10.2 Epidemiology

National surveys conducted in the United States from 1999 to 2008 showed a 6.8% overall prevalence of C. trachomatis infection among sexually active females aged 14–19 years (4.4% among non-Hispanic whites and 16.2% among non-Hispanic blacks) [10]. In the general population, represented by men and women aged 14–39, the Chlamydia prevalence during 2007–2008 was approximately 1.6% (2.2% among females and 1.1% among males); however, the prevalence among non-Hispanic black persons was 6.7% [13]. Based on these and other studies, it was estimated that approximately 2.8 million Chlamydia infections occur annually in the United States, with the highest prevalence in persons aged ≤ 25 years [10].

In Europe, Chlamydia is also the most frequently reported STI. For example, in the United Kingdom it was reported that 10.3% of women and 13.3% of men ≤ 25 years of age were infected; the prevalence in Switzerland ranged from 2.8% in women to 1.2% in men, and in France the prevalence was 1.5% in the general population and 3% among 18–24 year old individuals [3]. Globally, the estimated annual number of C. trachomatis infections, affecting primarily sexually active young adults, is over 90 million. For example, in a recent international study evaluating the incidence and correlates of symptomatic and asymptomatic chlamydial infection in 18,014 participants, age 18 or older, from five different countries (China, India, Peru, Russia, and Zimbabwe), the authors found an overall prevalence of 3.4% in males and 7.8% in females [14]. However, it is important to note that Chlamydia prevalence estimates vary considerably among different age groups and settings. For example, a systematic review and analysis of prevalence studies in the United Kingdom found a prevalence of 8.1% in the under 20 year old age group, 5.2% in 20–24 year olds, and 2.6% in 25–29 year olds, in a general practice surgical population. However, among under 20 year olds, estimates were 17.3% in genitourinary medicine clinics, 12.6% in antenatal clinics, 12.3% in termination of pregnancy clinics, 10.7% in youth clinics, 10.0% in family planning clinics, and 8.1% in general practice, compared to 5.0% in population-based studies [1].

The high prevalence of chlamydial infections can be explained by a relatively high transmission rate during unprotected sexual activities, poor immunity to reinfection, and mild or absence of clinical symptoms that would discourage sexual activity. Therefore, screening and treatment is essential for reducing the prevalence of chlamydial infection and the associated morbidity. However, in most regions of the world, including developed countries, only a small fraction of C. trachomatis infections are detected and treated, which leaves a large reservoir of transmissible infections.

In the United States, Chlamydia was only made a nationally notifiable disease in 1995, and since then it has become the most reported notifiable disease [7]. For example, in 2009, 1.2 million cases of Chlamydia were reported, four times more than the next notifiable disease on the list, which was gonorrhea [8]. Among women aged 20–24 years, the reported rate in 2009 was approximately 3300 cases per 100,000 people. Among men aged 20–24 years, the rate was less than half, approximately 1200 cases per 100,000. The lower reported rates in men are likely to be the result of reduced screening as compared to women. Therefore, it is expected that the apparent disparity in the rate of chlamydial infection between women and men will decrease as screening of sexually active young men and of those at high risk for infection will become more frequent.

Although in the United States and other developed countries the number of treated chlamydial cases has increased steadily over the past few decades, the number of reported infections has also increased. This paradox can be explained by the increase in the testing coverage and the use of NAATs, which detects more infected people as compared to other laboratory detection methods. For example, the prevalence of chlamydial infection in persons attending family planning clinics in Philadelphia, Pennsylvania has increased by 46% when NAATs replaced less sensitive laboratory diagnostic methods [15]. Similarly, a transition from less sensitive tests to NAATs in a short period (2005–2006) resulted in a 53% increase in Chlamydia prevalence in a study associated with the National Job Training Program [30].

Monitoring STD Chlamydia infections in various populations and predicting epidemiologic trends has been challenging during the transitory periods of changing testing technology and screening coverage. However, because a higher percentage of C. trachomatis infections are detected and treated, overall, it has been estimated that the disease burden as well as the transmission rate are declining, which is the ultimate goal of the screening programs.

In pregnant women, the prevalence of Chlamydia infection is relatively low. However, Chlamydia infection can lead to complications for the mother during pregnancy, and the rate of transmission to infants during virginal delivery is very high, up to 65% in some studies [32]. Therefore, CDC recommends screening all pregnant women at their first prenatal visit and additionally during the third trimester for all women who were positive at the initial visit or were at risk for new infection [9].

10.3 Biology

Chlamydia trachomatis has a unique and complex developmental cycle, which led to their original misclassification as protozoa, and later as viruses [12]. However, since the 1960s it has been known that C. trachomatis and other chlamydiae (e.g. C. pneumoniae, C. psittaci, and C. pecorum) infecting humans and various animal species are nonmotile, Gram-negative bacteria with an obligate intracellular developmental cycle.

Infection with C. trachomatis strains, or serovars, can causes trachoma, inclusion conjunctivitis, lymphogranuloma venereum (LGV), urogenital/rectal diseases and, in babies, respiratory tract infections. Interestingly, because of the lack of distinct clinical symptoms, chlamydial infection was not recognized as a sexually transmitted disease until 1976 [31]. Based on tropism and disease features, C. trachomatis serovars can be separated into three disease-associated groups, trachoma serovars (A–C), urogenital/rectal serovars (D–K), and LGV (L1–L3). The serovars traditionally have been identified based on serological markers specific for the major outer membrane protein (MOMP), which is the most abundant protein on the surface of the chlamydial cellular membrane. Currently, C. trachomatis strains are usually identified using genotyping methods that detect genetic variation in the ompA gene, which codes for MOMP, or in other variable chlamydial genes [28].

Chlamydiae have a unique life cycle consisting of two major developmental stages [24]. The extracellular infectious form, called the elementary body (EB), which is metabolically inert, enters the host cell by endocytosis and remains enclosed in a vacuole formed by the host membrane. Within the vacuole, the EB develops into a metabolically active, but noninfectious, reticulate body (RB), which grows and undergoes multiple rounds of division by binary fission. Throughout their intracellular developmental cycle, the chlamydial pathogens remain enclosed with distinctive vacuoles, called inclusions, which often fuse with each other, and can be identified by light or fluorescence microscopy, as they occupy much of the cell’s cytoplasm. After multiple rounds of division, which produce up to a thousand or more chlamydial progenies per inclusion, the RBs differentiate into new, infectious EBs. The EBs are released from the host cell by lysis or exocytosis and can infect new host cells in the same or, if transmitted, different individuals. In cell culture, the chlamydial developmental cycle usually takes 48–72 h, depending on the C. trachomatis strain and the host cells.

Most C. trachomatis strains isolated from patients carry multiple copies of an extrachromosomal dsDNA (i.e. plasmid), which codes for several proteins [29]. The plasmid confers C. trachomatis the ability to synthesize glycogen and it might also code for virulence factors. From a diagnostic perspective, the presence of a chlamydial plasmid is very important, as some of the NAATs specifically target DNA sequences located on this multicopy plasmid, which can increase their sensitivity. Interestingly, a new C. trachomatis variant (i.e., mutant), which lacks the plasmid targeted sequence of some of the NAATs, was recently discovered at relatively high prevalence in a population with a high rate of screening [25]. Apparently, due to broad screening and treatment, most of the circulating wild-type strains in the population were reduced whereas, in the absence of detection and treatment, the mutated variant spread very quickly. This isolated incident, which was promptly resolved, is strong testimony to the efficiency of C. trachomatis screening programs, and points to the importance of choosing NAATs gene targets that are essential for the life cycle of the infectious agents or for developing tests that target multiple sequences.

10.4 Natural history

Despite major advances in understanding the biology and pathogenicity of C. trachomatis

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