetal calf serum) • Treatment: – – – – ceftriaxone 250 mg IM -orazithromycin 1 gm PO -oramox/clav 500 PO tid x 7 days -orciprofloxacin 500 mg PO bid x 3 days Before Rx After Rx 18