The incidence of most STIs is increasing

This is typified by the situation in the UK where, in 2009, 482 700 new STD cases were reported by genitourinary medicine clinics, an increase of over 12 000 from the previous year. A similar situation exists in other countries, including the USA. The reasons for this increase include:

HIV infection and AIDS have overshadowed other STIs with immense impact as a highly lethal infectious disease. Measuring plasma HIV-1 RNA load, CD4 counts and percentage, together with antiretroviral resistance and tropism testing by sequence analysis have become mainstays in the management of HIV infection with regard to monitoring disease progress and response to antiretroviral therapy in resource-rich countries.

The most common STIs are listed in Table 21.1. Table 21.2 gives examples of the strategies used by the microorganisms to overcome host defences.

Table 21.1 The most common sexually transmitted infections (STIs)

Table 21.2 Strategies adopted by sexually transmitted microorganisms to combat host defences

The spread of STIs is inextricably linked with sexual behaviour

There are therefore many more opportunities for controlling STIs than, for instance, respiratory infections. Infected but asymptomatic individuals play an important role, and important determinants are promiscuity and sexual practices involving contact between different orifices and mucosal surfaces (see Ch. 13). For example, transmission between heterosexuals or male homosexuals can take place following oral or anal intercourse. The gonococcus, for instance, causes pharyngitis and proctitis, although it infects stratified squamous epithelium less readily than columnar epithelium. As described more fully in Chapter 31, calculations regarding the number of infected secondary cases resulting from each primary STD case depends on a variety of behavioural factors since the number of sexual partners acquired by a given individual, i.e. the level of promiscuity, varies considerably. Those who have many sexual partners are both more likely to acquire and to transmit infection and play a key role in the persistence of such infections in the community of sexually active individuals. People with many sexual partners are therefore an obvious target for treatment and education about safer sex practices (e.g. condom use, etc.)

Various host factors influence the risk of acquiring an STI

It is not surprising that the type of sexual activity is important or that genital lesions or ulcers increase the risk of acquiring infections such as HIV. Other factors are less well understood, such as the numerous observations that uncircumcised men have a higher risk of infection.

STIs do not necessarily occur singly, and the possibility of multiple infections must always be borne in mind. For instance, syphilis can accompany gonorrhoea, and there is evidence that genital herpes may be reactivated during an attack of gonorrhoea.

Syphilis is caused by the spirochete Treponema pallidum

Treponema pallidum is closely related to the treponemes that cause the non-venereal infections of pinta and yaws (Table 21.3; Fig. 21.1). T. pallidum has a worldwide distribution, and syphilis remains a serious problem not only in resource-rich countries but especially in resource-poor areas, due to the serious sequelae and the risk of congenital infection. Although syphilis rates in the USA fell to an all-time low in 2000, the incidence has since increased with a 70% greater risk in men during the past 5    years. A similar trend has also been seen in the UK.

Table 21.3 Spiral organisms of medical importance

Figure 21.1 (A) Typical penile chancre of primary syphilis. (Courtesy of R.D. Catterall.) (B) Yaws and (C) pinta are endemic in tropical and subtropical countries and are spread by direct contact.

(Courtesy of P.J. Cooper and G. Griffin.)

T. pallidum enters the body through minute abrasions on the skin or mucous membranes. Transmission of T. pallidum requires close personal contact because the organism does not survive well outside the body and is very sensitive to drying, heat and disinfectants. Horizontal spread (see Ch. 13) occurs through sexual contact, and vertical spread via transplacental infection of the fetus (see Ch. 23).

Local multiplication leads to plasma cell, polymorph and macrophage infiltration, with later endarteritis. The bacteria multiply very slowly, and the average incubation period is 3    weeks.

Classically, T. pallidum infection is divided into three stages

The three classical stages of syphilis are primary, secondary and tertiary syphilis (Table 21.4). However, not all patients go through all three stages; a substantial proportion remains permanently free of disease after suffering the primary or secondary stages of infection. The lesion of primary syphilis is illustrated in Figure 21.1. The secondary stage may be followed by a latent period of some 3–30    years, after which the disease may recur – the tertiary stage. Unlike most bacterial pathogens, T. pallidum can survive in the body for many years despite a vigorous immune response. It has been suggested that the healthy treponeme evades recognition and elimination by the host by maintaining a cell surface rich in lipid. This layer is antigenically unreactive and the antigens are only uncovered in dead and dying organisms when the host is then able to respond. Tissue damage is mostly due to the host response.

Table 21.4 The pathogenesis of syphilis

Stage of disease	Signs and symptoms	Pathogenesis
Initial contact		Multiplication of treponemas at site of infection; associated host response
2–10    weeks (depends on inoculum size)	Primary chancrea at site of infection
Primary syphilis	Enlarged inguinal nodes, spontaneous healing	Proliferation of treponemas in regional lymph nodes
1–3    months
Secondary syphilis 2–6    weeks	Flu-like illness; myalgia, headache, fever; mucocutaneous rasha; spontaneous resolution	Multiplication and production of lesion in lymph nodes, liver, joints, muscles, skin and mucous membranes
Latent syphilis		Treponemas dormant in liver or spleen
3–30    years		Re-awakening and multiplication of treponemas
Tertiary syphilis	Neurosyphilis; general paralysis of the insane, tabes dorsalis	Further dissemination and invasion and host response (cell-mediated hypersensitivity)
	Cardiovascular syphilis; aortic lesions, heart failure
	Progressive destructive disease	Gummas in skin, bones, testis

A feature of Treponema pallidum infection is its chronic nature, which seems to involve a delicately balanced relationship between pathogen and host.

a Chancre: Initially a papule; forms a painless ulcer; heals without treatment within 2    months. Live treponemas can be seen in dark-ground microscopy of fluid from lesions; patient highly infectious.

Despite many years of effort, T. pallidum still cannot be cultivated in the laboratory in artificial media. It has therefore been difficult to study possible virulence factors at a molecular level, although a variety of genes have been cloned, the entire chromosome has been sequenced, and major proteins have been characterized.

An infected woman can transmit T. pallidum to her baby in utero

Congenital syphilis is acquired after the first 3 months of pregnancy. The disease may manifest as:

Microscopy

Exudate from the primary chancre should be examined by either:

Serology

Serologic tests for syphilis are the mainstay of diagnosis. They are divided into non-specific and specific tests for the detection of antibodies in patients’ serum.

Non-specific tests (non-treponemal tests) for syphilis are the VDRL and RPR tests

The term non-specific is used because the antigens are not treponemal in origin, but are from extracts of normal mammalian tissues. Cardiolipin, from beef heart, allows the detection of anti-lipid IgG and IgM formed in the patient in response to lipoidal material released from cells damaged by the infection, as well as to lipids in the surface of T. pallidum. The two tests in common use today are:

Non-specific tests show up as positive within 4–6    weeks of infection (or 1–2    weeks after the primary chancre appears) and decline in positivity in tertiary syphilis or after effective antibiotic treatment of primary or secondary disease. Therefore, these tests are useful for screening. However, they are non-specific and may give positive results in conditions other than syphilis (biologic false positives, Table 21.5). All positive results should therefore be confirmed by a specific test. However, treatment (e.g. especially during the primary and secondary stages) tends to result in seroreversion to these tests. Thus, with confirmed disease (see below), these tests can provide at least an indication of therapeutic efficacy.

Table 21.5 Serologic tests for syphilis and conditions associated with false-positive results

Commonly used specific tests for syphilis are the treponemal antibody test, FTA-ABS test and the MHA-TP

These tests use recombinant proteins or treponemal antigens extracted from T. pallidum. Tests in common use include:

These tests should be used to confirm that a positive result with a non-specific test is truly due to syphilis. Also, because they become positive earlier in the course of the disease, they can be used for confirmation when the clinical picture is strongly indicative of syphilis. They tend to remain positive for many years and may be the only positive test in patients with late syphilis. However, they remain positive after appropriate antibiotic treatment and cannot therefore be used as indicators of therapeutic response. They can also give false-positive reactions (see Table 21.5).

Figure 21.2 The fluorescent treponemal antibody absorption test for syphilis. Antibody in the patient’s serum binds to bacteria and is visualized by a fluorescent dye.

Confirmation of a diagnosis of syphilis depends upon several serologic tests

Positive serologic test results for babies born to infected mothers may represent passive transfer of maternal antibody or the baby’s own response to infection. These two possibilities can be distinguished by testing for IgM and retesting at 6    months of age, by which time maternal antibody levels have waned. Antibody titres remain elevated in babies with congenital syphilis.

At present, several serologic tests are needed to confirm a diagnosis of syphilis. None of these tests distinguishes syphilis from the non-sexually transmitted treponematoses, yaws and pinta. Western blot assays using whole T. pallidum cells as antigen are an important newer confirmatory test.

Penicillin is the drug of choice for treating people with syphilis and their contacts

Penicillin is very active against T. pallidum (see Table 21.1). For patients who are allergic to penicillin, treatment with doxycycline should be given. Only penicillin therapy reliably treats the fetus when administered to a pregnant mother.

Prevention of secondary and tertiary disease depends upon early diagnosis and adequate treatment. Contact tracing with screening and treatment is also important. Several STIs may be present in one patient concurrently, and patients with other STIs should be screened for syphilis.

Congenital syphilis is completely preventable if women are screened serologically early in pregnancy (<    3    months) and those who are positive are treated with penicillin.

Gonorrhoea is caused by the Gram-negative coccus Neisseria gonorrhoeae (the ‘gonococcus’)

This bacterium is a human pathogen and does not cause natural infection in other animals. Therefore its reservoir is human and transmission is direct, usually through sexual contact, from person to person. The organism is sensitive to drying and does not survive well outside the human host, so intimate contact is required for transmission. It is thought that a woman has a 50% chance of becoming infected after a single sexual intercourse with an infected man, while a man has a 20% chance of acquiring infection from an infected woman.

Asymptomatically infected individuals (almost always women, see below) form the major reservoir of infection. Infection may also be transmitted vertically from an infected mother to her baby during childbirth. Infection in babies is usually manifest as ophthalmia neonatorum (see Ch. 23).

The gonococcus has special mechanisms to attach itself to mucosal cells

The usual site of entry of gonococci into the body is via the vagina or the urethral mucosa of the penis, but other sexual practices may result in the deposition of organisms in the throat or on the rectal mucosa. Special adhesive mechanisms (Fig. 21.3) prevent the bacteria from being washed away by urine or vaginal discharges. Following attachment, the gonococci rapidly multiply and spread through the cervix in women, and up the urethra in men. Spread is facilitated by various virulence factors (Fig. 21.3), although the organisms do not possess flagella and are non-motile. Production of an IgA protease helps to protect them from the host’s secretory antibodies.

Figure 21.3 The spread of Neisseria gonorrhoeae is facilitated by various virulence factors. Changes in the surface structure of the gonococcus render the organism avirulent.

Host damage in gonorrhoea results from gonococcal-induced inflammatory responses

The gonococci invade non-ciliated epithelial cells, which internalize the bacteria and allow them to multiply within intracellular vacuoles, protected from phagocytes and antibodies. These vacuoles move down through the cell and fuse with the basement membrane, discharging their bacterial contents into the subepithelial connective tissues. Neisseria gonorrhoeae does not produce a recognized exotoxin. Damage to the host results from inflammatory responses elicited by the organism (e.g. lipopolysaccharide and other cell wall components; see Ch. 2). Persistent untreated infection can result in chronic inflammation and fibrosis.

Infection is usually localized, but in some cases bacteria isolates (e.g. resistant to the bactericidal action of serum, etc.) can invade the bloodstream and so spread to other parts of the body.

Gonorrhoea is initially asymptomatic in many women, but can later cause infertility

Symptoms develop within 2–7    days of infection and are characterized:

Ophthalmia neonatorum is characterized by a sticky discharge (see Fig. 23.5).

Figure 21.4 Gonococcal urethritis. Typical purulent meatal discharge with inflammation of the glans.

(Courtesy of J. Clay.)

Gonococcal infection of the throat may result in a sore throat (see Ch. 18), and infection of the rectum also results in a purulent discharge.

In men, local complications of urethral infection are rare (Fig. 21.5). Invasive gonococcal disease is much more common in infected women than in men, but prompt treatment is important in containing local infection. The common occurrence of asymptomatic infection in women is an important factor in the occurrence of complications (i.e. the infection is unrecognized and untreated). In 10–20% of untreated women, infection spreads up the genital tract to cause pelvic inflammatory disease (PID) and damage to the fallopian tubes.

Figure 21.5 Local and systemic complications of gonococcal infection. (A) Skin lesions start as erythematous papules, which often become pustular and haemorrhagic with necrotic centres. (Courtesy of J.S. Bingham.) (B) Septic arthritis of the ankle with marked erythema and swelling of the ankle and leg.

(Courtesy of T.F. Sellers, Jr.)

Disseminated infection occurs in 1–3% of women, but is less common in men (see above and Fig. 21.6). It is a function not only of the strain of gonococcus (see above), but also host factors (e.g. about 5% of people with disseminated infection have deficiencies in the late-acting components of complement (C5–C8)).

Figure 21.6 Local and systemic spread of gonococcal infection and complications.

A diagnosis of gonorrhoea is made from microscopy and culture of appropriate specimens

Urethral and vaginal discharges and other specimens where indicated are used for microscopy and culture. Although a purulent discharge is characteristic of local gonococcal infection, it is not possible to distinguish reliably between gonococcal discharge and that caused by other pathogens such as Chlamydia trachomatis on clinical examination.

With experience, the finding of Gram-negative intracellular diplococci in a smear of urethral discharge from a symptomatic male patient is a highly sensitive and specific test for the diagnosis of gonorrhoea.

Culture is essential in the investigation of infection in women and asymptomatic men, and for specimens taken from sites other than the urethra. Specimens from symptomatic men should also be cultured:

Serologic tests are unsatisfactory. Commercial nucleic acid-based approaches (specific probes, amplification, etc.) are now available, providing reliable results within a few hours.

Antibacterials used to treat gonorrhoea are cefixime or ceftriaxone

The antibacterial agents of choice are shown in Table 21.1. Penicillinase-producing N. gonorrhoeae were first observed in 1976 with increasing resistance that has severely compromised the effective treatment of gonorrhoea in many parts of the world, especially SE Asia. Resistance to fluoroquinolones has also occurred. Since patients with gonorrhoea may also be infected with chlamydia (see below), treatment regimens often include a combination of agents targeting both organisms (e.g. ceftriaxone and doxycycline, respectively). Early treatment of a significant proportion of sexually promiscuous patients achieves a striking reduction in the duration of infectiousness and transmission rates. Prophylactic use of antibacterials has no effect in preventing sexually-acquired gonorrhoea, but the application of antibacterial eye drops to babies born to mothers with gonorrhoea or suspected gonorrhoea is effective. Infection can be prevented by the use of condoms.

Follow-up of patients and contact tracing are vital to control the spread of gonorrhoea. At present, effective vaccines are not available, but the possibility of using some of the pilus proteins or other outer membrane components of the gonococcal cell as antigens has been under investigation. However, immunization may prevent symptomatic disease without preventing infection, and the dangers of asymptomatic infection have been discussed above.

Repeated infections can occur with strains of bacteria with different pilin proteins (e.g. antigenic variation; see Ch. 16).

C. trachomatis serotypes D–K cause sexually transmitted genital infections

The chlamydiae are very small bacteria that are obligate intracellular parasites. They have a more complicated life cycle than free-living bacteria because they can exist in different forms:

Traditionally, three species of Chlamydia were recognized: C. trachomatis, C. psittaci and C. pneumoniae. However, the latter two have been moved to the genus, Chlamydophila (Table 21.6). Chlamydophila psittaci and Chlamydophila pneumoniae infect the respiratory tract and have been discussed in Chapter 19. The species Chlamydia trachomatis can be subdivided into different serotypes (also known as serovars) and these have been shown to be linked characteristically with different infections:

Figure 21.7 The life cycle of Chlamydia. EB, elementary body; RB, reticulate body.

Table 21.6 Medically important species of Chlamydiaceae

Table 21.7 Clinical syndromes and complications caused by C. trachomatis, serotypes D–K

a Urethritis, conjunctivitis, polyarthritis, mucocutaneous lesions.

The majority of infections are genital and are acquired during sexual intercourse. Asymptomatic infection is common, especially in women. Ocular infections in adults are probably acquired by autoinoculation from infected genitalia or by ocular–genital contact. Ocular infections in neonates are acquired during passage through an infected maternal birth canal, and the infant is also at risk of developing C. trachomatis pneumonia (see Ch. 19).