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1.  The localisation of treponemes and characterisation of the inflammatory infiltrate in skin biopsies from patients with primary or secondary syphilis, or early infectious yaws. 
Genitourinary Medicine  1993;69(2):102-107.
OBJECTIVE--To study the localisation of treponemes and to analyse the inflammatory infiltrate in biopsy specimens from patients with primary or secondary syphilis, or early infectious yaws. MATERIALS AND METHODS--Skin biopsies originating from human lesions of primary (29x) or secondary (15x) syphilis (Rotterdam), or early yaws (18x) (West Sumatra) were studied. Different histochemical and immunohistochemical detection methods were used in this study. RESULTS AND CONCLUSION--The histochemical silver staining method according to Steiner revealed the presence of T. pallidum in all cases of primary syphilis studied. In 10 out of 14 cases of secondary syphilis, treponemes were demonstrated. With an immunofluorescence staining technique (IF) using anti-T. pallidum antiserum raised in rabbits (a-Tp), T. pallidum was demonstrated in 28 out of 29 cases of primary syphilis, and in 14 out of 14 studied cases of secondary syphilis. The silver staining method and IF showed identical localisations of T. pallidum (mainly in the dermal-epidermal junction zone or throughout the dermis). Using a-Tp antiserum in the indirect immunofluorescence technique, T. pertenue could be demonstrated in the dermis more often than with Steiner silver staining. However, epidermotropism of T. pertenue in yaws specimens was remarkable, compared with more mesodermotropism of T. pallidum; numbers of T. pertenue in the dermis were limited in all specimens. The dermal inflammatory infiltrate in primary and secondary syphilis was composed mainly of lymphocytes and plasma cells. In most cases more T (CD3 positive) cells than B (CD22 positive) cells were present. Regarding T cell subpopulations, in primary syphilis, T helper/inducer (CD4 positive) cells predominated in 86% of cases. In secondary syphilitic lesions, numbers of T helper/inducer cells were less frequent than or equal to T-suppressor/cytotoxic (CD8 positive) cells in 60% of cases. Remarkably, in yaws specimens the inflammatory infiltrate consisted mainly of IgG, but also IgA and IgM producing plasma cells. T or B lymphocytes were scarce, which is in sharp contrast with findings in syphilitic lesions.
PMCID: PMC1195039  PMID: 8509088
From a study of the phenomena of the primary infection on the one hand, and the phenomena of local spread, or dissemination, on the other, it is seen that a multiplicity of lesions develops in the testicle and scrotum of the rabbit which have much the same characteristics irrespective of their origin. Some of these lesions are clearly recognizable as primary lesions or parts of a primary reaction to infection, while others are just as clearly the results of dissemination of the virus from a primary focus of infection or correspond with lesions which are commonly spoken of as secondary lesions. The effort to draw a sharp line of distinction between these two groups of lesions or between a primary and a secondary stage of infection in the rabbit, however, would be largely an arbitrary procedure. The fact is that the tissues of the scrotum and testicle of the rabbit constitute favorable surroundings for the localization and development of pallidum infections. Under ordinary circumstances, a large part of the reaction to infection which expresses itself in the formation of lesions recognizable by ordinary methods of examination takes place in these tissues. These lesions present certain broad and general characteristics without regard to whether they are primary or secondary in origin; the reaction is merely a reaction to a syphilitic infection which in either case may assume the most diverse character. Further, it would appear that in rabbits infected with such strains of Treponema pallidum as we have used, the virus is never confined to the area occupied by the so called primary lesion, or chancre, but always spreads and always gives rise to a regional adenopathy. There may be no lesions to indicate the progress of this dissemination, but an examination of the inguinal nodes shows that dissemination occurs very soon after inoculation, and a pallidum reaction may be detected in these glands even before infection can be recognized in the scrotum. Subsequently lesions develop in all parts of the scrotum and testicle, sometimes involving the entire testicle or scrotum, and at others, forming focalized lesions with an especial predilection for certain locations such as the epididymis, the mediastinum testis, the tunics, and the dorsal folds of the scrotum. In some instances, more or less continuous lesions form along the course of the perivascular lymphatics, suggesting that this is one path taken in the dissemination of the organism. It is probable, however, that lesions of a gross character develop more as a result of accumulation of spirochetes than of mere invasion of the lymphatics since they are not a constant accompaniment of the local infection, while invasion of the lymphatics and extension of the infection to the regional lymph nodes occur in all cases.
PMCID: PMC2128250  PMID: 19868424
3.  Immune Evasion and Recognition of the Syphilis Spirochete in Blood and Skin of Secondary Syphilis Patients: Two Immunologically Distinct Compartments 
The clinical syndrome associated with secondary syphilis (SS) reflects the propensity of Treponema pallidum (Tp) to escape immune recognition while simultaneously inducing inflammation.
To better understand the duality of immune evasion and immune recognition in human syphilis, herein we used a combination of flow cytometry, immunohistochemistry (IHC), and transcriptional profiling to study the immune response in the blood and skin of 27 HIV(-) SS patients in relation to spirochetal burdens. Ex vivo opsonophagocytosis assays using human syphilitic sera (HSS) were performed to model spirochete-monocyte/macrophage interactions in vivo.
Despite the presence of low-level spirochetemia, as well as immunophenotypic changes suggestive of monocyte activation, we did not detect systemic cytokine production. SS subjects had substantial decreases in circulating DCs and in IFNγ-producing and cytotoxic NK-cells, along with an emergent CD56−/CD16+ NK-cell subset in blood. Skin lesions, which had visible Tp by IHC and substantial amounts of Tp-DNA, had large numbers of macrophages (CD68+), a relative increase in CD8+ T-cells over CD4+ T-cells and were enriched for CD56+ NK-cells. Skin lesions contained transcripts for cytokines (IFN-γ, TNF-α), chemokines (CCL2, CXCL10), macrophage and DC activation markers (CD40, CD86), Fc-mediated phagocytosis receptors (FcγRI, FcγR3), IFN-β and effector molecules associated with CD8 and NK-cell cytotoxic responses. While HSS promoted uptake of Tp in conjunction with monocyte activation, most spirochetes were not internalized.
Our findings support the importance of macrophage driven opsonophagocytosis and cell mediated immunity in treponemal clearance, while suggesting that the balance between phagocytic uptake and evasion is influenced by the relative burdens of bacteria in blood and skin and the presence of Tp subpopulations with differential capacities for binding opsonic antibodies. They also bring to light the extent of the systemic innate and adaptive immunologic abnormalities that define the secondary stage of the disease, which in the skin of patients trends towards a T-cell cytolytic response.
Author Summary
Syphilis, a sexually transmitted disease caused by the spirochetal bacterium Treponema pallidum, affects close to 10 million people per year worldwide. Despite the robust nature of the humoral and cellular immune responses associated with the disease, weeks to months may elapse before the host gains control of the infection. Moreover, in the absence of antibiotic treatment, containment is often incomplete and relapses are common. Herein we studied aspects of the immune response in the blood and skin of patients with secondary syphilis to better understand the factors that determine whether the bacterium evades host defenses or is cleared in its natural human host. Our findings support the importance of the macrophage as a primary means of bacterial killing in the skin, while suggesting that the extent of bacterial clearance is determined by the bacterial loads present in either the blood or skin of patients and the appearance of spirochetes which are resistant to uptake (phagocytosis) by the macrophages. Study results underscore the extent of the systemic immunologic abnormalities triggered by the bacterium and provide new insights regarding the complexity of the immune response in the skin of untreated patients.
PMCID: PMC3398964  PMID: 22816000
4.  Syphilis infection among homosexual men reporting contact with syphilis: a case control study 
BMJ Open  2012;2(4):e001339.
High rates of syphilis have been reported among men who have sex with men (MSM) internationally. Guidelines recommend presumptive treatment of sexual contacts of individuals with syphilis at the point of care. The aim of this study was to determine the proportion who were infected with syphilis and the factors predictive of infection among men reporting contact with a man with syphilis.
Contacts who were syphilis infected (cases) were compared with those who were uninfected (controls).
This study was conducted at the main public sexually transmitted diseases clinic in Victoria, Australia.
One hundred and seventy-two MSM presenting as sexual contacts of men with syphilis at a sexual health service in Melbourne, Australia, between July 2007 and October 2011 were assessed for syphilis.
Outcome measures
Proportion of MSM who are infected with syphilis and factors associated with infection.
Of the 172 men who presented reporting contact with syphilis, 26 (15%, 95% CI 10 to 20%) had syphilis. One man had primary syphilis, 4 had secondary syphilis, while the remaining 21 had early latent syphilis. Infection was associated with unprotected anal sex over the prior 3 months (adjusted OR 6.1, 95% CI 1.4 to 26.8).
One in seven men presenting as contacts of syphilis had syphilis infection, most of whom were latently infected. Contacts reporting recent unprotected anal sex were more likely to have syphilis.
PMCID: PMC3425903  PMID: 22907046
Epidemiology -Syphylis; men who have sex with men; partner notification; contact tracing
5.  Repeat Syphilis Among Men Who Have Sex With Men in California, 2002–2006: Implications for Syphilis Elimination Efforts 
We examined rates of and risk factors for repeat syphilis infection among men who have sex with men (MSM) in California.
We analyzed 2002 to 2006 California syphilis surveillance system data.
During the study period, a mean of 5.9% (range: 4.9%–7.1% per year) of MSM had a repeat primary or secondary (PS) syphilis infection within 2 years of an initial infection. There was no significant increase in the annual proportion of MSM with a repeat syphilis infection (P=.42). In a multivariable model, factors associated with repeat syphilis infection were HIV infection (odds ratio [OR] = 1.65; 95% confidence interval [CI] = 1.14, 2.37), Black race (OR = 1.84; 95% CI = 1.12, 3.04), and 10 or more recent sex partners (OR = 1.99; 95% CI = 1.12, 3.50).
Approximately 6% of MSM in California have a repeat PS syphilis infection within 2 years of an initial infection. HIV infection, Black race, and having multiple sex partners are associated with increased odds of repeat infection. Syphilis elimination efforts should include messages about the risk for repeat infection and the importance of follow-up testing. Public health attention to individuals repeatedly infected with syphilis may help reduce local disease burdens.
PMCID: PMC3490561  PMID: 22095364
6.  Secondary Syphilis in Cali, Colombia: New Concepts in Disease Pathogenesis 
Venereal syphilis is a multi-stage, sexually transmitted disease caused by the spirochetal bacterium Treponema pallidum (Tp). Herein we describe a cohort of 57 patients (age 18–68 years) with secondary syphilis (SS) identified through a network of public sector primary health care providers in Cali, Colombia. To be eligible for participation, study subjects were required to have cutaneous lesions consistent with SS, a reactive Rapid Plasma Reagin test (RPR-titer ≥1∶4), and a confirmatory treponemal test (Fluorescent Treponemal Antibody Absorption test- FTA-ABS). Most subjects enrolled were women (64.9%), predominantly Afro-Colombian (38.6%) or mestizo (56.1%), and all were of low socio-economic status. Three (5.3%) subjects were newly diagnosed with HIV infection at study entry. The duration of signs and symptoms in most patients (53.6%) was less than 30 days; however, some patients reported being symptomatic for several months (range 5–240 days). The typical palmar and plantar exanthem of SS was the most common dermal manifestation (63%), followed by diffuse hypo- or hyperpigmented macules and papules on the trunk, abdomen and extremities. Three patients had patchy alopecia. Whole blood (WB) samples and punch biopsy material from a subset of SS patients were assayed for the presence of Tp DNA polymerase I gene (polA) target by real-time qualitative and quantitative PCR methods. Twelve (46%) of the 26 WB samples studied had quantifiable Tp DNA (ranging between 194.9 and 1954.2 Tp polA copies/ml blood) and seven (64%) were positive when WB DNA was extracted within 24 hours of collection. Tp DNA was also present in 8/12 (66%) skin biopsies available for testing. Strain typing analysis was attempted in all skin and WB samples with detectable Tp DNA. Using arp repeat size analysis and tpr RFLP patterns four different strain types were identified (14d, 16d, 13d and 22a). None of the WB samples had sufficient DNA for typing. The clinical and microbiologic observations presented herein, together with recent Cali syphilis seroprevalence data, provide additional evidence that venereal syphilis is highly endemic in this region of Colombia, thus underscoring the need for health care providers in the region to be acutely aware of the clinical manifestations of SS. This study also provides, for the first time, quantitative evidence that a significant proportion of untreated SS patients have substantial numbers of circulating spirochetes. How Tp is able to persist in the blood and skin of SS patients, despite the known presence of circulating treponemal opsonizing antibodies and the robust pro-inflammatory cellular immune responses characteristic of this stage of the disease, is not fully understood and requires further study.
Author Summary
Venereal syphilis is a sexually transmitted disease caused by the bacterium Treponema pallidum (Tp). We describe 57 patients (age 18–68 years) from Cali, Colombia diagnosed with secondary syphilis (SS). Most were women (64.9%); predominantly Afro-Colombian (38.6%) or mestizo (56.1%), and all of low socio-economic status. Three (5.3%) were newly diagnosed with HIV infection at study entry. The typical palmar and plantar rash of SS was the common clinical finding (63%). Whole blood (WB) samples and skin biopsies were assayed for Tp DNA by using molecular methods. 46% of the WB samples had circulating Tp DNA and 64% were positive when the DNA was extracted on the same day of collection. Tp DNA was also present in the skin of 66% (12/26) of biopsies tested by PCR. We conclude that primary care providers in countries like Colombia need to remain highly vigilant for the clinical presentation of SS. The study also provides, for the first time, qualitative and quantitative evidence that untreated SS patients have significant numbers of spirochetes in blood and skin, and that this occurs despite the known presence of circulating anti-treponemal antibodies and strong cellular immune responses associated with this stage of the disease.
PMCID: PMC2872645  PMID: 20502522
From the study of a large series of rabbits with outspoken manifestations of generalized syphilis, lesions of the skin and appendages were found to constitute one of the largest and most varied groups of such affections. The conditions noted consisted of alopecias, onychia and paronychia, and lesions of the skin proper. It was found to be a matter of some difficulty to make a positive diagnosis of syphilitic alopecia, but there were three and possibly four conditions which appeared to be attributable to such an infection. The first of these took the form of a general or local roughening of the coat with falling of the hair which produced the typical moth-eaten appearance associated with syphilitic alopecia in the human subject. A second form of alopecia was essentially an abnormal looseness of the hair which permitted large areas of the body to be completely denuded. The third type of alopecia was associated with definite skin changes, and the hair was readily removable together with an adherent mass of epithelial scales. Paronychia was comparatively rare but was readily recognized by a characteristic infiltration and exfoliation of the skin about the base of the nails. The incidence of onychia is uncertain. Late in the course of the investigation it was found that alterations in the nails which were not entirely characteristic in themselves might occur in consequence of a syphilitic involvement of the nail beds which could not be detected by ordinary methods of examination. The cases which were recognized as syphilitic were those which showed an associated paronychia. Lesions of the skin were found to be one of the most frequent manifestations of a generalized infection in the rabbit. These lesions were divided into three classes: first, granulomatous lesions, second, infiltrations, and third, erythemata. The granulomata were lesions of a fleshy character which tended to grow to a very large size and presented all the characteristics of circumscribed primary lesions of the scrotum. The conditions described as cutaneous infiltrations included two general types of lesions, one a flattened and rather diffuse process, the other an elevated and sharply circumscribed papule. As a class, these lesions were very prone to secondary alterations and in this way gave rise to a great variety of conditions which in general resembled the diffuse primary lesions of the scrotum and the papular lesions resulting from local dissemination. A third type of lesion resembling the macular erythemata of man was observed in a small number of animals, and while no definite proof of the specific origin of these lesions was obtained, the evidence available was strongly suggestive. In addition, several other cutaneous affections were noted which have not as yet been thoroughly investigated. It is suggested, however, that these processes may bear some relation to infection with Treponema pallidum.
PMCID: PMC2128292  PMID: 19868455
8.  Multilevel and spatial analysis of syphilis in Shenzhen, China, to inform spatially targeted control measures 
Sexually transmitted infections  2012;88(5):325-329.
The present study investigates the varied spatial distribution of syphilis cases in Shenzhen, China, and explores the individual-, neighbourhood- and district-level factors affecting the distribution.
This study uses spatial analysis and multi-level generalised estimating equations to explore the spatial distribution of reported syphilis cases among individuals in Shenzhen, Guangdong Province, China. The spatial distribution of primary/secondary and latent cases was investigated using the Moran’s I-statistic. Primary/secondary syphilis cases were compared with all syphilis cases using a three-level model with individual (n=6496), neighbourhood (n=55) and district (n=6) levels.
A total of 6496 syphilis cases were reported in 2009 with 35.8% primary and secondary syphilis cases. Both primary/secondary syphilis cases (Moran’s I value=0.33, p<0.01) and latent syphilis cases (Moran’s I value=0.19, p<0.01) showed significant spatial clustering at the neighbourhood level. Adjusting for the number of reporting hospitals, the best model found that the following characteristics were associated with primary/secondary syphilis infection: individuals who are younger in age (p=0.003), male (p<0.001), migrant labourers (p=0.047) and those who live in districts with a higher gross domestic product (p<0.001).
There is substantial clustering of primary and secondary syphilis cases at the neighbourhood level in Shenzhen, suggesting the need for greater STD health service provision in these clustered neighbourhoods. Spatially targeted syphilis control measures may be useful to optimise testing, treatment and partner services.
PMCID: PMC3642620  PMID: 22378936
9.  Azithromycin Treatment Failure Among Primary and Secondary Syphilis Patients in Shanghai 
Sexually transmitted diseases  2010;37(11):726-729.
Azithromycin has been used to treat primary and secondary syphilis and as prophylaxis for sexual partners. We evaluated syphilis treatment failure in patients who received azithromycin therapy.
Patients who did not respond to azithromycin therapy were referred to Shanghai Skin Disease and sexually transmitted disease hospital. Treatment failure was defined as follows: (1) persistent ulcers or cutaneous or mucosal lesions 1 month after therapy; or (2) detection of spirochetes in dark-field microscopy examination of a lesion at least 1 week after treatment; or (3) failure of rapid plasma reagin titers to decrease 4-fold at 3 months after treatment.
A total of 132 patients with primary and secondary syphilis who failed azithromycin therapy were referred to our hospital between January 2001 and October 2008. Of 132 patients, 42 (31.8%) had primary syphilis and 90 (68.2%) had secondary syphilis. Twenty-six patients with primary syphilis developed multiple lesions or secondary syphilis, or persistent ulcers despite using azithromycin. The skin or mucosal lesions did not resolve in 37 patients with secondary syphilis after azithromycin treatment. Ten patients had a positive dark-field examination for Treponema pallidum (T. pallidum) after treatment. The serum rapid plasma reagin titers studied in all cases had failed to decrease 4-fold at 3 months after therapy. The doses of azithromycin used for treatment ranged from 4 to 30 g.
The failure of azithromycin to cure a substantial number of patients with primary and secondary syphilis in Shanghai suggests that azithromycin has limited therapeutic value in this setting.
PMCID: PMC3114640  PMID: 20644500
10.  Antigenic Variation of TprK Facilitates Development of Secondary Syphilis 
Infection and Immunity  2014;82(12):4959-4967.
Although primary syphilis lesions heal spontaneously, the infection is chronic, with subsequent clinical stages. Healing of the primary chancre occurs as antibodies against outer membrane antigens facilitate opsonophagocytosis of the bacteria by activated macrophages. TprK is an outer membrane protein that undergoes antigenic variation at 7 variable regions, and variants are selected by immune pressure. We hypothesized that individual TprK variants escape immune clearance and seed new disseminated lesions to cause secondary syphilis. As in human syphilis, infected rabbits may develop disseminated secondary skin lesions. This study explores the nature of secondary syphilis, specifically, the contribution of antigenic variation to the development of secondary lesions. Our data from the rabbit model show that the odds of secondary lesions containing predominately TprK variant treponemes is 3.3 times higher than the odds of finding TprK variants in disseminated primary lesions (odds ratio [OR] = 3.3 [95% confidence interval {CI}, 0.98 to 11.0]; P = 0.055) and that 96% of TprK variant secondary lesions are likely seeded by single treponemes. Analysis of antibody responses demonstrates significantly higher antibody titers to tprK variable region sequences found in the inoculum compared to reactivity to tprK variant sequences found in newly arising secondary lesions. This suggests that tprK variants escape the initial immune response raised against the V regions expressed in the inoculum. These data further support a role for TprK in immune evasion and suggest that the ability of TprK variants to persist despite a robust immune response is instrumental in the development of later stages of syphilis.
PMCID: PMC4249288  PMID: 25225245
11.  A Laboratory-Based Evaluation of Four Rapid Point-of-Care Tests for Syphilis 
PLoS ONE  2014;9(3):e91504.
Syphilis point-of-care tests may reduce morbidity and ongoing transmission by increasing the proportion of people rapidly treated. Syphilis stage and co-infection with HIV may influence test performance. We evaluated four commercially available syphilis point-of-care devices in a head-to-head comparison using sera from laboratories in Australia.
Point-of-care tests were evaluated using sera stored at Sydney and Melbourne laboratories. Sensitivity and specificity were calculated by standard methods, comparing point-of-care results to treponemal immunoassay (IA) reference test results. Additional analyses by clinical syphilis stage, HIV status, and non-treponemal antibody titre were performed. Non-overlapping 95% confidence intervals (CI) were considered statistically significant differences in estimates.
In total 1203 specimens were tested (736 IA-reactive, 467 IA-nonreactive). Point-of-care test sensitivities were: Determine 97.3%(95%CI:95.8–98.3), Onsite 92.5%(90.3–94.3), DPP 89.8%(87.3–91.9) and Bioline 87.8%(85.1–90.0). Specificities were: Determine 96.4%(94.1–97.8), Onsite 92.5%(90.3–94.3), DPP 98.3%(96.5–99.2), and Bioline 98.5%(96.8–99.3). Sensitivity of the Determine test was 100% for primary and 100% for secondary syphilis. The three other tests had reduced sensitivity among primary (80.4–90.2%) compared to secondary syphilis (94.3–98.6%). No significant differences in sensitivity were observed by HIV status. Test sensitivities were significantly higher among high-RPR titre (RPR≥8) (range: 94.6–99.5%) than RPR non-reactive infections (range: 76.3–92.9%).
The Determine test had the highest sensitivity overall. All tests were most sensitive among high-RPR titre infections. Point-of-care tests have a role in syphilis control programs however in developed countries with established laboratory infrastructures, the lower sensitivities of some tests observed in primary syphilis suggest these would need to be supplemented with additional tests among populations where syphilis incidence is high to avoid missing early syphilis cases.
PMCID: PMC3950184  PMID: 24618681
12.  Serological Response to Treatment of Syphilis According to Disease Stage and HIV Status 
The serological response to treatment was studied in 264 syphilis patients; it was influenced by syphilis stage but not by human immunodeficiency virus infection and reinfection. Some of the recommendations of current guidelines are critically discussed, and amendments are proposed.
Background. Serology is the mainstay for syphilis diagnosis and treatment monitoring. We investigated serological response to treatment of syphilis according to disease stage and HIV status.
Methods. A retrospective cohort study of 264 patients with syphilis was conducted, including 90 primary, 133 secondary, 33 latent, and 8 tertiary syphilis cases. Response to treatment as measured by the Venereal Disease Research Laboratory (VDRL) test and a specific IgM (immunoglobulin M) capture enzyme-linked immunosorbent assay (ELISA; Pathozyme-IgM) was assessed by Cox regression analysis.
Results. Forty-two percent of primary syphilis patients had a negative VDRL test at their diagnosis. Three months after treatment, 85%–100% of primary syphilis patients had reached the VDRL endpoint, compared with 76%–89% of patients with secondary syphilis and 44%–79% with latent syphilis. In the overall multivariate Cox regression analysis, serological response to treatment was not influenced by human immunodeficiency virus (HIV) infection and reinfection. However, within primary syphilis, HIV patients with a CD4 count of <500 cells/μL had a slower treatment response (P = .012). Compared with primary syphilis, secondary and latent syphilis showed a slower serological response of VDRL (P = .092 and P < .001) and Pathozyme-IgM tests (P < .001 and P = .012).
Conclusions. The VDRL should not be recommended as a screening test owing to lack of sensitivity. The syphilis disease stage significantly influences treatment response whereas HIV coinfection only within primary syphilis has an impact. VDRL test titers should decline at least 4-fold within 3–6 months after therapy for primary or secondary syphilis, and within 12–24 months for latent syphilis. IgM ELISA might be a supplement for diagnosis and treatment monitoring.
PMCID: PMC3501331  PMID: 22955437
13.  Active syphilis in HIV infection: a multicentre retrospective survey. The German AIDS Study Group (GASG). 
Genitourinary Medicine  1996;72(3):176-181.
OBJECTIVE: To study syphilis in HIV infection focusing on immunocompromised patients with an atypical or aggressive clinical course of syphilis, inappropriate serological reactions or an unreliable response to therapy. STUDY DESIGN: A multicentre retrospective chart review using a standardised questionnaire for all patients with active syphilis. SETTINGS: Thirteen dermatological and medical centres throughout Germany, all members of the German AIDS Study Group (GASG). PATIENTS: Clinical data of 11,368 HIV infected patients have been analysed for cases of active syphilis requiring treatment. Asymptotic patients with reactive serological parameters indicating latent syphilis without a need for treatment were excluded. RESULTS: Active syphilis was reported in 151 of 11,368 HIV infected patients (1.33%, range per centre 0.3%-5.1%). Most of the 151 syphilis patients were male (93%) and belonged to the homosexual or bisexual exposure category for HIV infection (79%); another 6% were iv drug users. Among the 151 syphilis patients primary syphilis was diagnosed in 17.2%, maculopapular secondary syphilis in 29.1%, ulcerating secondary syphilis in 7.3%, neurosyphilis in 16.6% and latent seropositive syphilis without clinical symptoms but serological abnormalities indicating active syphilis in 25.2%. A history of prior treatments for syphilis was reported in 50%. At the time of syphilis diagnosis 26.5% of the patients were in CDC stage II, 33.8% in stage III and 24.5% in stage IV of HIV disease (CDC classification 1987). CD4 cell count was lowest in those with ulcerating secondary syphilis (mean 307, SD 140/microliters) and neurosyphilis (351, SD 235/ microliters). The highest CD4 count was found in patients with early primary and early secondary syphilis (444, SD 163/microliters and 470, SD 355/microliters). Inappropriate serological response to syphilis infection was found in 81 of 151 patients (54%). Remarkable findings were false negative VDRL titres (11 patients with non primary syphilis), false negative TPHA (1) or 19S-IgM-FTA-ABS-tests (16), and strongly reactive VDRL (> or = 512, 8) or TPHA titres (> or = 10 240, 47). Treatment failures were reported in at least 6 of 151 cases (4%). CONCLUSIONS: Atypical clinical and serological courses of syphilis were observed in HIV infected patients. Ulcerating secondary syphilis with general symptoms ("malignant syphilis") was 60 times more frequent than in historic syphilis series. Neurosyphilis was found in one sixth of those with active syphilis. Therefore lumbar puncture should be considered a routine in coinfections with HIV and syphilis. Treatment efficacy should be monitored carefully.
PMCID: PMC1195645  PMID: 8707318
14.  Clinical Value of Treponema pallidum Real-Time PCR for Diagnosis of Syphilis▿  
Journal of Clinical Microbiology  2009;48(2):497-502.
The diagnosis of syphilis can be complicated when it is based on diverse clinical manifestations, dark-field microscopy, and serology. In the present study, therefore, we examined the additional clinical value of a Treponema pallidum real-time TaqMan PCR for the detection of primary and secondary syphilis. The additional value of the T. pallidum real-time PCR for the diagnosis of primary syphilis was evaluated by the use of three different algorithms: (i) a head-to-head comparison of the dark-field microscopy result and the T. pallidum real-time PCR result, (ii) comparison of the clinical diagnosis made in a sexually transmitted infection clinic (STI) (including by dark-field microscopy) and the T. pallidum real-time PCR result, and (iii) comparison of the clinical diagnosis made in a general practitioner's office (without dark-field microscopy) and the T. pallidum real-time PCR result. A fourth algorithm was used to determine the performance of the T. pallidum real-time PCR regarding the detection of secondary syphilis. From December 2006 to April 2008, 716 patients with suspected cases of primary syphilis and 133 patients with suspected cases of secondary syphilis were included in the study. A kappa value of 0.601 was found for the agreement between dark-field microscopy and the T. pallidum real-time PCR. Good agreement was found between the T. pallidum real-time PCR and both the diagnosis of the general practitioner (kappa = 0.745) and the diagnosis of the STI clinic (kappa = 0.769). The sensitivity with respect to the STI clinic diagnosis was 72.8%, the specificity was 95.5%, the positive predictive value was 89.2%, and the negative predictive value was 95.0%. The T. pallidum real-time PCR is a fast, efficient, and reliable test for the diagnosis of primary syphilis in an STI outpatient clinic and a general practitioner setting, but it has no added diagnostic value for the diagnosis of secondary syphilis.
PMCID: PMC2815629  PMID: 20007388
15.  Syphilis in adults 
Sexually Transmitted Infections  2005;81(6):448-452.
Syphilis is a sexually transmitted disease with protean manifestations resulting from infection by Treponema pallidum. It is systemic early from the outset, the primary pathology being vasculitis. Acquired syphilis can be divided into primary, secondary, latent, and tertiary stages. The infection can also be transmitted vertically resulting in congenital syphilis, and occasionally by blood transfusion and non-sexual contact. Diagnosis is mainly by dark field microscopy in early syphilis and by serological tests. The management in the tropics depends on the diagnostic facilities available: in resource poor countries, primary syphilis is managed syndromically as for anogenital ulcer. The introduction of rapid "desktop" serological tests may simplify and promote widespread screening for syphilis. The mainstay of treatment is with long acting penicillin. Syphilis promotes the transmission of HIV and both infections can simulate and interact with each other. Treponemes may persist despite effective treatment and may have a role in reactivation in immunosuppressed patients. Partner notification, health education, and screening in high risk populations and pregnant women to prevent congenital syphilis are essential aspects in controlling the infection.
PMCID: PMC1745064  PMID: 16326843
16.  Use of PCR in the diagnosis of early syphilis in the United Kingdom 
Sexually Transmitted Infections  2003;79(6):479-483.
Objectives: To evaluate a Treponema pallidum polymerase chain reaction (PCR) test in the laboratory diagnosis of early syphilis in the United Kingdom.
Subjects and setting: Men and women attending genitourinary medicine clinics in England.
Methods: A trial PCR service was offered for the analysis of swabs of ano-genital or oral ulcers suspected to be syphilitic in origin. Clinical details, results of treponemal serology, and other relevant laboratory tests carried out by the sending laboratories were obtained retrospectively by questionnaire.
Results: Data from 98 patients, representing 100 episodes of ulceration, were analysed. The majority of patients (70) attended clinics in the Greater Manchester area. Eighty six patients were male and 58 were men who have sex with men (MSM), of whom 24 were HIV positive. PCR results agreed with the clinical diagnosis for 95 patients; samples from 26 patients were PCR positive and serologically diagnosed as primary (18) or secondary (8) syphilis, whereas 70 patients had PCR negative samples and were not diagnosed as having active syphilis. These data include two HIV positive patients who were PCR positive 12 and 21 days before their treponemal seroconversion. One positive PCR result was not supported by positive treponemal serology (this patient coincidentally received a 10 day course of co-amoxiclav 1 week after sampling). Three patients had negative PCR results but positive syphilis serology. The sensitivity, specificity, positive and negative predictive value for primary syphilis were 94.7%, 98.6%, 94.7%, and 98.6%, respectively, and for secondary syphilis these were 80.0%, 98.6%, 88.9%, and 97.2%, respectively.
Conclusion: PCR is a sensitive and specific test for T pallidum, and an important adjunct to dark ground microscopy and treponemal serology in diagnosing infectious syphilis in the United Kingdom.
PMCID: PMC1744778  PMID: 14663125
17.  Alterations in T lymphocytes and T-lymphocyte subpopulations in patients with syphilis. 
The distribution of T-lymphocyte subpopulations was studied in 34 patients with primary or secondary syphilis before and after treatment. An absolute and relative T lymphopenia was found in all patients. In primary syphilis the concentration of helper cells--T cells with Fc receptors for IgM (T mu)--was low whereas in secondary syphilis the suppressor cell concentration--T cells with Fc receptors for IgG (T gamma)--was reduced. Using lymphocytes from healthy subjects this could be imitated in vitro by the addition of serum from patients with secondary syphilis. In many autoimmune diseases a low concentration of T gamma may be a primary factor in the production of autoantibodies. The occurrence of similar changes in patients with secondary syphilis, however, indicates that such fluctuations in the T-cell subpopulations may take place during a strong immune response.
PMCID: PMC1045993  PMID: 6459815
18.  VDRL titres in early syphilis before and after treatment. 
Genitourinary Medicine  1992;68(2):120-122.
OBJECTIVE--To observe the pretreatment VDRL titres in different stages of early syphilis and evaluate the changes in VDRL titre following treatment using different treatment schedules. DESIGN--Retrospective study was carried out by analysing the records of cases of early syphilis treated between 1976 to 1981. SETTING--Armed Forces personnel treated at different service hospitals in India. SUBJECTS--Of 3183 cases of early syphilis treated with different regimens during this period, 1532 were fully followed-up for a period of 30 months. Records of these 1532 cases were analysed. MAIN OUTCOME MEASURES--Assessment of VDRL titres before treatment and during post treatment surveillance period of 30 months. Attainment of non-reactivity of VDRL test in various stages of early syphilis using different treatment schedules was evaluated. RESULTS--Relatively higher titres were observed in secondary syphilis. Following treatment it was observed that VDRL test was still reactive at the end of 6 months in 16.47% of primary, 27.56% of secondary and 18.95% of early latent cases; at the end of 12 months in 11.38% of primary, 17.25% of secondary and 15.79% of early latent cases while at 30 months reactivity was still observed in 6.60% of primary, 8.39% of secondary and 11.58% of early latent cases. CSF was examined in 1173 cases at 6 months, of which one case revealed VDRL reactivity while two cases showed reactivity amongst 1188 CSF examined at 30 months. There has been no significant difference with broad spectrum antibiotics and 2.4 MU benzathine penicillin. Results were better with 4.8 MU benzathine penicillin and procaine penicillin. CONCLUSION--VDRL test appears to be a reliable test for the follow-up of treated patients in early syphilis. Early treatment prevents development of seropositivity in seronegative syphilis while majority of seropositive cases attain seronegativity by 6 months. Higher doses of benzathine penicillin and procaine penicillin accelerate the speed of seroconversion.
PMCID: PMC1194824  PMID: 1582655
19.  Current status of acquired syphilis: A hospital-based 5-year study 
Prevalence of sexually transmitted infection shows regional variations. Though a rising trend of prevalence of viral STI s has been observed, syphilis still continues to remain a commonly diagnosed STI.
To study the current status of acquired syphilis in a tertiary care hospital.
Materials and Methods:
Retrospective analysis of all the cases of acquired syphilis registered in our hospital from 2005 to 2009 was done. Complete epidemiological, clinical, and investigational data were recorded and assessed.
Total of 570 cases attended the STI clinic from year 2005 to 2009. 42 (7.36%) cases were diagnosed as syphilis. There were 32 (74%) males and 11 (26%) were females. 25 (60%) were married. Only two patients were less than 15 years of age. Primary syphilis was diagnosed in 21 (50%), secondary in 10 (24%), and latent in 11 (26%) cases. Two (9.5%) of primary syphilis showed multiple chancre. Concomitant primary chancre and lesions of secondary syphilis were seen in 2 (20%) patients. Secondary syphilis presented as condyloma lata (50%), maculo-papular rash (40%), and lues maligna in one patient who was HIV positive. Mixed infection was diagnosed in eight patients of which herpes genitalis was the commonest. Two patients were serologically positive for HIV.
Incidence of syphilis had shown a constant trend over last 5 years. In lieu of change in trends of sexual practices, condyloma was the commonest presentation of secondary syphilis. Pustular syphilis was observed in association with HIV and could be a marker of the immune-deficient state.
PMCID: PMC3326846  PMID: 22529451
Acquired; syphilis; sexually transmitted infection
20.  Changes of serum IgG antibody reactivity to protein antigens of Treponema pallidum in syphilis patients after treatment. 
The changes of serum IgG antibody reactivity to protein antigens of Treponema pallidum after treatment of syphilis were observed using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blot. Until 9 to 12 months after treatment, it was seen that there was a loss of several antibodies and some diminution in their reactivity in primary, secondary and early latent syphilis, but no changes occurred in late latent and reinfected syphilis. In primary syphilis, there was a significant loss of two IgG antibodies to the treponemal antigens of molecular weights 68,500 and 47,000 at 11 months after treatment. According to our previous study, the treponemal antigen of molecular weight 68,500 was T. pallidum specific and appeared only in primary syphilis, and that of molecular weight 47,000 was one of the major antigens of T. pallidum. The reaction between serum IgG antibodies of 14 patients who had been treated for secondary, early latent and late latent syphilis 2 to 14 years ago and major antigens of T. pallidum was observed and any loss or decrease in reactivity was not discovered. From the results obtained, it was concluded that the observation of serum IgG antibody reactivity to protein antigens of T. pallidum is not helpful in evaluating the efficacy of treatment in secondary, early latent, late latent and reinfected syphilis. However, serum IgG antibodies to treponemal antigens of molecular weights 68,500 and 47,000 could possibly be useful in the assessment of the efficacy of treatment in primary syphilis.
PMCID: PMC3053684  PMID: 2688687
21.  The Global Epidemiology of Syphilis in the Past Century – A Systematic Review Based on Antenatal Syphilis Prevalence 
PLoS Neglected Tropical Diseases  2016;10(5):e0004711.
How can we explain the uneven decline of syphilis around the world following the introduction of penicillin? In this paper we use antenatal syphilis prevalence (ASP) to investigate how syphilis prevalence varied worldwide in the past century, and what risk factors correlate with this variance.
1) A systematic review using PubMed and Google Scholar was conducted to identify countries with published data relating to ASP estimates from before 1952 until the present. Eleven countries were identified (Canada, Denmark, Finland, India, Japan, Norway, Singapore, South Africa, United States of America (USA), United Kingdom (UK) and Zimbabwe). The ASP epidemic curve for each population was depicted graphically. In South Africa and the USA, results are reported separately for the black and white populations. 2) National antenatal syphilis prevalence estimates for 1990 to 1999 and 2008 were taken from an Institute for Health Metrics and Evaluation database on the prevalence of syphilis in low risk populations compiled for the Global Burden of Diseases study and from a recent review paper respectively. National ASPs were depicted graphically and regional median ASPs were calculated for both time periods. 3) Linear regression was used to test for an association between ASP in 1990–1999 and 2008 and four risk factors (efficacy of syphilis screening/treatment, health expenditure, GDP per capita and circumcision prevalence). WHO world regions were included as potential explanatory variables.
In most populations, ASP dropped to under 1% before 1960. In Zimbabwe and black South Africans, ASP was high in the pre-penicillin period, dropped in the post-penicillin period, but then plateaued at around 6% until the end of the 20th century when ASP dropped to just above 1%. In black Americans, ASP declined in the post penicillin period, but plateaued at 3–5% thereafter. ASP was statistically significantly higher in sub-Saharan Africa in 1990–1999 and 2008 than in the other world regions (P < 0.001). On multivariate analysis in both time periods, ASP was only associated with residence in sub-Saharan Africa.
Further research is necessary to elucidate the reasons for the higher prevalence of syphilis in sub-Saharan Africa.
Author Summary
Syphilis rates have varied tremendously between different populations around the world. We conducted a systematic review of syphilis prevalence in pregnant women in 13 populations with available data for the last 100 years. Our findings were that in most populations syphilis prevalence dropped to under 1% before 1960. In the 2 populations from sub Saharan Africa, the syphilis prevalence remained around 6% until 50 years after the introduction of penicillin. Other systematic reviews were utilized to provide syphilis prevalence estimates for all countries with available data for the periods 1990–1999 and 2008. We assessed if there was a correlation between national syphilis prevalence in these periods and five explanatory factors. Only residence in sub-Saharan Africa was associated with syphilis prevalence in both time periods. These findings, considered in conjunction with other types of evidence we review, such as the strong correlations at population level between syphilis prevalence and those of Herpes Simplex Virus-2 prevalence and HIV prevalence, suggest that common risk factors may underpin the spread of all three of these sexually transmitted diseases. Establishing what these factors are is of great importance to improve the health of highly affected populations such as those in sub-Saharan Africa.
PMCID: PMC4864207  PMID: 27167068
22.  Syphilis: an atypical case of sepsis and multiple anogenital lesions in secondary syphilis 
The incidence of syphilis has historically been cyclical in nature, often in relation to the rise and fall of public health initiatives directed toward eradication along with social attitudes toward sexual practices. The incidence of syphilis has increased by 15% in the last 6 years in the United States, with similar increases worldwide. Herein, we present an atypical case of syphilis presenting with severe septic shock and multiple anogenital lesions in an immunocompetent host. A 22-year-old male with no significant past medical history presented with fevers, chills, sore throat, diaphoresis, and diarrhea. He was febrile, tachycardic, hypotensive, and unresponsive to fluid resuscitation requiring short-term vasopressor support. Physical exam revealed diffuse lymphadenopathy; lower extremity macular rash involving the soles of the feet; papular non-pustular lesions on the scrotum; and a 0.5 cm non-tender irregular, healing lesion on the shaft of the penis. Laboratory analysis was significant for leukocytosis and elevated creatinine. Serum screening rapid plasma reagin was positive, and further testing revealed a titer of 1:32, with confirmation via fluorescent treponemal antibody absorption test. The patient was diagnosed with secondary syphilis, which was determined to be the underlying etiology of the sepsis as all other serological evaluations were negative. He was treated with penicillin G benzathine 2.4 million units intramuscular and supportive management, with improvement of symptoms. The patient engaged in high-risk sexual behaviors, including prior unprotected sexual contact with males. New research indicates that up to one-third of patients may present with atypical cutaneous manifestations, as demonstrated by this patient. It is important for physicians to familiarize themselves with the varied clinical presentations of syphilis, which include multiple anogenital lesions and tender primary lesions in primary or secondary syphilis.
PMCID: PMC5089154  PMID: 27802854
acquired syphilis; treponema; sepsis; immunocompetent; men who have sex with men; resurgence;  sexually transmitted infections
23.  Syphilis in the economic center of South China: results from a real-time, web-based surveillance program 
BMC Infectious Diseases  2015;15:318.
Guangzhou is the economic center of South China, which is currently suffering an insidious re-emergence of syphilis. Syphilis epidemic in this area is a matter of serious concern, because of the special economic position of Guangzhou and its large migrant population. Therefore, a comprehensive analysis of surveillance data is needed to provide further information for developing targeted control programs.
Case-based surveillance data obtained from a real-time, web-based system were analyzed. A hierarchical clustering method was applied to classify the 12 districts of Guangzhou into several epidemiological regions. The district-level annual incidence and clustering results were displayed on the same map to show the spatial patterns of syphilis in Guangzhou.
A total of 60,178 syphilis cases were reported during the period from 2005 to 2013, among which primary/secondary syphilis accounted for 15,864 cases (26.36 %), latent syphilis for 41,078 cases (68.26 %) and congenital syphilis for 2,090 cases (3.47 %). Moreover, primary/secondary syphilis burden slightly decreased from 17.5-18.0 cases per 100,000 people in the first years to 10.6 cases per 100,000 in 2013, with latent syphilis largely increasing from 18.5 cases per 100,000 to 43.4 cases per 100,000. Districts of Guangzhou could be classified into 3 epidemiological regions according to the syphilis burden over the last 3 years of the study period.
The burden of primary/secondary syphilis appears to be decreasing in recent years, whereas that of latent syphilis is increasing. Given the epidemiological features and the annual changes found in this study, it is suggested that future control programs should be more population-specific and spatially targeted.
Electronic supplementary material
The online version of this article (doi:10.1186/s12879-015-1072-z) contains supplementary material, which is available to authorized users.
PMCID: PMC4545813  PMID: 26253119
24.  Syphilis on the rise: A prolonged syphilis outbreak among HIV-infected patients in Northern Greece 
Germs  2016;6(3):83-90.
Sexually transmitted diseases (STDs) are a major public health issue in Europe. Numerous outbreaks of syphilis have been described recently and an increased prevalence of high-risk sexual practices has raised concern about the transmission of HIV and other STDs. Similarly, an increase in sexually transmitted infections has been recorded in Northern Greece.
This report describes a recent outbreak of syphilis in people living with HIV. The demographic, clinical, and serologic data of HIV patients diagnosed with syphilis were recorded and analyzed. Data on syphilis incidence from the general population was also compared to HIV patients’ data.
Fifty-eight HIV-patients of the Infectious Diseases Unit of a tertiary hospital (5.2%) were diagnosed with syphilis during a three-year period (2008-2010). Highly active antiretroviral therapy (HAART) and coexistence of other STDs were independent predictors of syphilis (OR: 2.4, 95CI%: 1.26, 4.63, p=0.008; OR: 9.4, 95%CI: 4.49, 19.64, p<0.001, respectively). Origin from a country other than Greece (p=0.005), and homosexual contact (p=0.003), were separate risk factors for syphilis in the general population in the same area.
Diagnosis of a sexually transmitted disease in an HIV patient is a crucial clinical event that should trigger the clinician’s suspicion for high-risk sexual behavior. Sexual health assessments should be a routine process for HIV patients.
PMCID: PMC5018389  PMID: 27622160
Syphilis; outbreak; HIV; sexually transmitted diseases; coinfection
25.  Musculoskeletal involvement of syphilis – a forgotten lesson 
BMJ Case Reports  2012;2012:bcr1120115142.
Syphilis is a sexually transmitted disease with a myriad of presentation and called ‘the great impostor’ for the variety of the symptoms. As a venereal disease it is transmissible mainly by sexual contact with infectious lesions but can spread by blood contamination. Without treatment it progresses through early and late syphilis. Since the introduction of penicillin its prevalence has strongly dropped but was never eradicated entirely. As the frequency and the progression are largely controlled there are several symptoms which are not common and can be a difficult differential diagnostic problem nowadays. The authors present a case where decades passed between the primary event and the actual hospitalisation with fever of unknown origin and coexistent swollen joint deformities. The patient was not treated entirely from his primary event and later, psoriasis was settled as a diagnosis, which was the cause of neglecting the secondary phase’s skin lesions.
PMCID: PMC3417008  PMID: 22787187

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