Although chlamydiae cause a number of human diseases, localized lower genital tract infections caused by C. trachomatis and the sequelae of such infections are the most important in terms of medical and economic impact. Oculogenital infections due to C. trachomatis serovars D–K are transmitted during sexual contact or from mother to baby during childbirth and are associated with many syndromes, including cervicitis, salpingitis, acute urethral syndrome, endometritis, ectopic pregnancy, infertility, and PID in female patients; urethritis, proctitis, and epididymitis in male patients; and conjunctivitis and pneumonia in infants. Women bear the greatest burden of morbidity because of the serious sequelae of these infections. Untreated infections lead to PID, and multiple episodes of PID can lead to tubal factor infertility and chronic pelvic pain. Studies estimate that up to 80–90% of women and >50% of men with C. trachomatis genital infections lack symptoms; other patients have very mild symptoms. Thus a large reservoir of infected persons continues to transmit infection to sexual partners.
As their designations reflect, the LGV serovars (L1, L2, and L3) cause LGV, an invasive sexually transmitted disease (STD) characterized by acute lymphadenitis with bubo formation and/or acute hemorrhagic proctitis (see “Lymphogranuloma Venereum,” below).
C. trachomatis genital infections are global in distribution. The World Health Organization (WHO) estimated in 2008 that >106.4 million cases occur annually worldwide. This figure makes chlamydial infection the most prevalent sexually transmitted bacterial infection in the world. The associated morbidity is substantial, and economic costs are high.
In the United States, chlamydial infections are the most commonly reported of all infectious diseases. In 2012, 1.3 million cases were reported to the U.S. Centers for Disease Control and Prevention (CDC); however, the CDC estimates that 2–3 million new cases occur per year, with substantial underreporting due to lack of screening in some populations. Rates of infection have increased every year; higher rates among women than among men reflect the focus on expansion of screening programs for women during the past 20 years, the use of increasingly sensitive diagnostic tests, an increased emphasis on case reporting, and improvements in the information systems used for reporting. The CDC and other professional organizations recommend annual screening of all sexually active women ≤25 years of age as well as rescreening of previously infected individuals at 3 months. Young women have the highest infection rates; in 2012, the figures were 3416.5 and 3722.5 cases per 100,000 population at 15–19 and 20–24 years of age, respectively. Age-specific rates among men, while much lower than those among women, were highest in the 20- to 24-year-old age group, at 1343.3 cases per 100,000. In 2012, rates increased for all racial and ethnic groups, with the highest rates among African Americans. For example, the rate of chlamydial infection among African-American girls 15–19 years of age was 7507.1 cases per 100,000—almost six times the rate among Caucasian girls in the same age group (1301.5/100,000). The rate among African-American women 20–24 years old was 4.8 times the rate among Caucasian women in the same age group. Similar racial disparities in reported rates of chlamydial infection exist among men. For boys 15–19 years of age, the rate among African Americans was 11.1 times the rate among Caucasians. The rate among Native Americans/Alaska Natives was more than four times the rate among Caucasians (648.3), and the rate among Latinos (383.6) was two times higher than that among Caucasians. These disparities are important reflections of health inequities in the United States.
The above statistics are based on case reporting. Studies based on screening surveys estimate that the U.S. prevalence of C. trachomatis cervical infection is 5% among asymptomatic female college students and prenatal patients, >10% among women seen in family planning clinics, and >20% among women seen in STD clinics. The prevalence of genital C. trachomatis infections varies substantially by geographic locale, with the highest rates in the southeastern United States. However, asymptomatic infections have been detected in >8–10% of young female military recruits from all parts of the country. The prevalence of C. trachomatis in the cervix of pregnant women is 5–10 times higher than that of Neisseria gonorrhoeae. The prevalence of genital infection with either agent is highest among women who are between the ages of 18 and 24, single, and non-Caucasian (e.g., African-American, Latina, Asian, Pacific Islander). Infections recur frequently in these same risk groups and are often acquired from untreated sexual partners. The use of oral contraception and the presence of cervical ectopy also confer an increased risk. The proportion of infections that are asymptomatic appears to be higher for C. trachomatis than for N. gonorrhoeae, and symptomatic C. trachomatis infections are clinically less severe. Mild or asymptomatic C. trachomatis infections of the fallopian tubes nonetheless cause ongoing tubal damage and infertility. The costs of C. trachomatis infections and their complications to the U.S. health care system have recently been estimated to exceed $516.7 million annually.
NONGONOCOCCAL AND POSTGONOCOCCAL URETHRITIS
C. trachomatis is the most common cause of nongonococcal urethritis (NGU) and postgonococcal urethritis (PGU). The designation PGU refers to NGU developing in men 2–3 weeks after treatment of gonococcal urethritis with single doses of agents such as penicillin or cephalosporins, which lack antimicrobial activity against chlamydiae. Since current treatment regimens for gonorrhea have evolved and now include combination therapy with tetracycline, doxycycline, or azithromycin—all of which are effective against concomitant chlamydial infection—both the incidence of PGU and the causative role of C. trachomatis in this syndrome have declined.
In the United States, most of the estimated 2 million cases of acute urethritis are NGU, and C. trachomatis is implicated in 30–50% of these cases. The cause of most of the remaining cases of NGU is uncertain, but recent evidence suggests that Ureaplasma urealyticum, Mycoplasma genitalium, Trichomonas vaginalis, and herpes simplex virus (HSV) cause some cases. The rate of involvement of C. trachomatis in urethral infection ranges from 3–7% among asymptomatic men to 15–20% among symptomatic men attending STD clinics. A multisite study of men in Baltimore, Seattle, Denver, and San Francisco reported an overall chlamydial prevalence of 7% in urine samples assessed by nucleic acid amplification tests (NAATs). As in women, infection in men is age related, with young age as the greatest risk factor for chlamydial urethritis. The prevalence among men is highest at 20–24 years of age. In STD clinics, urethritis is usually less prevalent among men who have sex with men (MSM) than among heterosexual men and is almost always much more common among African-American men than among Caucasian men. One study reported prevalences of 19% and 9% among nonwhite and white heterosexual men, respectively.
NGU is diagnosed by documentation of a leukocytic urethral exudate and by exclusion of gonorrhea by Gram’s staining or culture. C. trachomatis urethritis is generally less severe than gonococcal urethritis, although in any individual patient these two forms of urethritis cannot reliably be differentiated solely on clinical grounds. Symptoms include urethral discharge (often whitish and mucoid rather than frankly purulent), dysuria, and urethral itching. Physical examination may reveal meatal erythema and tenderness as well as a urethral exudate that is often demonstrable only by stripping of the urethra.
At least one-third of male patients with C. trachomatis urethral infection have no evident signs or symptoms of urethritis. The availability of NAATs for first-void urine specimens has facilitated broader-based testing for asymptomatic infection in male patients. As a result, asymptomatic chlamydial urethritis has been demonstrated in 5–10% of sexually active male adolescents screened at school-based clinics or community centers. Such patients generally have pyuria (≥15 leukocytes per 400× microscopic field in the sediment of first-void urine), a positive leukocyte esterase test, or an increased number of leukocytes on a Gram-stained smear prepared from a urogenital swab inserted 1–2 cm into the anterior urethra. To differentiate between true urethritis and functional symptoms in symptomatic patients or to make a presumptive diagnosis of C. trachomatis infection in high-risk but asymptomatic men (e.g., male patients in STD clinics, sex partners of women with nongonococcal salpingitis or mucopurulent cervicitis, fathers of children with inclusion conjunctivitis), the examination of an endourethral specimen for increased leukocytes is useful if specific diagnostic tests for chlamydiae are not available. Alternatively, urethritis can be assayed noninvasively by examination of a first-void urine sample for pyuria, either by microscopy or by the leukocyte esterase test. Urine (or a urethral swab) can also be tested directly for chlamydiae by DNA amplification methods, as described below (see “Detection Methods”).
Chlamydial urethritis may be followed by acute epididymitis, but this condition is rare, generally occurring in sexually active patients <35 years of age; in older men, epididymitis is usually associated with gram-negative bacterial infection and/or instrumentation procedures. It is estimated that 50–70% of cases of acute epididymitis are caused by C. trachomatis. The condition usually presents as unilateral scrotal pain with tenderness, swelling, and fever in a young man, often occurring in association with chlamydial urethritis. The illness may be mild enough to treat with oral antibiotics on an outpatient basis or severe enough to require hospitalization and parenteral therapy. Testicular torsion should be excluded promptly by radionuclide scan, Doppler flow study, or surgical exploration in a teenager or young adult who presents with acute unilateral testicular pain without urethritis. The possibility of testicular tumor or chronic infection (e.g., tuberculosis) should be excluded when a patient with unilateral intrascrotal pain and swelling does not respond to appropriate anti-microbial therapy.
Reactive arthritis consists of conjunctivitis, urethritis (or, in female patients, cervicitis), arthritis, and characteristic mucocutaneous lesions. It may develop in 1–2% of cases of NGU and is thought to be the most common type of peripheral inflammatory arthritis in young men. C. trachomatis has been recovered from the urethra of 16–44% of patients with reactive arthritis and from 69% of men who have signs of urogenital inflammation at the time of examination. Antibodies to C. trachomatis have also been detected in 46–67% of patients with reactive arthritis, and Chlamydia-specific cell-mediated immunity has been documented in 72%. In addition, C. trachomatis has been isolated from synovial biopsy samples from 15 of 29 patients in a number of small series and from a smaller proportion of synovial fluid specimens. Chlamydial nucleic acids have been identified in synovial membranes and chlamydial EBs in joint fluid. The pathogenesis of reactive arthritis is unclear, but this condition probably represents an abnormal host response to a number of infectious agents, including those associated with bacterial gastroenteritis (e.g., Salmonella, Shigella, Yersinia, or Campylobacter), or to infection with C. trachomatis or N. gonorrhoeae. Since >80% of affected patients have the HLA-B27 phenotype and since other mucosal infections produce an identical syndrome, chlamydial infection is thought to initiate an aberrant hyperactive immune response that produces inflammation of the involved target organs in these genetically predisposed individuals. Evidence of exaggerated cell-mediated and humoral immune responses to chlamydial antigens in reactive arthritis supports this hypothesis. The finding of chlamydial EBs and DNA in joint fluid and synovial tissue from patients with reactive arthritis suggests that chlamydiae may actually spread from genital to joint tissues in these patients—perhaps in macrophages.
NGU is the initial manifestation of reactive arthritis in 80% of patients, typically occurring within 14 days after sexual exposure. The urethritis may be mild and may even go unnoticed by the patient. Similarly, gonococcal urethritis may precede reactive arthritis, but co-infection with an agent of NGU is difficult to rule out. The urethral discharge may be purulent or mucopurulent, and patients may or may not report dysuria. Accompanying prostatitis, usually asymptomatic, has been described. Arthritis usually begins ~4 weeks after the onset of urethritis but may develop sooner or, in a small percentage of cases, may actually precede urethritis. The knees are most frequently involved; next most commonly affected are the ankles and small joints of the feet. Sacroiliitis, either symmetrical or asymmetrical, is documented in two-thirds of patients. Mild bilateral conjunctivitis, iritis, keratitis, or uveitis is sometimes present but lasts for only a few days. Finally, dermatologic manifestations occur in up to 50% of patients. The initial lesions—usually papules with a central yellow spot—most often involve the soles and palms and, in ~25% of patients, eventually epithelialize and thicken to produce keratoderma blenorrhagicum. Circinate balanitis is usually painless and occurs in fewer than half of patients. The initial episode of reactive arthritis usually lasts 2–6 months.
Primary anal or rectal infections with C. trachomatis have been described in women and MSM who practice anal intercourse. In these infections, rectal involvement is initially characterized by severe anorectal pain, a bloody mucopurulent discharge, and tenesmus. Oculogenital serovars D–K and LGV serovars L1, L2, and L3 have been found to cause proctitis. The LGV serovars are far more invasive and cause much more severely symptomatic disease, including severe ulcerative proctocolitis that can be clinically confused with HSV proctitis. Histologically, LGV proctitis may resemble Crohn’s disease in that giant cell formation and granulomas are detected. In the United States and Europe, cases of LGV proctitis occur almost exclusively in MSM, many of whom are positive for HIV infection.
The less invasive non-LGV serovars of C. trachomatis cause mild proctitis. Many infected individuals are asymptomatic, and in these cases infection is diagnosed only by routine culture or NAAT of rectal swabs. The number of fecal leukocytes is usually abnormal in both asymptomatic and symptomatic cases. Sigmoidoscopy may yield normal findings or may reveal mild inflammatory changes or small erosions or follicles in the lower 10 cm of the rectum. Histologic examination of rectal biopsies generally shows anal crypts and prominent follicles as well as neutrophilic infiltration of the lamina propria. Chlamydial proctitis is best diagnosed by isolation of C. trachomatis from the rectum and documentation of a response to appropriate therapy. NAATs are reportedly more sensitive than culture for diagnosis and are also specific.
Although many women with chlamydial infections of the cervix have no symptoms, almost half generally have local signs of infection on examination. Cervicitis is usually characterized by the presence of a mucopurulent discharge, with >20 neutrophils per microscopic field visible in strands of cervical mucus in a thinly smeared, gram-stained preparation of endocervical exudate. Hypertrophic ectopy of the cervix may also be evident as an edematous area near the cervical os that is congested and bleeds easily on minor trauma (e.g., when a specimen is collected with a swab). A Papanicolaou smear shows increased numbers of neutrophils as well as a characteristic pattern of mononuclear inflammatory cells including plasma cells, transformed lymphocytes, and histiocytes. Cervical biopsy shows a predominantly mononuclear cell infiltrate of the subepithelial stroma. Clinical experience and collaborative studies indicate that a cutoff of >30 polymorphonuclear neutrophils (PMNs) per 1000× field in a gram-stained smear of cervical mucus correlates best with chlamydial or gonococcal cervicitis.
Clinical recognition of chlamydial cervicitis depends on a high index of suspicion and careful cervical examination. No genital symptoms are specifically correlated with chlamydial cervical infection. The differential diagnosis of a mucopurulent discharge from the endocervical canal in a young, sexually active woman includes gonococcal endocervicitis, salpingitis, endometritis, and intrauterine contraceptive device–induced inflammation. Diagnosis of cervicitis is based on the presence of PMNs on a cervical swab as noted above; the presence of chlamydiae is confirmed by either culture or NAAT.
PELVIC INFLAMMATORY DISEASE
Inflammation of sections of the fallopian tube is often referred to as salpingitis or PID. The proportion of acute salpingitis cases caused by C. trachomatis varies geographically and with the population studied. It has been estimated that C. trachomatis causes up to 50% of PID cases in the United States. PID occurs via ascending intraluminal spread of C. trachomatis or N. gonorrhoeae from the lower genital tract. Mucopurulent cervicitis is often followed by endometritis, endosalpingitis, and finally pelvic peritonitis. Evidence of mucopurulent cervicitis is often found in women with laparoscopically verified salpingitis. Similarly, endometritis, demonstrated by an endometrial biopsy showing plasma cell infiltration of the endometrial epithelium, is documented in most women with laparoscopy-verified chlamydial (or gonococcal) salpingitis. Chlamydial endometritis can also occur in the absence of clinical evidence of salpingitis. Histologic evidence of endometritis has been correlated with a syndrome consisting of vaginal bleeding, lower abdominal pain, and uterine tenderness in the absence of adnexal tenderness. Chlamydial salpingitis produces milder symptoms than gonococcal salpingitis and may be associated with less marked adnexal tenderness. Thus, mild adnexal or uterine tenderness in a sexually active woman with cervicitis suggests chlamydial PID.
Chronic untreated endometrial and tubal inflammation can result in tubal scarring, impaired tubal function, tubal occlusion, and infertility, even among women who report no prior treatment for PID. C. trachomatis has been implicated particularly often in “subclinical” PID on the basis of (1) a lack of history of PID among Chlamydia-seropositive women with tubal damage or (2) detection of chlamydial DNA or antigen among asymptomatic women with tubal infertility. These data suggest that the best method to prevent PID and its sequelae is surveillance and control of lower genital tract infections along with diagnosis and treatment of sex partners and prevention of reinfections. Promotion of early symptom recognition and health care presentation may reduce the frequency and severity of sequelae of PID.
The Fitz-Hugh–Curtis syndrome was originally described as a complication of gonococcal PID. However, studies over the past several decades have suggested that chlamydial infection is more commonly associated with perihepatitis than is N. gonorrhoeae. Perihepatitis should be suspected in young, sexually active women who develop right-upper-quadrant pain, fever, or nausea. Evidence of salpingitis may or may not be found on examination. Frequently, perihepatitis is strongly associated with extensive tubal scarring, adhesions, and inflammation observed at laparoscopy, and high titers of antibody to the 57-kDa chlamydial heat-shock protein have been documented. Culture and/or serologic evidence of C. trachomatis is found in three-fourths of women with this syndrome.
URETHRAL SYNDROME IN WOMEN
In the absence of infection with uropathogens such as coliforms or Staphylococcus saprophyticus, C. trachomatis is the pathogen most commonly isolated from college women with dysuria, frequency, and pyuria. Screening studies can recover C. trachomatis from both the cervix and the urethra; in up to 25% of infected women, the organism is isolated only from the urethra. The urethral syndrome in women consists of dysuria and frequency in conjunction with chlamydial urethritis, pyuria, and no bacteriuria or urinary pathogens. Although symptoms of the urethral syndrome may develop in some women with chlamydial infection, the majority of women attending STD clinics for urethral chlamydial infection do not have dysuria or frequency. Even in women with chlamydial urethritis causing the acute urethral syndrome, signs of urethritis such as urethral discharge, meatal redness, and swelling are uncommon. However, mucopurulent cervicitis in a woman presenting with dysuria and frequency strongly suggests C. trachomatis urethritis. Other correlates of chlamydial urethral syndrome include a duration of dysuria of >7–10 days, lack of hematuria, and lack of suprapubic tenderness. Abnormal urethral Gram’s stains showing >10 PMNs per 1000× field in women with dysuria but without coliform bacteriuria support the diagnosis of chlamydial urethritis. Other possible diagnoses include gonococcal or trichomonal infection of the urethra.
INFECTION IN PREGNANCY AND THE NEONATAL PERIOD
Infections during pregnancy can be transmitted to infants during delivery. Approximately 20–30% of infants exposed to C. trachomatis in the birth canal develop conjunctivitis, and 10–15% subsequently develop pneumonia. Consequently, all newborn infants receive ocular prophylaxis at birth to prevent ophthalmia neonatorum. Without treatment, conjunctivitis usually develops at 5–19 days of life and often results in a profuse mucopurulent discharge. Roughly half of infected infants develop clinical evidence of inclusion conjunctivitis. However, it is impossible to differentiate chlamydial conjunctivitis from other forms of neonatal conjunctivitis (e.g., that due to N. gonorrhoeae, Haemophilus influenzae, Streptococcus pneumoniae, or HSV) on clinical grounds; thus laboratory diagnosis is required. Inclusions within epithelial cells are often detected in Giemsa-stained conjunctival smears, but these smears are considerably less sensitive than cultures or NAATs for chlamydiae. Gram-stained smears may show gonococci or occasional small gram-negative coccobacilli in Haemophilus conjunctivitis, but smears should be accompanied by cultures or NAATs for these agents.
C. trachomatis has also been isolated frequently and persistently from the nasopharynx, rectum, and vagina of infected infants—occasionally for >1 year in the absence of treatment. In some cases, otitis media results from perinatally acquired chlamydial infection. Pneumonia may develop in infants from 2 weeks to 4 months of age. C. trachomatis is estimated to cause 20–30% of pneumonia cases in infants <6 months of age. Epidemiologic studies have linked chlamydial pulmonary infection in infants with increased occurrence of subacute lung disease (bronchitis, asthma, wheezing) in later childhood.
C. trachomatis serovars L1, L2, and L3 cause LGV, an invasive systemic STD. The peak incidence of LGV corresponds with the age of greatest sexual activity: the second and third decades of life. The worldwide incidence of LGV is falling, but the disease is still endemic and a major cause of morbidity in parts of Asia, Africa, South America, and the Caribbean. LGV is rare in industrialized countries; for more than a decade, the reported incidence in the United States has been only 0.1 case per 100,000 population. In the Bahamas, an apparent outbreak of LGV was described in association with a concurrent increase in heterosexual infection with HIV. Reports of outbreaks with the newly identified variant L2b in Europe, Australia, and the United States indicate that LGV is becoming more prevalent among MSM. These cases have usually presented as hemorrhagic proctocolitis in HIV-positive men. More widespread use of NAATs for identification of rectal infections may have enhanced case recognition.
LGV begins as a small painless papule that tends to ulcerate at the site of inoculation, often escaping attention. This primary lesion heals in a few days without scarring and is usually recognized as LGV only in retrospect. LGV strains of C. trachomatis have occasionally been recovered from genital ulcers and from the urethra of men and the endocervix of women who present with inguinal adenopathy; these areas may be the primary sites of infection in some cases. Proctitis is more common among people who practice receptive anal intercourse, and an elevated white blood cell count in anorectal smears may predict LGV in these patients. Ulcer formation may facilitate transmission of HIV infection and other sexually transmitted and blood-borne diseases.
As NAATs for C. trachomatis are being used more often, increasing numbers of cases of LGV proctitis are being recognized in MSM. Such patients present with anorectal pain and mucopurulent, bloody rectal discharge. Sigmoidoscopy reveals ulcerative proctitis or proctocolitis, with purulent exudate and mucosal bleeding. Histopathologic findings in the rectal mucosa include granulomas with giant cells, crypt abscesses, and extensive inflammation. These clinical, sigmoidoscopic, and histopathologic findings may closely resemble those of Crohn’s disease of the rectum.
The most common presenting picture in heterosexual men and women is the inguinal syndrome, which is characterized by painful inguinal lymphadenopathy beginning 2–6 weeks after presumed exposure; in rare instances, the onset comes after a few months. The inguinal adenopathy is unilateral in two-thirds of cases, and palpable enlargement of the iliac and femoral nodes is often evident on the same side as the enlarged inguinal nodes. The nodes are initially discrete, but progressive periadenitis results in a matted mass of nodes that becomes fluctuant and suppurative. The overlying skin becomes fixed, inflamed, and thin, and multiple draining fistulas finally develop. Extensive enlargement of chains of inguinal nodes above and below the inguinal ligament (“the sign of the groove”) is not specific and, although not uncommon, is documented in only a minority of cases. Spontaneous healing usually takes place after several months; inguinal scars or granulomatous masses of various sizes persist for life. Massive pelvic lymphadenopathy may lead to exploratory laparotomy.
Constitutional symptoms are common during the stage of regional lymphadenopathy and, in cases of proctitis, may include fever, chills, headache, meningismus, anorexia, myalgias, and arthralgias. Other systemic complications are infrequent but include arthritis with sterile effusion, aseptic meningitis, meningoencephalitis, conjunctivitis, hepatitis, and erythema nodosum (Fig. 25e-40). Complications of untreated anorectal infection include perirectal abscess; anal fistulas; and rectovaginal, rectovesical, and ischiorectal fistulas. Secondary bacterial infection probably contributes to these complications. Rectal stricture is a late complication of anorectal infection and usually develops 2–6 cm from the anal orifice—i.e., at a site within reach on digital rectal examination. A small percentage of cases of LGV in men present as chronic progressive infiltrative, ulcerative, or fistular lesions of the penis, urethra, or scrotum. Associated lymphatic obstruction may produce elephantiasis. When urethral stricture occurs, it usually involves the posterior urethra and causes incontinence or difficulty with urination.
Historically, chlamydiae were cultivated in the yolk sac of embryonated eggs. The organisms can be grown more easily in tissue culture, but cell culture—once considered the diagnostic gold standard—has been replaced by nonculture assays (Table 213-1). In general, culture for chlamydiae in clinical specimens is now performed only in specialized laboratories. The first nonculture assays, such as DFA staining of clinical material and enzyme immunoassay (EIA), have been replaced by NAATS, which are molecular tests that amplify the nucleic acids in clinical specimens. NAATS are currently recommended by the CDC as the diagnostic assays of choice; four or five NAAT assays approved by the U.S. Food and Drug Administration (FDA) are commercially available, some as high-throughput robotic platforms. Point-of-care diagnostic assays (including NAATs), by which patients can be treated before leaving the clinic, are of increasing interest and are becoming available.
TABLE 213-1Diagnostic Tests for Sexually Transmitted and Perinatal Chlamydia trachomatis Infection ||Download (.pdf) TABLE 213-1Diagnostic Tests for Sexually Transmitted and Perinatal Chlamydia trachomatis Infection
|Infection ||Suggestive Signs/Symptoms ||Presumptive Diagnosisa ||Confirmatory Test of Choice |
|NGU, PGU ||Discharge, dysuria ||Gram’s stain with >4 neutrophils per oil-immersion field; no gonococci ||Urine or urethral NAAT for C. trachomatis |
|Epididymitis ||Unilateral intrascrotal swelling, pain, tenderness; fever; NGU ||Gram’s stain with >4 neutrophils per oil-immersion field; no gonococci; urinalysis with pyuria ||Urine or urethral NAAT for C. trachomatis |
|Cervicitis ||Mucopurulent cervical discharge, bleeding and edema of the zone of cervical ectopy ||Cervical Gram’s stain with ≥20 neutrophils per oil-immersion field in cervical mucus ||Urine, cervical, or vaginal NAAT for C. trachomatis |
|Salpingitis ||Lower abdominal pain, cervical motion tenderness, adnexal tenderness or masses ||C. trachomatis always potentially present in salpingitis ||Urine, cervical, or vaginal NAAT for C. trachomatis |
|Urethritis ||Dysuria and frequency without hematuria ||MPC; sterile pyuria; negative routine urine culture ||Urine or urethral NAAT for C. trachomatis |
|Adults of Either Sex |
|Proctitis ||Rectal pain, discharge, tenesmus, bleeding; history of receptive anorectal intercourse ||Negative gonococcal culture and Gram’s stain; at least 1 neutrophil per oil-immersion field in rectal Gram’s stain ||Rectal NAAT for C. trachomatis or culture |
|Reactive arthritis ||NGU, arthritis, conjunctivitis, typical skin lesions ||Gram’s stain with >4 neutrophils per oil-immersion field; lack of gonococci indicative of NGU ||Urine or urethral NAAT for C. trachomatis |
|LGV ||Regional adenopathy, primary lesion, proctitis, systemic symptoms ||None ||Culture of LGV strain from node or rectum, occasionally from urethra or cervix; NAAT for C. trachomatis from these sites; LGV CF titer, ≥1:64; micro-IF titer, ≥1:512 |
|Conjunctivitis ||Purulent conjunctival discharge 6–18 days after delivery ||Negative culture and Gram’s stain for gonococci, Haemophilus spp., pneumococci, staphylococci ||Conjunctival NAAT for C. trachomatis; FA-stained scraping of conjunctival material |
|Infant pneumonia ||Afebrile; staccato cough, diffuse rales, bilateral hyperinflation, interstitial infiltrates ||None ||Chlamydial culture or NAAT of sputum, pharynx, eye, rectum; micro-IF antibody to C. trachomatis—fourfold change in IgG or IgM antibody titer |
Cervical and urethral swabs have traditionally been used for the diagnosis of STDs in female and male patients, respectively. However, given the greatly increased sensitivity and specificity of NAATs, less invasive samples (e.g., urine for both sexes and vaginal swabs for women) can be used. For screening of asymptomatic women, the CDC now recommends that self-collected or clinician-collected vaginal swabs, which are slightly more sensitive than urine, be used. Urine screening tests are often used in outreach screening programs, however. For symptomatic women undergoing a pelvic examination, cervical swab samples are desirable because they have slightly higher chlamydial counts. For male patients, a urine specimen is the sample of choice, but self-collected penile-meatal swabs have been explored.
ALTERNATIVE SPECIMEN TYPES
Ocular samples from babies and adults can be assessed by NAATs. However, since commercial NAATs for this purpose have not yet been approved by the FDA, laboratories must perform their own verification studies. Samples from rectal and pharyngeal sites have been used successfully to detect chlamydiae, but laboratories must verify test performance.
Because NAATs detect nucleic acids instead of live organisms, they should be used with caution as test-of-cure assays. Residual nucleic acid from cells rendered noninfective by antibiotics may continue to yield a positive result in NAATs until as long as 3 weeks after therapy, when viable organisms have actually been eradicated. Therefore, clinicians should not use NAATs for test of cure until after 3 weeks. The CDC currently does not recommend a test of cure after treatment for infection with C. trachomatis. However, because incidence studies have demonstrated that previous chlamydial infection increases the probability of becoming reinfected, the CDC does recommend that previously infected individuals be rescreened 3 months after treatment.
Serologic testing may be helpful in the diagnosis of LGV and neonatal pneumonia caused by C. trachomatis. The serologic test of choice is the microimmunofluorescence (MIF) test, in which high-titer purified EBs mixed with embryonated chicken yolk-sac material are affixed to a glass microscope slide to which dilutions of serum are applied. After incubation and washing, fluorescein-conjugated IgG or IgM antibody is applied. The test is read with an epifluorescence microscope, with the highest dilution of serum producing visible fluorescence designated as the titer. The MIF test is not widely available and is highly labor intensive. Although the complement fixation (CF) test also can be used, it employs only lipopolysaccharide (LPS) as the antigen and therefore identifies the pathogen only to the genus level. Single-point titers of >1:64 support a diagnosis of LGV, in which it is difficult to demonstrate rising antibody titers; i.e., paired serum samples are difficult to obtain since, by its very nature, the disease results in the patient’s being seen by the physician after the acute stage. Any antibody titer of >1:16 is considered significant evidence of exposure to chlamydiae. However, serologic testing is never recommended for diagnosis of uncomplicated genital infections of the cervix, urethra, and lower genital tract or for C. trachomatis screening of asymptomatic individuals.
TREATMENT C. Trachomatis Genital Infections
A 7-day course of tetracycline (500 mg four times daily), doxycycline (100 mg twice daily), erythromycin (500 mg four times daily), or a fluoroquinolone (ofloxacin, 300 mg twice daily; or levofloxacin, 500 mg/d) can be used for treatment of uncomplicated chlamydial infections. A single 1-g oral dose of azithromycin is as effective as a 7-day course of doxycycline for the treatment of uncomplicated genital C. trachomatis infections in adults. Azithromycin causes fewer adverse gastrointestinal reactions than do older macrolides such as erythromycin. The single-dose regimen of azithromycin has great appeal for the treatment of patients with uncomplicated chlamydial infection (especially those without symptoms and those with a likelihood of poor compliance) and of the sexual partners of infected patients. These advantages must be weighed against the considerably greater cost of azithromycin. Whenever possible, the single 1-g dose should be given as directly observed therapy. Although not approved by the FDA for use in pregnancy, this regimen appears to be safe and effective for this purpose. However, amoxicillin (500 mg three times daily for 7 days) also can be given to pregnant women. The fluoroquinolones are contraindicated in pregnancy. A 2-week course of treatment is recommended for complicated chlamydial infections (e.g., PID, epididymitis) and at least a 3-week course of doxycycline (100 mg orally twice daily) or erythromycin base (500 mg orally four times daily) for LGV. Failure of treatment with a tetracycline in genital infections usually indicates poor compliance or reinfection rather than involvement of a drug-resistant strain. To date, clinically significant drug resistance has not been observed in C. trachomatis.
Treatment or testing for chlamydiae should be considered among N. gonorrhoeae–infected patients because of the frequency of co-infection. Systemic treatment with erythromycin has been recommended for ophthalmia neonatorum and for C. trachomatis pneumonia in infants. For the treatment of adult inclusion conjunctivitis, a single 1-g dose of azithromycin is as effective as standard 10-day treatment with doxycycline. Recommended treatment regimens for both bubonic and anogenital LGV include tetracycline, doxycycline, or erythromycin for 21 days. SEX PARTNERS
The continued high prevalence of chlamydial infections in most parts of the United States is due primarily to the failure to diagnose—and therefore treat—patients with symptomatic or asymptomatic infection and their sex partners. Urethral or cervical infection with C. trachomatis has been well documented in a high proportion of the sex partners of patients with NGU, epididymitis, reactive arthritis, salpingitis, and endocervicitis. If possible, confirmatory laboratory tests for chlamydiae should be undertaken in these individuals, but even those without positive tests or evidence of clinical disease who have recently been exposed to proven or possible chlamydial infection (e.g., NGU) should be offered therapy. A novel approach is partner-delivered therapy, in which infected patients receive treatment and are also provided with single-dose azithromycin to give to their sex partner(s). NEONATES AND INFANTS
In neonates with conjunctivitis or infants with pneumonia, erythromycin ethylsuccinate or estolate can be given orally at a dosage of 50 mg/kg per day, preferably in four divided doses, for 2 weeks. Careful attention must be given to compliance with therapy—a frequent problem. Relapses of eye infection are common after topical treatment with erythromycin or tetracycline ophthalmic ointment and may also follow oral erythromycin therapy. Thus follow-up cultures should be performed after treatment. Both parents should be examined for C. trachomatis infection and, if diagnostic testing is not readily available, should be treated with doxycycline or azithromycin.
Since many chlamydial infections are asymptomatic, effective control and prevention must involve periodic screening of individuals at risk. Selective cost-effective screening criteria have been developed. Among women, young age (generally <25 years) is a critical risk factor for chlamydial infections in nearly all studies. Other risk factors include mucopurulent cervicitis; multiple, new, or symptomatic male sex partners; and lack of barrier contraceptive use. In some settings, screening based on young age may be as sensitive as criteria that incorporate behavioral and clinical measures. Another strategy is universal testing of all patients in high-prevalence clinic populations (e.g., STD clinics, juvenile detention facilities, and family planning clinics).
The effectiveness of selective screening in reducing the prevalence of chlamydial infection among women has been demonstrated in several studies. In the Pacific Northwest, where extensive screening began in family planning clinics in 1998 and in STD clinics in 1993, the prevalence declined from 10% in the 1980s to <5% in 2000. Similar trends have occurred in association with screening programs elsewhere. In addition, screening can effect a reduction in upper genital tract disease. In Seattle, women at a large health maintenance organization who were screened for chlamydial infection on a routine basis had a lower incidence of symptomatic PID than did women who received standard care and underwent more selective screening.
In settings with low to moderate prevalence, the prevalence at which selective screening becomes more cost-effective than universal screening must be defined. Most studies have concluded that universal screening is preferable in settings with a chlamydial prevalence of >3–7%. Depending on the criteria used, selective screening is likely to be more cost-effective when prevalence falls below 3%. Nearly all regions of the United States have now initiated screening programs, particularly in family planning and STD clinics. Along with single-dose therapy, the availability of highly sensitive and specific diagnostic NAATs using urine specimens and self-obtained vaginal swabs makes it feasible to mount an effective nationwide Chlamydia control program, with screening of high-risk individuals in traditional health-care settings and in novel outreach and community-based settings. The U.S. Preventive Services Task Force has given C. trachomatis screening a Grade A recommendation, which means that private insurance and Medicare will cover its cost under the Affordable Care Act.
Trachoma—a sequela of ocular disease in developing countries—continues to be a leading cause of preventable infectious blindness worldwide. The WHO estimates that ~6 million people have been blinded by trachoma and that ~1.3 million people in developing countries still suffer from preventable blindness due to trachoma; certainly hundreds of millions live in trachoma-endemic areas. Foci of trachoma persist in Australia, the South Pacific, and Latin America. Serovars A, B, Ba, and C are isolated from patients with clinical trachoma in areas of endemicity in developing countries in Africa, the Middle East, Asia, and South America.
The trachoma-hyperendemic areas of the world are in northern and sub-Saharan Africa, the Middle East, drier regions of the Indian subcontinent, and Southeast Asia. In hyperendemic areas, the prevalence of trachoma is essentially 100% by the second or third year of life. Active disease is most common among young children, who are the reservoir for trachoma. By adulthood, active infection is infrequent but sequelae result in blindness. In such areas, trachoma constitutes the major cause of blindness.
Trachoma is transmitted through contact with discharges from the eyes of infected patients. Transmission is most common under poor hygienic conditions and most often takes place between family members or between families with shared facilities. Flies can also transfer the mucopurulent ocular discharges, carrying the organisms on their legs from one person to another. The International Trachoma Initiative founded by the WHO in 1998 aims to eliminate blinding trachoma globally by 2020.
Both endemic trachoma and adult inclusion conjunctivitis present initially as conjunctivitis characterized by small lymphoid follicles in the conjunctiva. In regions with hyperendemic classic blinding trachoma, the disease usually starts insidiously before the age of 2 years. Reinfection is common and probably contributes to the pathogenesis of trachoma. Studies using polymerase chain reaction (PCR) or other NAATs indicate that chlamydial DNA is often present in the ocular secretions of patients with trachoma, even in the absence of positive cultures. Thus persistent infection may be more common than was previously thought.
The cornea becomes involved, with inflammatory leukocytic infiltrations and superficial vascularization (pannus formation). As the inflammation continues, conjunctival scarring eventually distorts the eyelids, causing them to turn inward so that the lashes constantly abrade the eyeball (trichiasis and entropion); eventually the corneal epithelium is abraded and may ulcerate, with subsequent corneal scarring and blindness. Destruction of the conjunctival goblet cells, lacrimal ducts, and lacrimal gland may produce a “dry-eye” syndrome, with resultant corneal opacity due to drying (xerosis) or secondary bacterial corneal ulcers.
Communities with blinding trachoma often experience seasonal epidemics of conjunctivitis due to H. influenzae that contribute to the intensity of the inflammatory process. In such areas, the active infectious process usually resolves spontaneously in affected persons at 10–15 years of age, but conjunctival scars continue to shrink, producing trichiasis and entropion with subsequent corneal scarring in adults. In areas with milder and less prevalent disease, the process may be much slower, with active disease continuing into adulthood; blindness is rare in these cases.
Eye infection with oculogenital C. trachomatis strains in sexually active young adults presents as an acute onset of unilateral follicular conjunctivitis and preauricular lymphadenopathy similar to that seen in acute conjunctivitis caused by adenovirus or HSV. If untreated, the disease may persist for 6 weeks to 2 years. It is frequently associated with corneal inflammation in the form of discrete opacities (“infiltrates”), punctate epithelial erosions, and minor degrees of superficial corneal vascularization. Very rarely, conjunctival scarring and eyelid distortion occur, particularly in patients treated for many months with topical glucocorticoids. Recurrent eye infections develop most often in patients whose sexual partners are not treated with antimicrobial agents.
The clinical diagnosis of classic trachoma can be made if two of the following signs are present: (1) lymphoid follicles on the upper tarsal conjunctiva; (2) typical conjunctival scarring; (3) vascular pannus; or (4) limbal follicles or their sequelae, Herbert’s pits. The clinical diagnosis of endemic trachoma should be confirmed by laboratory tests in children with relatively marked degrees of inflammation. Intracytoplasmic chlamydial inclusions are found in 10–60% of Giemsa-stained conjunctival smears in such populations, but chlamydial NAATs are more sensitive and are often positive when smears or cultures are negative. Follicular conjunctivitis in European or American adults living in trachomatous regions is rarely due to trachoma.
Adult inclusion conjunctivitis responds well to treatment with the same regimens used in uncomplicated genital infections—namely, azithromycin (a 1-g single oral dose) or doxycycline (100 mg twice daily for 7 days). Simultaneous treatment of all sexual partners is necessary to prevent ocular reinfection and chlamydial genital disease. Topical antibiotic treatment is not required for patients who receive systemic antibiotics.