Disease Watch Focus: Syphilis
CAUSATIVE AGENTS. Syphilis is a chronic infectious disease caused by the spirochaete Treponema pallidum. Syphilis is usually transmitted by sexual contact or from mother to infant, although endemic syphilis is transmitted by non-sexual contact in communities living under poor hygiene conditions. T. pallidum can also be transmitted by blood transfusion. In spite of provoking a strong humoral and cell-mediated immune response, T. pallidum is able to survive in the human host for several decades. After an incubation period of about 21 days, an ulcer (the primary chancre) appears at the site of inoculation. This resolves spontaneously and 6–8 weeks later is followed by the secondary stage, at which time the organism has disseminated via the blood stream and any organ can be affected. Tertiary syphilis, which can affect the skin, bones or central nervous and cardiovascular systems, can occur many years later . In pregnant women, syphilis can lead to stillbirth or congenital infection of the neonate, resulting in neonatal death or late sequelae . Parenteral penicillin remains the treatment of choice, and resistance to it has not been described. As T. pallidum divides slowly, a long-acting preparation is recommended.
DISTRIBUTION. T. pallidum only infects humans;there is no animal reservoir. Venereal syphilis has a worldwide distribution  (Fig. 1). In common with other bacterial sexually transmitted infections (STIs), it is more common in poor populations who lack access to treatment, and in those with many sexual partners. Endemic syphilis and other non-venereal treponemal diseases, such as yaws, were controlled by penicillin mass treatment programmes in most endemic foci in the 1950s and 1960s, and represented one of the most successful health programmes ever implemented by the World Health Organization (WHO). However, these diseases are now reappearing in some rural populations in Africa and South-east Asia, sometimes in a clinically attenuated form . Figure 1 | Estimated new cases of syphilis among adults, 1999.The global total is 12 million.
CURRENT GLOBAL STATUS. The WHO estimated that 12 million new cases of venereal syphilis occurred in 1999, more than 90% of them in developing countries , with a rapidly increasing number of cases in eastern Europe  (Fig. 1). Recent outbreaks have been reported in several cities in Europe and North America among men who have sex with men . In the United States, a programme for the elimination of syphilis was proposed in the late 1990s, but the number of reported cases has increased in the past 5 years .
NEW BASIC KNOWLEDGE. The genome of T. pallidum was sequenced in 1998 (Ref. 8). The wealth of new information regarding its predicted physiological and biochemical functions and processes might facilitate research that generates novel diagnostic and vaccine targets, and yield some insights into the pathogenesis of syphilis and other treponematoses.
NEW TOOLS AND INTERVENTION METHODS. T. pallidum cannot be cultured in vitro. Diagnosis depends on the visualization of organisms using fluorescent or darkfield microscopy of smears from ulcer material, or on serology. The traditional approach to serodiagnosis is to screen with a non-treponemal test such as the rapid plasma reagin (RPR) test and confirm with a treponemal test such as the T. pallidum particle agglutination assay (TPPA). The RPR test is sensitive, inexpensive and simple to perform, but is often not available in primary healthcare settings because it requires cold storage for reagents and electricity to operate a rotator. New RPR reagents that are stable at room temperature are now commercially available, as are solar-powered rotators. Confirmatory assays are usually not available outside of reference laboratories in developing countries. Simple, rapid treponemal tests that do not require electricity or equipment are now available, and seem to have sensitivities and specificities comparable to the TPPA. The sexually transmitted diseases diagnostics initiative (SDI) is evaluating the performance and utility of these tests in six countries. New enzyme immunoassays that are both sensitive and specific have the potential to replace the traditional testing combination of non-treponemal and treponemal tests .
Successful treatment of syphilis should result in elimination of the organism from the body but, in practice, treatment success is usually defined in terms of serological response — a decreasing or negative RPR titre. Given the uncertainty surrounding the interpretation of syphilis serology, it is not surprising that there is still little consensus on recommended treatment regimens [7,10], although there is general agreement that parenteral penicillin should be the first treatment method. There is an urgent public health need for a single-dose oral treatment, and preliminary studies have indicated that a 2 gram dose of azithromycin might be effective ; however, several treatment failures have been recently reported from the United States . Targeted mass treatment using azithromycin to control an outbreak of syphilis in injection drug users was not effective .
NEW STRATEGIES, POLICIES AND PARTNERSHIPS. In developing countries, the main priority is to screen pregnant women to prevent congenital syphilis. Successful programmes depend on the decentralization of screening services, so that women in primary health centres can be tested and treated at the same clinic visit. The introduction of decentralized testing in Haiti has been shown to reduce the incidence of congenital syphilis by 75% in 2 years . New rapid treponemal tests will facilitate decentralized screening in other resource-limited settings. Many developing countries are now scaling-up programmes for the prevention of mother-to-child transmission of HIV. This offers an unprecedented opportunity to implement screening programmes for syphilis, which are universally recommended but rarely implemented.
CONCLUSIONS AND FUTURE OUTLOOK
The Millennium Development Goals call for a two-thirds reduction in mortality among children under five by the year 2015. In Mwanza, Tanzania, the prevalence of syphilis in patients attending antenatal clinics was only 4%, yet syphilis was responsible for 50% of stillbirths . Congenital syphilis is also an important cause of mortality in live-born infants; 52% of live-born infants with congenital syphilis died in the first year of life in Haiti . Now that decentralized syphilis screening is possible, and large sums of money are being made available to screen pregnant women for HIV, policy makers must not be allowed to overlook this opportunity to reduce perinatal and infant mortality.
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