1. HAZIRLAYAN:IŞIN ERDOĞAN

2. History Syphilis has been of great historical importance and has played a major role in medicine for over a century. The disease was named after an afflicted shepherd named Syphilus in 1530. Theories on the origin of the disease in the late fifteenth century are controversial. One theory proposes that Christopher Columbus and his crew acquired the disease from Native Americans living in the Caribbean islands and brought it back to a nonimmune population in Europe in 1493, as signs of syphilis have been found in skeletons of pre-Columbian Native Americans. Another theory is that venereal syphilis may have already been endemic but became more widespread and severe as a consequence of the wars at that time in Europe. Lastly, the environmental theory claims that venereal syphilis is a variant of other diseases caused by Treponema spp. and became modified by environmental factors, especially temperature

3. Information on the natural course of untreated syphilis has come primarily from two large studies: The Oslo Study was a prospective investigation of infected, but untreated, individuals conducted between 1890 and 1910, with a follow-up period of 50 years. Approximately one-quarter of infected persons had at least one additional relapse of secondary syphilis, often occurring during the first year (90%). Approximately 15% of infected persons developed benign late syphilis with gummas of the skin (70%), bones (10%) and mucous membranes (10%). Cardiovascular syphilis was reported in approximately 14% of men and 8% of women, while neurosyphilis was observed in 10% of men and 5% of women. Altogether, the study concluded that 17% of men and 8% of women died as a result of untreated syphilis. The Tuskegee Study was undertaken in 1932 in infected black men, with regular examinations for short- and long-term consequences of untreated infection. This represented a highly unethical investigation, as penicillin treatment was withheld without written consent. The principal finding was an increased mortality rate in the syphilitic group compared to the controls, with an approximately 20% loss-of-life expectancy at an interval of 12 years. Specific lesions of late syphilis were found in about 14% of infected men at the 20-year evaluation, and 12% after 30 years, with cardiovascular syphilis and neurosyphilis representing the primary causes of death

4. Biology of T. pallidum T. pallidum is a member of the genus Treponema of the order Spirochaetales, and it was identified in 1905 by Schaudinn and Hoffmann

9. Epidemiology Syphilis is distributed worldwide and is particularly problematic in low-income countries, where it is a leading cause of genital ulcer disease. Worldwide, the rates of primary and secondary syphilis decreased dramatically with the introduction of penicillin treatment after the Second World War. In contrast to Western European countries, an increase in the infection rate was observed during the late 1980s in rural southern and urban regions of the US. Although the number of syphilis cases per year in the US subsequently declined and in 2000 fell to its lowest point since reporting began in 1941, in the past decade the number of primary and secondary syphilis cases diagnosed per year in men has more than doubled. In 2010, the incidence rate of primary and secondary syphilis in the US was 7.9 cases per 100 000 population in men and 1.1 cases per 100 000 population in women. In the US, the incidence in black and Hispanic individuals, as well as in men who have sex with men (MSM), is 5- to 25-fold higher than in other population groups. In a Centers for Disease Control and Prevention (CDC) study of MSM receiving care at STD clinics in eight US cities, rates of syphilis seroreactivity increased from 4% in 1999 to 11% in 2008. With the resurgence of syphilis in Eastern Europe in the 1990s and migration of sex workers from this region to Western Europe, syphilis has been observed more frequently in Western European countries over the past decade.

11. Pathogenesis of Untreated Syphilis Syphilis is a chronic systemic infection that progresses through active and latent stages. Inoculation and penetration occurs via mucosal surfaces and abraded skin, followed by attachment to host cells and multiplication of the microorganism. Within a few hours, treponemes disseminate to the regional lymph nodes and internal organs.

14. Clinical Features Syphilis is usually sexually acquired, but maternal–fetal transmission also occurs and can result in congenital syphilis. Syphilis is an intermittent disease with primary, secondary and tertiary stages as well as a latent period of variable length that precedes the onset of tertiary syphilis The definitions of early and late syphilis by the CDC and World Health Organization (WHO) differ slightly. Early syphilis includes the primary and secondary stages as well as early latency (CDC: acquired <1 year previously; WHO: acquired <2 years previously). Late syphilis extends from late latency (CDC: acquired >1 year previously; WHO: acquired >2 years previously) through the tertiary stage.

15. Primary stage The primary lesion develops 10–90 days after infection (median of 3 weeks) as an indolent papule, followed by surface necrosis and the typical well-circumscribed ulceration that is firm to palpation (chancre), as well as enlarged regional lymph nodes. Histopathologically, the microorganism is observed among cells typical of a Th1-predominant cellular response; the latter leads to macrophage activation and destruction of a large number of treponemes. Several pathogenic mechanisms have been proposed, including an antigenically inert treponemal cell surface, resistance to phagocytosis, and premature down-regulation of the local host immune response.

16. Primary syphilis The chancre usually presents as a single, indolent, round or oval, indurated ulcer that is associated with regional adenopathy. Some patients report a preceding painless papule that enlarged and ulcerated a few days later. Untreated, chancres heal within a few weeks

18. Secondary stage dissemination and multiplication of the microorganism in different tissues, either simultaneously with or up to 6 months after healing of the primary local lesion. follows primary syphilis in almost every patient in the absence of appropriate treatment. Circulating immune complexes (which contain treponemal outer membrane proteins), human fibronectin, antibodies and complement are present during this stage of the disease and play a role in the pathogenesis of the different types of lesions. Secondary syphilis is characterized by a broad spectrum of clinical manifestations involving the skin as well as systemic signs such as malaise, fever and generalized enlargement of the lymph nodes. It lasts several weeks or months, with relapses in approximately 25% of patients. Pregnant women can infect a fetus via transplacental passage of the microorganism.

19. Secondary syphilis results from the hematogenous and lymphatic dissemination of treponemes after a few weeks or months (3–10 weeks). Prodromal symptoms include low-grade fever, malaise, sore throat, adenopathy, weight loss, muscle aches and sometimes a headache from meningeal irritation. During the second stage of syphilis, the most commonly observed clinical presentation (80%) is a generalized, non-pruritic papulosquamous eruption. Lesions can range from 1–2 mm to 15– 20 mm in diameter, and they vary in color from pink to violaceous to red– brown. Mucosal lesions range from small, superficial ulcers that resemble painless aphthae to large gray plaques. Condylomata lata are often observed in the moist regions of the anogenital area due to local spreading of the microorganisms. Lymph node enlargement is present in the majority of patients. Focal neurologic findings occasionally occur. Additional clinical presentations of secondary syphilis include annular or figurate plaques with central hyperpigmentation on the face, non-scarring “moth-eaten” alopecia, split papules at the oral commissures, granulomatous nodules and plaques and crusted necrotic lesions. Malignant syphilis (lues maligna) is extremely rare; the disseminated lesions resemble primary chancres. Without treatment, the lesions resolve over several weeks to months. Relapse occurs in approximately 20% of patients within 1 year, often with mucosal or mucocutaneous manifestations in the anogenital area.

20. Laboratory diagnosis of secondary syphilis: Presence of treponemes by darkfield examination of serous exudates from localized lesions of the skin and mucous membranes (the exception being the oral cavity; see below). Serologic tests are more useful in secondary (as compared to primary) syphilis. Cardiolipin antibodies (e.g. RPR or VDRL tests) as well as specific antibodies are always positive in patients with secondary (as well as tertiary or latent) syphilis Occasionally, spirochetes are detected in biopsy specimens Management considerations for patients diagnosed with secondary syphilis include the following: All patients should be tested for HIV infection, and testing should be repeated in those who fail to respond to treatment. Patients with ocular symptoms (e.g. photophobia, visual changes) should undergo ophthalmologic evaluation to assess for uveitis and neuroretinitis, including slit- lamp examination. A lumbar puncture and cerebrospinal fluid (CSF) analysis should be performed in patients with ocular or neurologic (e.g. headache, hearing loss, cranial neuropathies) signs/symptoms and when treatment failure is suspected (e.g. persistent/recurrent signs/ symptoms or failure of non-treponemal test titers to decline fourfold within 6–12 months).

25. Latency Latency is the period between healing of the clinical lesions and appearance of late manifestations, and it can last for many years. About 70% of untreated individuals will remain in this stage for the rest of their lives and are immune to new primary infection. Latent syphilis is divided into early (1 year or less) and late (more than 1 year) subsets it is characterized by positive serologic tests for specific antibodies without clinical signs or symptoms. Infectivity may occur intermittently due to the presence of treponemes in the bloodstream, and pregnant women with latent syphilis may infect the fetus in utero.

26. Latent syphilis After a period of 3–12 weeks, untreated secondary syphilis typically resolves spontaneously, leaving the patient in an asymptomatic state. Diagnosis is based on a positive syphilis serology test result in the setting of no clinical evidence of treponemal infection. The two stages are: ● Early latent stage: within 1 year of the onset of latency (CDC definition), with the possibility of recurrence of the disease. About 90% of secondary relapses occur within the first year. ● Late latent stage: after 1 year from the onset of the disease (CDC definition); relapses after 1 year are very infrequent. This disease state may last for many months or years. Diagnosis of latent syphilis is established by reactivity in an RPR or VDRL assay, a positive MHA-TP or FTA-ABS test, and the absence of any clinical signs of the disease. The diagnosis is easy to establish if there is a history of a chancre or skin manifestations that fit the clinical picture of syphilis. In many cases, the medical history provides no useful information regarding the presence of clinical symptoms in the previous weeks to months or whether the patient was previously treated. In such instances, differentiation between early and late latency is not possible and patients are regarded as having late latent syphilis from a management standpoint (see below). Response of latent syphilis to treatment is indicated by a decline in the RPR or VDRL titer. Persistently high (e.g. lack of a fourfold decline within 12– 24 months) or rising titers are a sign of treatment failure, and examination of the CSF should be performed.

27. Tertiary stage The tertiary stage is also called late syphilis and is characterized by the presence of a small number of organisms and a high cellular immune reactivity against the organism. Signs of late syphilis can be recognized in approximately one- third of untreated individuals several months to years after being infected with treponemes. The microorganisms may invade the central nervous and cardiovascular systems as well as the skin (and other organs), leading to damage related to host delayed-type hypersensitivity responses, which produce local inflammation and gummas in affected tissues.

28. Tertiary (late) syphilis Classic tertiary syphilis, as a consequence of untreated syphilis, is nowadays rare. It has a variable range of manifestations that appear months to years after initial infection. In particular, these include involvement of the skin, bones, CNS, heart and great vessels. Approximately one-half of patients with tertiary syphilis have “benign” late syphilis with the development of gummas, about one-quarter develop cardiovascular manifestations, and one-quarter develop neurologic symptoms (with additional overlap of different manifestations). In tertiary syphilis, non-treponemal serologic tests are usually positive with high titers. Patients with tertiary syphilis (or any symptoms related to late syphilis) should undergo lumbar puncture and CSF examination to determine if neurosyphilis is present before therapy is initiated.

29. “Benign” late syphilis The most common feature of late syphilis is gummas, which are locally destructive lesions in the skin, bones, liver and other organs. nodular or noduloulcerative lesions, often with an arciform pattern. They remain for weeks to months and then involute with scarring, but eventually new nodules reappear. With treatment, resolution of the lesions is prompt and complete. A solitary gumma that is located subcutaneously may become necrotic, similar to a “cold” abscess, resulting in ulceration of the skin or mucous membranes as well as destruction of underlying bones. Bones are affected as frequently as the skin. The gumma is a destructive bony lesion that is typically accompanied by periostitis and osteitis. Clinical manifestations include pain, swelling and limited range of motion. Other sites that can be affected by gummas include the tongue and oral cavity, upper respiratory tract, myocardium, and digestive as well as nervous systems.

34. Cardiovascular syphilis Cardiovascular syphilis has a late onset, with a latent period of 15–30 years, and it occurs in about 8–10% of individuals with untreated infection. During the early stage of the disease, T. pallidum demonstrates a predilection for the vasa vasorum of the proximal aorta and produces transmural inflammatory lesions, which lead to endarteritis of the vessels. The organisms then remain there in a latent state for many years.

36. Neurosyphilis a manifestation of tertiary syphilis, neurosyphilis can occur at any stage of the disease. the reflection of a chronic (or sometimes acute) form of meningitis, with vascular and parenchymatous sequelae in the cerebrum and spinal cord. Asymptomatic neurosyphilis is defined by the presence of abnormalities in the CSF but the absence of any neurologic symptoms or clinical findings. While in some individuals the CSF abnormalities may resolve spontaneously or persist into advanced age, asymptomatic neurosyphilis can progress to late symptomatic neurosyphilis. The basic pathomechanism for cerebrovascular syphilis is an infarction secondary to syphilitic endarteritis; this can result in hemiparesis or hemiplegia. Parenchymatous neurosyphilis (general paresis, dementia paralytica, paretic neurosyphilis) is due to direct invasion of the cerebrum by treponemes. It is a rare and late form of neurosyphilis, with dementia and neurologic symptoms (e.g. paralysis) that (untreated) progress until death occurs. Tabes dorsalis, which affects up to a third of patients with neurosyphilis after a long latent period:typical clinical signs and symptoms, including diplopia, lightning pains (painful paresthesias, especially of the extremities), loss of vibratory and position sense, reduced reflexes in the legs, ataxia, sphincter dysfunction,visceral crisis (abdominal, rectal and laryngeal pain), and Argyll Robertson pupils (abnormal pupillary light reflexes: loss of direct and consensual;retention of accommodation). Tabes dorsalis may burn out even without treatment.

39. Congenital syphilis Early congenital syphilis Infants generally present with symptoms during the neonatal period or within the first 3 months of life. At the latest, they develop symptoms within the first 2 years of life. Typical manifestations are marasmic syphilis (i.e. cachexia) and skin lesions similar to those of acquired secondary syphilis, except that they may be bullous (pemphigus syphiliticus) and tend to be more erosive. Additional clinical findings are “snuffles” (bloody or purulent mucinous nasal discharge), perioral and perianal fissures, lymphadenopathy and hepatosplenomegaly. Skeletal involvement (i.e. osteochondritis) may result in pseudoparalysis of Parrot because of reduced movement of the extremities due to pain; other manifestations include anemia, thrombocytopenia, syphilitic pneumonitis (pneumonia alba), hepatitis, nephropathy and congenital neurosyphilis. Late congenital syphilis and stigmata Late congenital syphilis in a child or adolescent corresponds to tertiary syphilis in an adult and is not infectious. The stigmata represent the delayed consequences of localized inflammation at the sites of treponemal infection. In about one-third of children, an interstitial keratitis is seen; this finding together with typical dental abnormalities (Hutchinson’s teeth) and neural deafness forms the Hutchinson triad.

44. Syphilis and HIV Syphilis and other STIs that produce genital ulcers further increase the risk of acquiring HIV. Reasons for the increased risk of HIV transmission include: ● lack of an epithelial barrier due to ulceration of the skin or mucous membranes ● large numbers of macrophages and T cells with receptors for HIV ● production of cytokines by macrophages stimulated by treponemal lipoproteins. In addition, syphilitic manifestations are altered in HIV- positive patients, with a higher likelihood of neurologic findings and (in those with secondary syphilis) ulcerative lesions.

45. Laboratory Diagnosis of Syphilis The diagnosis of syphilis is based on the direct detection of treponemes or treponemal DNA by microscopy or molecular biologic techniques serologic tests that assess antibody responses to either cardiolipin (non-treponemal tests) or treponemal antigens (treponemal tests). Diagnosis of the different stages of syphilis depends on the interpretation of laboratory test results, the presence of clinical signs and symptoms, and their history. All patients who have syphilis should also be tested for HIV infection.

46. Identification of T. pallidum Microscopic examination and molecular assays, since T. pallidum cannot be routinely cultured in vitro. For propagation and experimental studies, growth in rabbit testicles is possible. Microscopic examination Darkfield microscopy permits the definite diagnosis of syphilis by visual detection of motile spirochetes from lesions of the skin. It requires careful specimen collection, ideally consisting of serous fluid free of red blood cells. Due to the presence of saprophytic spirochetes in the oral cavity, there is limited utility for darkfield examination of serous exudate from lesions in this site. Immunologic detection of the microorganism by the indirect fluorescent antibody test, which utilizes fluorescein-labeled anti-T. pallidum antibodies, is especially useful for oral lesions. In the case of a negative result from microscopic examination, repeat testing is recommended. Serologic tests are also indicated.

47. Polymerase chain reaction-based assays PCR-based assays for detection of T. pallidum DNA are commercially available and may be useful in special circumstances, e.g. neurosyphilis and congenital syphilis.

48. Serologic tests for syphilis Non-treponemal tests The VDRL and RPR tests and related assays such as the unheated serum reagin (USR), reagin screen test (RST) and toluidine red unheated serum test (TRUST) detect antibodies to cardiolipin. The latter is a component of mammalian cells that is incorporated and modified by treponemes, which results in the development of host antibodies against it (comparable with autoantibodies directed against phospholipids. All these tests measure IgG and IgM antibodies against this lipoprotein-like material released from damaged host cells and from treponemes. Titers of these antibodies correlate with disease activity and are useful in screening and monitoring treatment. A fourfold decrease in the antibody titer indicates successful treatment, while a fourfold increase indicates relapse or reinfection. In the case of early and efficacious treatment, non-treponemal assays usually become negative.

49. Treponemal tests The major indication for treponemal tests for syphilis is confirmation of reactive non-treponemal tests. IgM and IgG andetected in these assays by the end of the fourth week after infection. The specific treponemal tests generally remain positive indefinitely, and only in the case of treatment of very early syphilis do they revert to negative. The specificity is very high and false-positive reactions seldom occur. The sensitivity varies with the stage of syphilis: between 70% and 100% in primary syphilis, 100% in secondary and latent syphilis, and about 95% in late syphilis15. There is no differentiation between antibodies to T. pallidum and other treponemes and spirochetes. Specific assays include the following: ● TPHA, MHA-TP, T. pallidum particle agglutination test (TPPA): these assays measure antibodies directed against surface proteins of T. pallidum (sonicated fragments of treponemes) attached to rabbit erythrocytes as antigen carriers. A positive result means that the patient had or still has active syphilis, but no assessment about the activity of the disease can be concluded from the qualitative result. Ninety percent of patients are positive at the time they seek medical care for a chancre. ● FTA-ABS assay: the serum reacts with the whole treponeme and forms antigen–antibody complexes visualized by fluorescein-isothiocyanate. To avoid nonspecific reactions with antibodies directed against saprophytic treponemes, a further step with Reiter treponemes is included to absorb nonspecific antibodies. The differentiation into IgM and IgG is possible by including selective anti-Ig antibodies. ● FTA-ABS-19S-IgM test: the isolated IgM antibody fraction is separately tested and provides a higher specificity than other tests. It is restricted to special situations, e.g. congenital syphilis or the differentiation of relapsing syphilis from reinfection. ● Solid phase hemadsorption test (SPHA) or IgM ELISA: the SPHA test is used for the detection of specific IgM antibodies that attach to the solid phase of microtiter plates by reacting with the treponemal antigen on rabbit erythrocytes as antigen carriers. IgM antibodies can also be measured by the ELISA technology. These tests are useful for the diagnosis of congenital syphilis, neurosyphilis (positive, but low-titer) and reinfection.

52. Pathology In primary syphilis, there is ulceration and a diffuse dermal infiltrate of plasma cells, lymphocytes and histiocytes. Endothelial swelling is also present. Spirochetes may be detected with Warthin–Starry or immunohistochemical staining. In secondary syphilis, the epidermis may be normal, psoriasiform, necrotic or ulcerated. Pustules may be found in the epidermis. Dermal infiltrates of plasma cells, lymphocytes and histiocytes can be perivascular, lichenoid, nodular or diffuse. Older lesions of secondary syphilis may be granulomatous and can resemble sarcoidosis except for the presence of plasma cells. Endothelial swelling and vascular proliferation can also be found in secondary syphilis. Spirochetes are identified in up to one-third of cases. Lues maligna is characterized by vasculitis. In tertiary syphilis, tuberculoid granulomas (with or without caseation) are present together with plasma cells. Endothelial swelling is evident, but organisms are usually no longer seen.