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Syphilis: Epidemiology, pathophysiology, and clinical manifestations in HIV­uninfected patients

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Syphilis: Epidemiology, pathophysiology, and clinical manifestations in HIV­uninfected patients
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  2017-5-4 Syphilis: Epidemiology, pathophysiology, and clinical manifestations in HIV-uninfected patients - UpToDatehttps://www.uptodate.com/contents/syphilis-epidemiology-pathophysiology-and-clinical-manifestations-in-hiv-uninfected-patients/print?source=search_result&searc… 1/25 Official reprint from UpToDate www.uptodate.com ©2017 UpToDate Syphilis: Epidemiology, pathophysiology, and clinical manifestations in HIV-uninfected patients  Authors: Charles B Hicks, MD, Meredith Clement, MD Section Editor: Noreen A Hynes, MD, MPH, DTM&HDeputy Editor: Jennifer Mitty, MD, MPH  All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through:  Apr 2017. | This topic last updated:  Nov 21, 2016. INTRODUCTION  — Syphilis is an infection caused by the bacterium Treponema pallidum . Most new cases of syphilis are sexually acquired. The clinical manifestations depend upon the stage of disease. Studies performedin the pre-antibiotic era permit a relatively complete understanding of the natural history of untreated syphilis.Information about the natural history of untreated syphilis in humans derives from data collected from severalsources:The epidemiology, pathogenesis, and clinical manifestations of syphilis will be reviewed here. Discussions of thediagnosis and treatment of syphilis, as well as syphilis in special populations are found elsewhere: MICROBIOLOGY  — T. pallidum , the causative organism of syphilis, was first identified in 1905 [4]. It is abacterium from the order Spirochaetales and is one of several closely related treponemes which cause humandisease [5   ]. T. pallidum  is approximately 10 to 13 microns long but only 0.15 microns in width, making it tooslender to be visualized by direct microscopy. This feature greatly complicates diagnosis.The organism can be seen with darkfield microscopy, a technique that employs a special condenser that casts anoblique light. When visualized by this method, T. pallidum  is a delicate, corkscrew-shaped organism with tightlywound spirals (picture 1). It exhibits a characteristic rotary motion with flexing and back-and-forth movement,features considered sufficiently characteristic to be diagnostic [6   ]. EPIDEMIOLOGY ®® In the late 19th century, a Norwegian physician described the evolution of infection in more than 1400patients with primary and secondary syphilis. Because he believed that the available therapies at the timewere highly toxic and of little benefit, patients received no treatment [1].● Additional data were collected from a study of 382 adults with syphilis who underwent autopsies between1917 and 1941 [2]. This compilation provided pathologic confirmation of the late manifestations of syphilis.●Finally, the infamous Tuskegee study conducted between 1932 and 1972 collected data on 431 Black menwhose syphilis was untreated [3].●(See "Syphilis: Treatment and monitoring".)● (See "Syphilis: Screening and diagnostic testing".)● (See "Epidemiology, clinical presentation, and diagnosis of syphilis in the HIV-infected patient".)● (See "Syphilis in pregnancy".)● (See "Congenital syphilis: Clinical features and diagnosis".)● (See "Congenital syphilis: Evaluation, management, and prevention".)●  2017-5-4 Syphilis: Epidemiology, pathophysiology, and clinical manifestations in HIV-uninfected patients - UpToDatehttps://www.uptodate.com/contents/syphilis-epidemiology-pathophysiology-and-clinical-manifestations-in-hiv-uninfected-patients/print?source=search_result&searc… 2/25 Worldwide  — The World Health Organization (WHO) estimates that worldwide in 2012, there were 18million prevalent cases of syphilis in adolescents and adults aged 15 to 49, and 5.6 million new cases [7].The global incidence rate was 1.5 cases per 1000 females and 1.5 cases per 1000 males.●The highest prevalence was reported in the WHO African region, followed by the South-East Asian region,and the Western Pacific region [7]. In the Western Pacific region, the highest incidence of syphilis cases in2012 were reported in Mongolia and Fiji (approximately 180 and 80 per 100,000 population, respectively) [8].In China, a national surveillance program demonstrated that after the virtual eradication of syphilis from the1960s to the 1980s, syphilis has re-emerged with a total of 171,026 primary and secondary syphilis casesreported in 2013 [9]. United States  — In the United States, syphilis has been a nationally notifiable disease since 1944. Itsunique laboratory diagnostic features ensure that most cases are reported. Thus, there are relativelyaccurate statistics on the incidence of new infections [10].●In the late 1980s and early 1990s, there was a mini epidemic of early syphilis that produced case rates thatwere higher than at any time since the introduction of penicillin in 1943. The number of cases peaked in1990 (20.3 cases per 100,000 population) but subsequently fell to a new nadir in 2000, raising hopes for eradication (figure 1) [11,12   ].However, the number of cases of primary and secondary syphilis increased again in 2001, and this trend hasmostly continued through 2015. From 2005 to 2014, the overall number of reported primary and secondarysyphilis cases increased significantly from 8724 to 19,999 [13,14]. In 2015, a total of 23,872 primary andsecondary syphilis cases were reported, and the national rate increased by 19 percent to 7.5 cases per 100,000 population, which is the highest rate reported since 1994 [15].During 2014 to 2015, primary and secondary syphilis rates increased among men and women in everyregion of the country and in every racial and ethnic group except for American Indians and Alaska Natives[15]. Specific epidemiologic trends include the following:The rise in the rate of reported syphilis cases is primarily attributable to increased cases among menwho have sex with men (MSM). As an example, approximately 90 percent of primary and secondarysyphilis cases occur in men, and the majority (81 percent) occur in MSM [15   ]. Among MSM with syphilis,risk factors for acquisition include methamphetamine use, and having acquired recent sexual partnersfrom the internet [16,17].•There is a high rate of HIV coinfection among MSM with syphilis. Available data from the United StatesCenters for Disease Control and Prevention (CDC) suggest that approximately 50 percent of MSM withprimary and secondary syphilis are HIV-infected, compared with 10 percent of men who have sex withwomen and 3.9 percent of women [15]. A more detailed discussion of HIV and syphilis is foundelsewhere. (See "Epidemiology, clinical presentation, and diagnosis of syphilis in the HIV-infectedpatient".)•The rate of reported primary and secondary syphilis cases remains highest among Blacks, with theoverall rate of syphilis being highest in Black men. As an example, in 2015, the rate of reported casesper 100,000 population was 39.0 in Black men, 16.6 in Hispanic men, and 7.6 in White men [15].• Among women, the reported primary and secondary syphilis rates have ranged from 0.8/100,000 in2005 to 1.5 in 2008 [13,14]. In 2015, the rate among women was 1.4 cases per 100,000 females, whichincreased by approximately 27 percent compared with 2014; the largest increases were in the West and•  2017-5-4 Syphilis: Epidemiology, pathophysiology, and clinical manifestations in HIV-uninfected patients - UpToDatehttps://www.uptodate.com/contents/syphilis-epidemiology-pathophysiology-and-clinical-manifestations-in-hiv-uninfected-patients/print?source=search_result&searc… 3/25 TRANSMISSION  — Transmission of T. pallidum  usually occurs via direct contact with an infectious lesion duringsex. In addition, T. pallidum  readily crosses the placenta, thereby resulting in fetal infection. The acquisition of syphilis through transfused blood is very rare because all donors are screened and T. pallidum  cannot survivelonger than 24 to 48 hours under blood bank storage conditions. Additional discussions of syphilis transmissionduring pregnancy and through blood donations are found elsewhere. (See "Syphilis in pregnancy" and"Congenital syphilis: Clinical features and diagnosis", section on 'Transmission' and "Blood donor screening:Laboratory testing", section on 'Syphilis'.)Sexual transmission requires exposure to open lesions with organisms present, features seen with the primarychancre and with some of the manifestations of secondary syphilis (mucous patches and condyloma lata). Theselesions are very infectious, with an efficiency of transmission estimated at approximately 30 percent [3,18]. Incontrast, the cutaneous lesions of secondary syphilis contain few treponemes, and the risk of transmissionthrough intact skin is low. Patients with early latent syphilis are considered infectious due to lesions that wererecently active, but are no longer present, or were missed on the initial evaluation. T. pallidum  can initiate infection wherever inoculation occurs. Thus, contact of infected secretions with almost anytissue can lead to a primary syphilis lesion at that site, and syphilis can be spread by kissing or touching a personwho has active lesions on the lips, oral cavity, breasts, or genitals. As an example, transmission of syphilis hasbeen identified in men who have sex with men (MSM) who have reported oral sex as their only risk factor for acquisition [19].Syphilis is also associated with the transmission and acquisition of other sexually transmitted infections (eg, HIV). As an example, in a study examining the HIV incidence among men with new primary and secondary syphilis, 1in 20 MSM were diagnosed with HIV within one year of a syphilis diagnosis [20   ]. (See "Epidemiology, clinicalpresentation, and diagnosis of syphilis in the HIV-infected patient", section on 'Effect of syphilis on HIV' and"Approach to the patient with genital ulcers".) PATHOPHYSIOLOGY  — The understanding of T. pallidum  pathophysiology is impeded by the inability to growthe organism in culture. Thus, knowledge of the growth characteristics and metabolism of this bacterium are quitelimited. Data in animal models and human volunteers form the basis of most of the available information on thispathogen [5,21   ]. The pathogenesis of neurosyphilis is discussed elsewhere. (See "Neurosyphilis", section on'Pathogenesis'.)Northeast. The rate was highest in Black women (5.3 per 100,000 population) compared with Hispanicand White women (1.4 and 0.6, respectively) [15   ].Late syphilis occurs in an uncertain proportion of patients infected by T. pallidum due to the lack of reliablesystems for reporting late stages of the disease. However, there has also been an upward trend in late andlate latent syphilis since 2009, with the CDC reporting 5.6 cases per 100,000 in 2009 and 8.2 cases per 100,000 in 2014 [15]. This may be due in part to the resurgence in early syphilis that occurred in the UnitedStates in the late 1980s and early 1990s. Implementation of the reverse sequence screening method (ie, aninitial treponemal test followed by a confirmatory nontreponemal test) in many labs across the country mayalso contribute to this upward trend in late and late latent syphilis cases. The reverse approach detectscases of late and late latent syphilis in patients whose nontreponemal test has become nonreactive over time. (See "Syphilis: Screening and diagnostic testing", section on 'Serologic testing algorithms'.)The overall rate of reported congenital syphilis has also increased, with 12.4 cases per 100,000 live birthsreported in 2015 [15]. The epidemiology of congenital syphilis is discussed in detail elsewhere. (See"Congenital syphilis: Clinical features and diagnosis", section on 'Epidemiology'.)  2017-5-4 Syphilis: Epidemiology, pathophysiology, and clinical manifestations in HIV-uninfected patients - UpToDatehttps://www.uptodate.com/contents/syphilis-epidemiology-pathophysiology-and-clinical-manifestations-in-hiv-uninfected-patients/print?source=search_result&searc… 4/25 Early local infection  — T. pallidum  initiates infection when it gains access to subcutaneous tissues viamicroscopic abrasions [22]. Despite a slow estimated dividing time of 30 hours, the spirochete evades early hostimmune responses and establishes the initial ulcerative lesion, the chancre (picture 2). During the period of earlylocal replication, some organisms establish infection in regional draining lymph nodes, with subsequentdissemination. T. pallidum  elicits innate and adaptive cellular immune responses in skin and blood. The host immune responsebegins with lesional infiltration of polymorphonuclear leukocytes, which are soon replaced by T lymphocytes [23].In one study of 23 patients with secondary syphilis, leukocytes were obtained from syphilitic lesions andperipheral blood mononuclear cells [24]. Compared with peripheral blood, lesional fluids were enriched withCD4+ and CD8+ T cells, activated monocytes, macrophages, and dendritic cells. Many of these dendritic cellsalso expressed HIV coreceptors (eg, CCR5 and DC-SIGN), which may help explain the epidemiologic linkbetween syphilis and HIV transmission. (See "Epidemiology, clinical presentation, and diagnosis of syphilis in theHIV-infected patient" and "Factors affecting HIV progression", section on 'Coreceptor usage'.)  After acquisition on T. pallidum , humoral immune responses are also generated. This leads to the development of a variety of antibodies that can be detected relatively early in the course of syphilis. (See "Syphilis: Screeningand diagnostic testing".)In some respects, the immune response to T. pallidum  is paradoxical. On one hand, the various immuneresponses during early infection appear to be efficacious, since they coincide with resolution of the primarychancre, even in the absence of therapy. However, despite this apparent immune control, widespreaddissemination of spirochetes occurs at the same time, leading to subsequent clinical manifestations of secondaryor tertiary syphilis in untreated patients. (See 'Clinical manifestations' below.) Late infection  — Cellular immunity is important for control of syphilis in experimental infection and probablycontributes to the pathogenesis of late syphilis [25]. The prolonged latent period that is characteristic of mosttypes of late syphilis suggests that immune mechanisms may be involved in one of two ways. Waning immunitywith aging may facilitate recrudescence of a small number of treponemes that had survived in sequestered sites. Alternatively, a partially immune hypersensitive host may react to the presence of treponemes, engendering achronic inflammatory response.Gummas, or late benign syphilis often involving the skin, viscera, or other tissues (eg, bone, brain, abdominalviscera), are characterized pathologically by the presence of granulomas, a finding that is consistent with acellular hypersensitivity reaction (see 'Gummatous syphilis' below). Experimental studies with human subjectswho were inoculated cutaneously with small numbers of live T. pallidum  found that gummas developed only inthose who had previous syphilis [21   ]. This suggests that development of gummas requires an immune responseinsufficient to be protective, but substantial enough to cause tissue damage and granuloma formation in thereinfected host.Cardiovascular syphilis with involvement of the ascending arch of the aorta and aortic valve is a consequence of vasculitis of the vasa vasorum ("endarteritis obliterans"). Small vessel vasculitis is a common manifestation of secondary and later stages of syphilis as evidenced by the presence of lymphocytes and plasma cells infiltratingblood vessels and perivascular tissues. STAGES OF DISEASE  — Patients with syphilis can present with a wide range of symptoms depending upon thestage of disease. Others will have serologic evidence of syphilis based upon laboratory testing, but will not havesymptoms (ie, latent syphilis). (See 'Latent syphilis (asymptomatic)' below.)Syphilis is generally divided into early and late stages (table 1).  2017-5-4 Syphilis: Epidemiology, pathophysiology, and clinical manifestations in HIV-uninfected patients - UpToDatehttps://www.uptodate.com/contents/syphilis-epidemiology-pathophysiology-and-clinical-manifestations-in-hiv-uninfected-patients/print?source=search_result&searc… 5/25 Patients can present with central nervous system manifestations (neurosyphilis) at any time during the course of infection. A detailed discussion of neurosyphilis is found elsewhere. (See "Neurosyphilis".) CLINICAL MANIFESTATIONS  — Patients with signs and symptoms consistent with syphilis should undergoserologic testing to confirm the diagnosis. However, certain patients can be treated empirically based upon theclinical findings (eg, patients with a suspected chancre and a known exposure). Discussions of the diagnosis andtreatment of syphilis are found elsewhere. (See "Syphilis: Screening and diagnostic testing" and "Syphilis: Treatment and monitoring".) Early syphilisPrimary syphilis (chancre)  — Following acquisition of T. pallidum , the initial clinical manifestation of infectionis a localized skin lesion termed a chancre. The median incubation period before the chancre appears is 21 days(range 3 to 90 days) [26]. (See 'Pathophysiology' above.) The lesion begins as a papule, which is typically (but not always) painless, appearing at the site of inoculation.This soon ulcerates to produce the classic chancre of primary syphilis, a 1 to 2 centimeter ulcer with a raised,indurated margin (picture 2). The ulcer generally has a non-exudative base and is associated with mild tomoderate regional lymphadenopathy that is often bilateral. Such lesions usually occur on the genitalia, butoccasionally patients may develop chancres at other sites of inoculation. These sites may include areas that maynot be noticeable to the patient, including the posterior pharynx, anus, or vagina. Infrequently, multiple chancresoccur, particularly in the setting of HIV infection. (See "Epidemiology, clinical presentation, and diagnosis of syphilis in the HIV-infected patient".)Chancres heal spontaneously within three to six weeks even in the absence of treatment. Since the ulcer ispainless, many patients do not seek medical attention, a feature that enhances the likelihood of transmission.The mechanism of healing is unknown, but is thought to be a consequence of local immune responses [27]. (See'Early local infection' above.)The chancre represents an initial local infection, but syphilis quickly becomes systemic with widespreaddissemination of the spirochete. This dissemination may or may not be associated with concurrent systemicsymptoms, but is the pathophysiologic basis for subsequent secondary and/or late syphilis, includingneurosyphilis. Secondary syphilis  — Within weeks to a few months after the chancre develops, approximately 25 percentof individuals with untreated infection develop a systemic illness that represents secondary syphilis [1]. Patientswith secondary syphilis may not have a history of a preceding chancre since the primary infection may have beenasymptomatic and/or gone unnoticed.Similar to primary disease, the acute manifestations of secondary syphilis typically resolve spontaneously, evenin the absence of therapy, except in the case of severe ulcerations called lues maligna (picture 3). Occasionally,untreated patients experience additional episodes of relapsing secondary syphilis, which can occur for up to fiveyears after their initial episode [1   ].Early syphilis — Early syphilis comprises primary and secondary syphilis, as well as early latent syphilis. Theclinical manifestations of early syphilis (eg, primary and secondary) typically occur within weeks to monthsafter initial infection. (See 'Primary syphilis (chancre)' below and 'Secondary syphilis' below.) ●Late syphilis — When patients are untreated during the earlier stages of syphilis, they can progress to latelatent disease (which is asymptomatic) or develop major complications of the infection (eg, tertiary syphilis).The clinical events occurring as a consequence of late syphilis may appear at any time from 1 to 30 yearsafter primary infection and can involve a wide variety of different tissues. (See 'Late syphilis' below.)●
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