General Goal: To know the major cause(s) of these infections, how they are transmitted, and the major manifestations of the infections.
Specific Educational Objectives: The student should be able to:
1. identify the common cause of each of the STI's discussed in this handout and the next two STI handouts. Know the common or pathognomonic signs of the infections.
2. describe the major manifestations of each infection and differentiate it from other infections in the course.
3. describe how you diagnose, treat and prevent these infections.
Reading: MEDICAL MICROBIOLOGY by P.R. Murray, K.S. Rosenthal, G.S. Kobayashi and M.A. Pfaller, 6th Edition. depends on the organism.
F.S. Southwick, Infectious Diseases A Clinical Short Course, 2nd edition, McGraw Hill.
Lecture: Dr. Neal R. Chamberlain
Burstein GR, Zenilman JM. Nongonococcal urethritis--a new paradigm. Clin Infect Dis 1999 Jan;28 Suppl 1:S66-73
CDC. The national plan to eliminate syphilis from the United States. Atlanta, Georgia: US Department of Health and Human Services, CDC, National Center for HIV, STD, and TB Prevention, 1999:1--84.
Transmitted Disease Guidelines 2002. Recommendations
May 10, 2002/Vol. 51/No.RR-6 (http://www.cdc.gov/std/treatment/TOC2002TG.htm)
This webpage includes STI’s that do not fit into the previous groupings
PID is a disease of women defined as the clinical syndrome resulting from the ascending spread of microorganisms from the vagina and endocervix to the endometrium, the fallopian tubes and to contiguous structures. It can include any combination of endometritis, salpingitis, tubo-ovarian abscess, and pelvic peritonitis. More than one organism causes PID. Signs and symptoms can result from any or all the following endometritis, salpingitis, tuba-ovarian abscess, and pelvic peritonitis.
N gonorrhoeae and C trachomatis (D and K serovars) are the most common causes of PID. Other causes of PID include anaerobic bacteria (Bacteroides, Prevotella, Peptostreptococcus, and Peptococcus), Streptococcus species, facultative gram-negative rods (ex. Gardnerella vaginalis, Escherichia coli and Haemophilus influenzae), Mycoplasma hominis and Actinomyces israelii (usually seen in women with long-standing intrauterine devices).
The signs and symptoms vary depending on the location and extent of the infection. Many women with PID have minimal symptoms, and some may have no symptoms ("silent PID") at all. If the infection is limited to the cervix and endometrium then the patient may only complain of vaginal discharge and irregular bleeding. However, if the infection has ascended up into the fallopian tubes and then gained access to the peritoneum the patient may have fever, irregular bleeding, bilateral lower abdominal pain, tenderness on cervical motion, tender adnexal masses, nausea, vomiting, and abdominal rebound tenderness. The following symptoms can occur in a patient with PID; moderate fever (generally above 101°F), bilateral lower abdominal pain that is maximal in the region of the fallopian tubes, increased vaginal discharge, irregular bleeding, tenderness on cervical motion, dyspareunia, tender adnexal mass(es), purulent endocervical discharge, nausea and vomiting. Only about 20% of the women with PID show all these signs. These signs are quite similar to other pathologic conditions such as appendicitis, ectopic pregnancy, septic abortion, rupture of an ovarian cyst and pyelonephritis.
PID is the most common cause of involuntary infertility in women. Dissemination to the liver can result in a perihepatitis also called Fitz-Hugh-Curtis syndrome. Adhesions that appear like "Violin Strings" form between the abdominal wall and liver capsule (may occur in both gonococcal and nongonococcal types of PID). Other complications include unilateral or bilateral ovarian abscesses, tubal occlusion, scarring, and adhesions (the adhesions can result in chronic abdominal pain), and death.
PID results when an infection of the vagina and cervix ascends to the upper genital tract of the female. Prior asymptomatic infections of the fallopian tubes, usually with N gonorrhoeae or C trachomatis, take place resulting in damage to the ciliary cells lining the fallopian tubes. Another infection ensues and the organisms are able to ascend the fallopian tubes and cause infections in contiguous structures. Sexually active women in their childbearing years are most at risk, and those under age 25 are more likely to develop PID than those older than 25. The cervix of teenage girls and young women is not fully matured as a result they are more likely to develop STI’s that result in PID.
At least four factors appear to contribute to the ascent of these bacteria and are associated with the pathogenesis of PID.
Clinical diagnosis of PID is difficult because of the wide variation in signs and symptoms among women with this condition. Because of the potential for damage to the reproductive health of women following even a mild case of PID, a "low threshold for diagnosis" of PID is encouraged.
Definitive diagnosis consists of direct visualization of inflamed fallopian tube(s) on laparoscopy, laparotomy, or biopsy evidence of salpingitis. Only a confirmed culture of a biopsy of the fallopian tube positively identifies the etiology of salpingitis. However, these diagnostic tools are oftentimes neither readily available for acute cases nor easily justified when symptoms and signs are mild and/or vague. In addition, laparoscopy will not detect endometritis and may not detect mild inflammation of the fallopian tubes.
Therefore, the diagnosis of PID is oftentimes based on clinical findings supplemented with results of cultures or non-culture tests of samples obtained from the endocervix. Unfortunately, no single historical, physical or laboratory finding is both sensitive and specific for the diagnosis of acute PID.
Empiric treatment of PID should be started in sexually active young women and other women at risk for STDs if they are experiencing pelvic or lower abdominal pain, if no cause for the illness other than PID can be identified (e.g., negative for pregnancy test, no acute appendicitis), and if one or more of the following minimum criteria are present on pelvic examination:
Requiring the minimum criteria may result in low sensitivity in some patients at high risk for infection. In patients with both pelvic tenderness and signs of lower genital tract inflammation, the diagnosis of PID should also be considered. Treatment may have to be started based simply on a patient’s risk profile. A more elaborate diagnostic evaluation is usually necessary, since an incorrect diagnosis and management can cause unwanted patient morbidity. These additional criteria may be used to enhance the specificity of the minimum criteria. Additional criteria that support a diagnosis of PID include the following:
• Oral temperature >101oF (>38.3oC);
• Abnormal cervical or vaginal mucopurulent discharge;
• Presence of white blood cells (WBC’s) on saline microscopy of vaginal secretions;
• Elevated erythrocyte sedimentation rate;
• Elevated C-reactive protein; and
• Laboratory documentation of cervical infection with Neisseria gonorrhoeae or Chlamydia trachomatis.
Most women with PID have either mucopurulent cervical discharge or evidence of inflammation when WBC’s are observed by a microscopic evaluation of a saline preparation of vaginal fluid. If the cervical discharge appears normal and no white blood cells are found on the vaginal fluid saline preparation, the diagnosis of PID is unlikely, and other causes of pain should be sought. The most specific criteria for the diagnosis of PID include:
• Endometrial biopsy with histopathologic evidence of endometritis;
• Transvaginal sonography or magnetic resonance imaging techniques showing thickened, fluid-filled tubes with or without free pelvic fluid or tubo-ovarian complex; and
• Laparoscopic abnormalities consistent with PID.
A diagnostic evaluation that includes some of these more extensive studies may be necessary in certain cases.
Treatment of PID is oftentimes empiric and it should cover the wide variety of possible etiologies (Neisseria gonorrhoeae, Chlamydia trachomatis, anaerobes, Gram-negative facultative bacteria, and streptococci). Treatment should be started as soon as the presumptive diagnosis has been made, because prevention of long-term sequelae has been linked directly with immediate administration of appropriate antibiotics.
In many cases PID can be treated on an outpatient basis but only if their temperature is <38oC, WBC <11,000/mm3, there is minimal evidence of peritonitis, active bowel sounds, and they are able to tolerate oral nourishment and treatment.
However, if the following is present the patient should be hospitalized and treated.
• Surgical emergencies (e.g., appendicitis) cannot be excluded;
• The patient is pregnant;
• The patient does not respond clinically to oral antimicrobial therapy;
• The patient is unable to follow or tolerate an outpatient oral regimen;
• The patient has severe illness, nausea and vomiting, or high fever; and
• The patient has a tubo-ovarian abscess.
Due to the wide number of different pathogens capable of causing PID broad-spectrum treatment appears to be effective in treating PID. Parenteral therapy can be given in an outpatient setting as well as in the hospital and its use in an outpatient setting depends on patient compliance with this type of therapy. Parenteral therapy includes cefotetan or cefoxitin AND doxycycline (orally due to pain on infusion). Parenteral therapy is usually given 24-48 hours after clinical improvement of the patient and then oral therapy can be initiated.
Oral therapy can be utilized to begin therapy in many patients. However, if the patient does not respond to this therapy within 72 hours then they should be reevaluated to confirm the diagnosis and should then be given parenteral therapy. Oral therapy includes ceftriaxone or cefoxitin plus doxycycline with or without metronidazole.
Follow-up of the patient following therapy is essential due to the higher failure rates of therapeutic regimens. Patients should demonstrate substantial clinical improvement (e.g., defervescence; reduction in direct or rebound abdominal tenderness; and reduction in uterine, adnexal, and cervical motion tenderness) within 3 days after therapy begins. Those patients that do not improve within this time period usually require hospitalization, additional diagnostic tests, and surgical intervention. Some physicians encourage confirmation of clinical resolution by repeating exam and endocervical culture 4-6 weeks after completing therapy.
To prevent further PID episodes the patient’s sexual partner(s) should be check for STI's. The IUD should be removed during therapy. Chlamydial screening of sexually active adolescent females twice a year can reduce the incidence of the chlamydial infections that can cause scarring and set the patient up for PID.
There are over 100 different types of Human Papilloma virus (HPV). Different types of the virus are associated with distinct clinical manifestations. Most HPV infections are asymptomatic, unrecognized or subclinical. Over 40 different types of this virus infect the genital tract. The various types of HPV are classified into low- and high-risk types based on their oncogenic potential. The low risk group usually is associated with visible genital warts (Condyloma Acuminata) and is most commonly caused by HPV types 6 and 11. The high-risk group does not usually produce visible genital warts and is caused by HPV types 16, 18, 31, 33 and 45. HPV types 16, 18, 31, 33 and 45 are strongly associated with cervical dysplasia and carcinoma. Types 16 and 18 are the most common causes of cervical neoplasia.
The genital wart lesion is usually a soft, fleshy, cauliflower-like lesion (exophytic) that may be present on the skin, external genitalia, perineum, and perianal and intra-anal regions. These genital warts may also be painful, friable, and pruritic. Many of these HPV infections are asymptomatic.
The HPV (types 16, 18, 31, 33 and 35) infected cells of the cervix do not in many cases have any recognizable lesion. Only after the addition of dilute acetic acid can the "acetowhite" epithelium is visualized. These HPV types have been associated with vaginal, anal, and cervical intraepithelial dysplasia and squamous cell carcinoma.
HPV types 16, 18, 31, 33 and 35 are found occasionally in visible genital warts and have been associated with external genital (i.e., vulvar, penile, and anal) squamous intraepithelial neoplasia (i.e., squamous cell carcinoma in situ, bowenoid papulosis, Erythroplasia of Queyrat, or Bowen’s disease of the genitalia). Patients who have visible genital warts can be infected simultaneously with multiple HPV types.
HPV infects and replicates in squamous epithelial cells, also known as keratinocytes, present in the skin and mucous membranes. The incubation period for genital wart formation is 3-4 months. HPV types 6 and 11 are the most common causes of genital warts and induce the keratinocytes to proliferate. This proliferation of the keratinocytes causes a thickening of the stratum granulosum and the basal and prickle cell layers in the stratum spinosum. This thickening results in formation of the verrucae (warts). HPV also causes the keratinocytes to become koilocytes (important term to remember concerning HPV). Koilocytes are enlarged keratinocytes with a halo around a larger than normal nucleus. Genital warts usually remain localized and recede spontaneously. Recurrences of genital warts are more common in immunocompromised patients.
The neoplastic HPV types 16 and 18 infect keratinocyte too. After the virus infects the cell it integrates into the host chromosome. Viral proteins E6 and E7 are produced in these keratinocytes and they bind to and inactivate the host cells proteins that suppress cell growth and multiplication (i.e., p53 and p105). The keratinocytes are no longer suppressed by p53 and p105 then begin enlarging and multiplying. These rapidly growing keratinocytes are now more susceptible to mutation, chromosomal aberrations, or the action of other cofactors (e.g., toxins from tobacco smoke) and become neoplastic cells.
Diagnosis of the cauliflower-like lesions is usually clinically determined however these lesions should be differentiated from condyloma lata and molluscum contagiosum. Diagnosis of genital warts can be confirmed by biopsy. However, biopsy is only needed under certain circumstances (e.g., if the diagnosis is uncertain; the lesions do not respond to standard therapy; the disease worsens during therapy; the patient is immunocompromised; or warts are pigmented, indurated, fixed, and ulcerated).
Placing dilute acetic acid (3-5%) on the cervix can reveal the acetowhite epithelium. A "PAP" smear should be performed and the pathologist will look for koilocytosis. Precursor cells (cervical dysplasia, CIN) develop into invasive cervical cancer over a number of years. CIN grades I, II, and III correspond to mild, moderate, and severe cervical dysplasia. CIN III, which includes severe dysplasia and carcinoma in situ, is unlikely to regress spontaneously and, if untreated, may eventually penetrate the basement membrane, becoming invasive carcinoma.
A definitive diagnosis of HPV infection is based on detection of viral nucleic acid (i.e., DNA or RNA) or capsid protein.
If no genital warts or cervical squamous intraepithelial lesions (SIL) are present, treatment is not recommended, whether diagnosed by colposcopy, biopsy, acetic acid application, or by detection of HPV with laboratory tests. Genital HPV infection oftentimes goes away on its own, and no therapy has been identified that can eradicate infection. In the presence of coexistent SIL, management should be based on histopathologic findings.
The goal of treating visible genital warts is the removal of the lesions. In most patients, treatment can induce wart-free periods. If left untreated, visible genital warts can resolve, remain unchanged, or increase in size and number. Treatment may reduce, but does not eliminate, HPV infection. Currently available therapies for genital warts appear to reduce infectivity but do not eradicate infectivity. No evidence indicates that the presence of genital warts or their treatment is associated with the development of cervical cancer. Various treatments exist and their use depends on the preferences of the patient, the available resources, and the experience of the health-care provider. Treatments include cryotherapy, surgical excision, laser vaporization, cautery, podophyllin, podophyllotoxin, 5-fluorouracil, trichloroacetic acid or interferon or imiquimode (imiquimode is an immunomodulator that acts via stimulation of Toll-like receptor 7 to induce the secretion of interferon alpha) for exophytic lesions.
Annual pap smears to stage subclinical infections with various treatments depending of the stage of the disease progression (squamous intraepithelial lesions (SIL)) or to cervical carcinoma. Invasive squamous cell carcinoma usually remains localized or regional for a considerable time; distant metastases occur late. The 5-yr survival rates are 80 to 90% for CIN stage I, 50 to 65% for stage II, 25 to 35% for stage III, and 0 to 15% for stage IV.
To avoid transmission to others avoid contact with lesions. The likelihood of transmission to future partners and the duration of infectivity after treatment are unknown. The use of latex condoms has been associated with a lower rate of cervical cancer, an HPV-associated disease. A quadrivalent vaccine against human papillomavirus (HPV types 6, 11, 16, 18) is available and licensed for females aged 9-26 years.
The FDA is currently (9/9/09) deciding if they should approve the use of the HPV vaccine in 9-26 year old males. This would prevent most genital warts, penile cancer, and anal cancer in males.
Among sexually active men aged <35 years, epididymitis is most often caused by C. trachomatis or N. gonorrhoeae. Epididymitis caused by sexually transmitted enteric organisms (e.g., Escherichia coli) also occurs among men who are the insertive partner during anal intercourse.
Nonsexually transmitted epididymitis that is associated with urinary-tract infections caused by Gram-negative enteric organisms occurs more frequently among men aged >35 years, men who have recently undergone urinary-tract instrumentation or surgery, and men who have anatomical abnormalities of the urinary tract.
Sexually transmitted epididymitis usually is accompanied by urethritis, which often is asymptomatic. Men who have epididymitis typically have unilateral testicular pain and tenderness; hydrocele and palpable swelling of the epididymis usually are present.
Testicular torsion which is not an infection but has similar symptoms is a surgical emergency and should be considered in all cases. It occurs more frequently among adolescents and in men without evidence of inflammation or infection.
The evaluation of men for epididymitis should include the following procedures.
Empiric therapy is indicated before culture results are available. Treatment of epididymitis caused by C. trachomatis or N. gonorrhoeae will result in a) microbiologic cure of infection, b) improvement of signs and symptoms, c) prevention of transmission to others, and d) a decrease in potential complications (e.g., infertility or chronic pain). As an adjunct to therapy, bed rest, scrotal elevation, and analgesics are recommended until fever and local inflammation have subsided.
For epididymitis most likely caused by gonococcal or chlamydial infection:
Ceftriaxone 250 mg IM in a single dose
Doxycycline 100 mg orally twice a day for 10 days.
For epididymitis most likely caused by enteric organisms, for patients allergic to cephalosporins and/or tetracyclines, or for epididymitis in patients aged >35 years:
Ofloxacin 300 mg orally twice a day for 10 days
Levofloxacin 500 mg orally once daily for 10 days
Although most patients can be treated on an outpatient basis, hospitalization should be considered when severe pain suggests other diagnoses (e.g., torsion, testicular infarction, or abscess) or when patients are febrile or noncompliant in taking an antimicrobial regimen.
Proctitis and proctocolitis are usually transmitted following anal intercourse. Enteritis is acquired among persons whose sexual practices include oral-fecal contact.
Proctitis- is an inflammatory condition involving the anus and rectum (the distal 10--12 cm). There are many causes of proctitis. They can be broken down into four basic groups:
The agents that can cause sexually-transmitted proctitis include N.
gonorrhoeae , HSV, T. pallidum, Chlamydia trachomatis and the
lymphogranuloma venereum serotypes of Chlamydia trachomatis. Entamoeba
histolytica is another agent which can cause proctitis and can be
transmitted by ano-oral sex.
Non-sexually transmitted infections causing proctitis are seen less frequently than STD proctitis. The classical example of non-sexually transmitted infection occurs in children and the proctitis is caused by Streptococcus pyogenes, the same organism which causes strep throat.
Autoimmune proctitis is associated with diseases such as ulcerative colitis
or Crohn's disease.
Proctitis may also be caused by physical agents including chemicals inserted into the rectum, medications and radiation. Radiation proctitis is seen in association with radiotherapy as part of cancer treatment.
Risk factors include high-risk sexual practices, homosexuality, and autoimmune disorders.
Proctocolitis- Pathogenic organisms include Campylobacter sp., Shigella sp., Entamoeba histolytica, and, rarely, LGV serovars of C. trachomatis. CMV or other opportunistic agents may be involved in immunosuppressed HIV-infected patients.
Enteritis- In otherwise healthy persons, Giardia lamblia is most frequently implicated.
Proctitis is inflammation limited to the rectum (the distal 10--12 cm) that may be associated with anorectal pain, tenesmus, or rectal discharge.
Proctocolitis is associated with symptoms of proctitis plus diarrhea or abdominal cramps and inflammation of the colonic mucosa extending to 12 cm above the anus.
Enteritis usually results in diarrhea and abdominal cramping without signs of proctitis or proctocolitis; it occurs among persons whose sexual practices include oral-fecal contact.
Evaluation for these syndromes should include appropriate diagnostic procedures (e.g., anoscopy or sigmoidoscopy, stool examination, and culture).
Proctocolitis- Fecal leukocytes may be detected on stool examination depending on the pathogen.
Enteritis- Multiple stool examinations may be necessary to detect Giardia.
When laboratory diagnostic capabilities are available, treatment decisions should be based on the specific diagnosis.
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