The epidemiology of chlamydia is interesting because the reporting scheme includes a number of artifacts. Reported chlamydia infections are more common in women (610.6/100,000) than in men
(233.7/100,000), and rates have increased substantially since 1984 (Figure 24-1).³ Both of these trends may be somewhat artificial, however. The rate differential between women and men is mainly due to different ascertainment and reporting practices. Women are typically diagnosed with an etiologic diagnosis of chlamydia on the basis of a chlamydia screening test performed at physical examination. Clinical practice guidelines strongly recommend routine chlamydia screening for sexually active women younger than the age of 25.⁵, ¹⁹ This practice has also been incorporated into quality assurance guidelines for managed care organizations (HEDIS).²⁰ In contrast, men are often treated for chlamydia infection on the basis of presentation of a syndrome of urethritis or as a contact to a woman with chlamydia, with definitive etiologic diagnoses never being made. As a consequence, these cases may not meet surveillance definitions for chlamydia and may not be reported.

The trend of increasing incidence of infection likely results from increased screening activity, because women are routinely screened for this STD (and men are not).³ The ascertainment bias favors increased disease reporting in women. A true estimate of chlamydia prevalence is not known, which presents major problems in evaluating trends.¹¹

The rates of chlamydia are highest in adolescent women and drop off steeply past that age. For example, the reported rate for women between the ages of 15 and 19 is 3,378.2/100,000, but drops off to 530.9/100,000 for women ages 30-34.³ There is a strong hypothesis that this steep decline in incidence may not be related solely to behavior, but rather may also reflect the development of partial immunity to clinical infection through periodic repeated exposures.

In 2010, 309,341 cases of gonorrhea in the United States were reported to the CDC by local and state health departments, representing a nationwide population-based rate of 110.8/100,000; this rate has been fairly stable since 1997.³ An additional 1-2 cases are thought to occur for every officially reported case. The highest rates are seen in adolescent women (age 15-19 years) and young adult men (20-24 years), representing, in part, sexual behavior patterns.

One of the problems with the CDC-reported data is that they are based on a passive case-based reporting system. Population-based studies have demonstrated that the epidemiology of incident symptomatic disease, as represented by passive reporting, is different from prevalent asymptomatic infection. For example, in a survey conducted in Baltimore in 1997-1998, a population-based sample of individuals aged 18-35 years were interviewed in their households, and urine samples were assayed by NAAT for chlamydia and gonorrhea. Gonorrhea estimates using this population were more than three times greater than the rates reported by health departments.⁴⁹ Although gonorrhea incidence has decreased by nearly 70% since the peak of the gonorrhea epidemic in the mid-1970s, the infection has become increasingly prevalent in inner-city areas affected by other social problems, especially drug use and pregnancy. In these areas, incidence rates among adolescents often exceed 15% per year.

Disseminated gonococcal infection (DGI), or gonococcal septicemia, occurs in approximately 0.5-3% of untreated gonococcal cases.⁴⁰ DGI is more commonly seen in women, in particular during pregnancy, and is also more common in persons with complement deficiencies.

Perinatal infection with gonorrhea is relatively rare in the United States, but is often found in the developing world. Perinatal gonococcal disease is transmitted by direct exposure, as an infant passes through the birth canal of an infected cervix.

Gonococcal ophthalmia is a severe public health problem in the developing world and can be effectively prevented with inexpensive prophylaxis. The incidence of gonococcal ophthalmia is estimated to be 42% of infants exposed to an infected cervical canal. These infants develop a purulent conjunctivitis that can then rapidly progress to keratitis and subsequent corneal blindness. Because of the severe sequelae of this infection, public health authorities instituted postnatal prophylaxis with ophthalmic silver nitrate as early as 1910, effectively preventing corneal infection in 95% of exposed infants. Prevention of perinatal infection is the rationale for aggressive screening programs in pregnant women.

The same perinatal ophthalmia can be caused by C. trachomatis. Ophthalmia is also occasionally seen in adults, usually as a result of self-inoculation.

The availability of nucleic acid amplification tests has revolutionized gonorrhea and chlamydia diagnostics. NAATs are highly sensitive and are able to detect as few as 10 organisms per specimen. These tests have been applied in a large number of field settings, including emergency departments, job centers, middle and high schools, and military training sites. The largest studies have been done in military
recruits being inducted at large bases in the eastern United States that processed inductees from all 50 states; these investigations found prevalences of 10% in females and approximately 5% in male recruits.³⁹, ⁵⁷, ⁵⁸ and ⁵⁹ In another sample, consisting of more than 12,000 adolescents in the United States, the overall prevalence of chlamydial infection was estimated to be 4.2%.⁶⁰ Hospital emergency departments have also been sites for urine screening of young adults presenting for reasons other than reproductive health care and have demonstrated high prevalence as well.⁶¹, ⁶² and ⁶³

Combining the NAAT technology with population-based surveys provides new insights into the burden of these STDs in the general population. A survey in Baltimore provided estimates representative of adults living in the city between the ages of 18 and 35 years.⁴⁹ The prevalence of gonococcal infection overall was 3.0% in all adults aged 18 to 35 years; it ranged from 8% in 19- and 20-year-olds to 0.5% in 33- to 35-year-olds.

Transmission of syphilis is relatively inefficient. Studies have demonstrated that the transmission efficiency of this disease between an infected partner and an uninfected partner is only 20%. After the initial exposure, a latency period of three weeks passes prior to the development of the initial symptoms. During this latency period (or, in epidemiologic terms, the “critical period”), a newly infected individual is not infectious to his or her sexual partners. However, this status changes rapidly after development of the initial genital ulcerative lesion (chancre). The chancre is a primary syphilis ulceration that occurs at the site of mucosal inoculation.

Syphilis occurs in settings where there is high turnover of sex partners. Commercial sex workers and other transient individuals with multiple sex partners are at increased risk. In developed countries, moreover, syphilis has been associated with a variety of social and behavioral factors, including bathhouses frequented by homosexual men, prostitution related to drug abuse, and poor access to health care.⁸⁵ In the developing world, more important issues are prostitution, transience, and poor access to health care.

Syphilis rates in the United States reached a plateau in the late 1960s and continued to drop until 1975. At this time, the epidemiology of syphilis reflected the broader, societal social trends in the United States (Figure 24-3). During 1975-1980, rates increased nearly 50%, but nearly all of the increase was due to greater incidence among homosexual men. MSM culture was undergoing the “gay revolution” at this time, with homosexual men demonstrating increased sexual openness and pride in their sexual orientation. During 1980-1985, rates declined by 40% as men dramatically reduced their sexual risk practices in response to the HIV epidemic. Rates again increased nearly 100% between 1985 and 1991 (Figure 24-3).⁸⁶ This epidemic was due to increased rates among heterosexuals, especially racial and ethnic minorities, and corresponded to increased use of crack cocaine, which was introduced to the United States in 1985. Aggressive control programs, especially a large national syphilis elimination effort in African American communities that included extensive medical ethnography and grassroots efforts, led to a sustained decrease in syphilis rates in this community since 1991.⁵, ⁸⁷

More recently, as described earlier, syphilis has again increased in MSM, just as it did in the 1970s. Increased rates of risky sexual behavior in MSM have been correlated with a reduction in concern about HIV due to the development of highly effective antiretroviral therapy and “safe-sex fatigue,” where men are tired of maintaining safe sexual practices.³

Initial infection with T. pallidum occurs through sexual contact at a mucosal membrane. The incubation period for this infection ranges between 10 and 30 days.⁸⁴ Typically, 3 weeks after the initial
exposure, a chancre develops at the site of contact. The chancre is a painless lesion with an indurated border and has associated painless lymphadenopathy. Syphilis is a systemic disease, however—even in primary syphilis, systemic dissemination may occur. In some studies, 10% to 15% of patients with early primary syphilis have demonstrated cerebrospinal fluid (CSF) abnormalities.⁸⁸ Left untreated, the chancre spontaneously heals within 2-3 weeks.

Four to eight weeks later, the secondary syphilis syndrome develops. Secondary syphilis consists of a systemic vasculitis caused by high levels of T. pallidum in the blood and associated immunologic responses. The most characteristic findings are dermatological in nature, including the classic palmar plantar rash, but patterns may include papular, maculopapular, papulosquamous, and psoriasiform lesions. Patchy alopecia may develop, especially on the scalp. On the mucosal surfaces, mucous patches may be noted. Condyloma lata—large, fleshy, wart-like lesions— may develop on the genitalia. Condyloma lata and mucous patches are highly infectious. Left untreated, the secondary syphilis syndrome spontaneously resolves usually within 1-2 months of onset.

Late complications of syphilis, such as neurosyphilis, cardiovascular syphilis, and gummatous syphilis, do not develop until 10-20 years after the resolution of early syphilis. In HIV patients, case reports have suggested that late complications may occur earlier.⁸⁹

Early latent syphilis is a serologic diagnosis in which a fourfold increase in titer (i.e., two dilutions) occurs within 1 year with previous documentation of the earlier serology. Late latent syphilis is a serologic diagnosis of syphilis occurring more than 1 year after baseline diagnosis. The differentiation between early latent and late latent syphilis has both treatment and public health implications.

All stages of syphilis are seen more commonly in HIV-infected patients. Studies in STD clinics have demonstrated that HIV prevalence in patients with syphilis is as much as three times higher than the number of nonsyphilis patients in these settings.⁸³, ⁸⁹ However, the serologic manifestations and serologic response to treatment are largely unaffected by HIV status. Because of initial reports of treatment failure, many experts believed that all patients with syphilis, and especially patients with coexistent HIV infection, should be aggressively treated. Prospective studies by CDC investigators have demonstrated that in the majority of cases, such therapy is not necessary.⁹⁵

In women who have untreated primary or secondary syphilis, the vertical transmission rate is estimated to be in the range of 75-95%.⁹⁶ Late congenital syphilis is rarely seen in today’s antibiotic era. Transmission does occur transplacentally. Screening and treatment for congenital syphilis during pregnancy can effectively prevent this disorder, however. Thus congenital syphilis is completely preventable through screening, diagnosis, and treatment during the prenatal period. Therefore, congenital syphilis is considered a sentinel public health event and warrants an investigation. These cases occur almost exclusively in situations where there was inadequate prenatal care or where there are deviations from medical practice.

All state and many local health departments in the United States maintain a syphilis “reactor registry.” Positive serological tests are reportable by law (by the laboratory); therefore, reporting is reasonably complete. Reactor registries compile test results and histories of treatment and can be useful in determining whether an individual patient had a previous serology and whether a positive test represents early latent, late latent, or previously treated disease. Useful epidemiological databases are also available to conduct operational and clinical research.

Syphilis presents the prototype disease for the use of partner notification and presumptive treatment of partners.⁹⁹ Although the empirical evidence strongly suggests that this strategy has been an effective approach in syphilis control, no randomized trials to date have been performed to demonstrate this relationship. Furthermore, partner notification is complicated in situations where large numbers of anonymous sex partners are the secondary spread contacts—a consideration that has been especially problematic in evaluation of disease intervention approaches in the homosexual bathhouses and in crack cocaine-associated epidemics.¹⁰⁰, ¹⁰¹ In these situations, many public health intervention strategies have revolved around aggressive screening and presumptive treatment of partners.

Another intriguing aspect of syphilis is the relationship of immunology to infectiousness. The infectiousness of syphilis to sexual partners is largely concentrated in the primary and secondary stages. Individuals who are in late stages of syphilis (late latent, tertiary) are infected but not infectious and cannot be reinfected themselves during that time.¹⁰² Theoretically, then, it is possible to “saturate” a community to the point where there are so many latent infections that the pool of susceptibles decreases and “burns out” the outbreak. Paradoxically, in this situation, treating infected persons would revert many individuals back to a susceptible state.

Genital herpes can occur at any mucosal exposed site (genitalia, rectum, and mouth). In primary disease, the ulceration develops 5-10 days after exposure; there may also be associated systemic signs, such as fever, myalgias, headache, and occasionally meningeal irritation.¹⁰⁴ Recurrent herpes can develop at any time after the primary infection. In many settings, patients report a prodrome, which may consist of low-grade fever, pruritus, and tingling at the site of recurrence. Patients often report that they are able to feel the recurrence developing with nonspecific signs and symptoms, which is most likely related to irritation of the peripheral nerve roots.

Because many patients have asymptomatic primary infection, differentiation of a clinical first episode into primary disease or recurrence (in patients who have had an asymptomatic primary episode) is often not possible. In the research setting, primary infections are defined as an initial clinical episode with no serological evidence of prior infection. Most patients, however, when presenting with their initial episode, actually have serological evidence of prior infection.¹⁰⁷ This condition is termed first clinical episode of recurrent disease. This distinction is often a very confusing point to clinicians and can be diagnosed by using type-specific serological tests. In some studies, more than 90% of persons with recurrent herpes diagnosed serologically could not identify a primary outbreak occurrence in the past. Symptomatic recurrences are less symptomatic and heal more rapidly than the primary episode. Recurrences are most frequent within the first year after primary infection and decrease thereafter. The factors involved in inducing recurrent episodes are not well characterized.¹⁰⁴ Physical and physiological stresses have been classically cited as important cofactors, but there are few well-controlled studies that have been able to clearly elucidate these relationships.

Asymptomatic shedding plays a major role in transmission of HSV. This type of shedding occurs between clinical outbreaks, especially in the first few years after diagnosis.¹⁰⁷ Initial culture studies of women with a recent diagnosis of primary herpes found that asymptomatic shedding occurred approximately 1% of the time. The asymptomatic culture-diagnosed shedding represents a potential infectious inoculum (approximately 10⁴ viral particles). Further recent work with PCR demonstrated that shedding detectable by PCR occurred almost on a daily basis.¹⁰⁸ Asymptomatic shedding rates are increased in persons with HIV or other immunodeficiencies.¹⁰⁹

Culture or other direct viral-specific tests from a lesion specimen establish the virological diagnosis of herpes. The highest yield of samples is that from the base of a wet genital ulcer or an aspirate of a vesicular eruption prior to breakdown. Serological testing using recombinant type-specific antigens is useful in ascertaining the presence of an IgG response to HSV-2.¹¹⁰ This response is typically detectable 4-6 weeks after exposure. The most commonly used commercial test has been shown to have acceptable sensitivity and specificity in African countries if the cutoff level is increased from 1.1 to 2.1.¹¹¹

Persons who have positive cultures but who are seronegative are defined as having primary HSV infection. In contrast, persons with a first clinical outbreak, but who are HSV-2 seropositive, have recurrent infection. Serology can also be useful in defining whether an individual will benefit from suppressive therapy to reduce transmission.

The major concern with herpes simplex in pregnant women is preventing transmission to the neonate.¹¹² Recurrent herpes during pregnancy is not a severe clinical problem unless lesions are present in the birth canal at time of delivery, which is an indication for a cesarean section. Another approach advocated by some obstetricians and perinatologists is routine cultures of the birth canal at parturition. If herpes simplex is diagnosed within 1-2 days, the infant may be started on prophylactic antiviral therapy.

The major risk in pregnant women is development of primary herpes during the last trimester of pregnancy. In those cases, as many as one-third of infants will be born with neonatal herpes syndrome, which may be fatal or lead to disability.¹⁰⁴ Fetal infection is presumed to occur transplacentally. Primary infection during pregnancy can occur only if the
pregnant woman is previously uninfected and has an infected male partner. This is the type of setting where serologic diagnoses of previously unrecognized HSV are useful.