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1.  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
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.  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
4.  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
5.  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
For convenience the results are summarized in tabular form. Table I shows a comparison of the primary reaction in the groups of female and male rabbits inoculated intradermally. In Table II the incidence of metastatic lesions is shown in the various groups of animals. In Table III are shown the character and date of appearance of the generalized lesions (exclusive of orchitis) in the various groups of animals. The results presented in Tables I, II, and III, together with a study of the individual protocols, permit the following general statements to be made relative to the effect of the factors studied upon the course of experimental syphilis in the rabbit. Sex.—In the group of females inoculated intradermally the lesions at the site of inoculation were in general less marked than in the group of males similarly inoculated. Moreover, they attained their maximum size earlier and began to recede earlier than was the case in the males. In none of the females was there clinical evidence of the production of generalized lesions, while in the corresponding group of males metastatic lesions of skin or bones detectible by clinical examination occurred in one instance, or 14.3 per cent. In both groups there was wide variation in the character of the initial reaction in individual rabbits and in the time required for it to reach its maximum size. See PDF for Structure Age.—In the five young males inoculated intratesticularly the disease was not greatly different from that observed in the older males similarly inoculated. The initial reactions were slightly slower in making their appearance, but the magnitude of the reaction, as judged by enlargement of the testicles, was somewhat greater. The percentage incidence of metastatic orchitis was almost the same in the two groups. The younger animals showed a slightly greater incidence of generalized lesions involving structures other than the testicles, although the difference was insignificant, but the lesions were smaller, fewer in number, and confined entirely to the skin, and there was no instance of severe generalized lesions. Moreover, the occurrence of metastatic lesions (skin) in the younger animals was definitely delayed. Method of Injection.—In the animals inoculated by the intratesticular route the development of the primary reaction and the incidence of generalized lesions involving skin and bone were much greater than in See PDF for Structure the animals inoculated intradermally. Thus, of the latter group only one, or 14.3 per cent, showed a secondary metastatic lesion (skin), while in the group inoculated by the testicular route the incidence of metastatic skin and bone lesions was as high as 71.4 per cent. The difference in the character of the disease exhibited by these two groups of animals inoculated in a different manner is quite striking. Intratesticular inoculation produced a much more violent local reaction and a much greater incidence of generalized lesions than did intradermal inoculation. Effect of Castration.—In the group of animals with unilateral orchitis in which the infection was allowed to run its course without any attempt at suppression by removal of the initial focus, metastatic lesions appeared more promptly and in slightly greater incidence than See PDF for Structure in the group of animals in which the initial local reaction was suppressed by removal of the focus itself through castration. The percentage differences are not very great, but they are constantly in favor of the first group, as is the time interval of appearance. This experiment is not in strict accord with similar experiments observed by Brown and Pearce (3) in the past, and while the reasons for this difference are not clear the fact may be noted that the incidence of generalized lesions in uncastrated animals is somewhat higher than that reported by these authors, also that there was a high percentage of recurrence of primary lesions.
PMCID: PMC2128489  PMID: 19868814
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.  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
9.  Rapid Syphilis Testing Uptake for Female Sex Workers at Sex Venues in Southern China: Implications for Expanding Syphilis Screening 
PLoS ONE  2012;7(12):e52579.
Accessibility of syphilis testing services is critical in syphilis control programs for female sex workers (FSWs), but few FSWs attend public STI clinics or other testing sites. Introduction of free rapid syphilis testing (RST) into outreach programs for FSWs will help improve test uptake.
Commercial sex venues were identified in two cities in South China. In cooperation with health advocacy organizations, health outreach teams from local public health or medical facilities approached all types of sex venues in study areas to offer free RST. Acceptability and uptake of RST among FSWs were evaluated.
A total of 2812 FSWs were offered RST and 2670 (95.0%) accepted syphilis testing. 182 (6.8%) FSWs had a positive RST result among whom 136 (74.7%) were willing to attend an STD clinic for confirmatory testing and treatment. More than half (89, 66.4%) of those with syphilis were not willing to notify their sex partners. Multivariate logistic analysis showed that syphilis test uptake was associated with residing in Jiangmen (AOR, 1.78; 95% CI, 1.15–2.77), older age (AOR, 2.11, 95% CI, 1.17–3.79 for age of 31 years or above), and not working at a service venue (AOR, 1.60; 95% CI, 1.10–2.34).
RST at sex venues is well accepted by FSWs when it is integrated into ongoing outreach services. Such programs provide excellent opportunities for expanding syphilis screening efforts among specific subgroups of FSW who are difficult to reach through clinic-based programs.
PMCID: PMC3531440  PMID: 23300709
10.  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
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.  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
13.  Evaluation of a New Competitive Immunoassay (BioElisa Syphilis) for Screening for Treponema pallidum Antibodies at Various Stages of Syphilis 
Journal of Clinical Microbiology  1998;36(2):358-361.
The BioElisa Syphilis, a new competitive enzyme immunoassay (EIA) for Treponema pallidum whole antigen that uses specific human immunoglobulin G (IgG) antibodies as the competitor, was evaluated for potential use in screening for syphilis at various stages. The results obtained by this competitive EIA were compared with those obtained by the fluorescent treponemal antibody absorption (FTA-abs) test and the T. pallidum hemagglutination assay (TPHA). Serum samples from 434 patients with positive TPHA and FTA-abs test results, including patients with primary, latent, secondary, and tertiary syphilis and neurosyphilis, were investigated. Two samples tested negative by competitive EIA but were weakly reactive by the TPHA and the FTA-abs test. Sixteen serum samples from patients with clinically documented active syphilis, including several patients infected with human immunodeficiency virus, tested positive by the competitive EIA. There was a direct inverse correlation between EIA indices and titers in the TPHA and the FTA-abs test for all samples that tested positive. Specificity was assessed by testing 358 serum samples which tested negative for syphilis by TPHA and the FTA-abs test, including 100 serum samples from patients with documented infectious or autoimmune diseases. Only two serum samples gave a weakly positive EIA result. Thus, competitive EIA had a sensitivity of 99.5% and a specificity of 99.4% relative to the results of the FTA-abs test and TPHA. Our evaluation shows that BioElisa Syphilis is a sensitive, specific, and simple assay for screening for syphilis.
PMCID: PMC104542  PMID: 9466741
14.  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
15.  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
16.  Comparison of Serological Response to Doxycycline versus Benzathine Penicillin G in the Treatment of Early Syphilis in HIV-Infected Patients: A Multi-Center Observational Study 
PLoS ONE  2014;9(10):e109813.
While doxycycline is recommended as an alternative treatment of syphilis in patients with penicillin allergy or intolerance, clinical studies to compare serological response to doxycycline versus benzathine penicillin in treatment of early syphilis among HIV-infected patients remain sparse.
We retrospectively reviewed the medical records of HIV-infected patients with early syphilis who received doxycycline 100 mg twice daily for 14 days (doxycycline group) and those who received 1 dose of benzathine penicillin (2.4 million units) (penicillin group) between 2007 and 2013. Serological responses defined as a decline of rapid plasma reagin titer by 4-fold or greater at 6 and 12 months of treatment were compared between the two groups.
During the study period, 123 and 271 patients in the doxycycline and penicillin group, respectively, completed 6 months or longer follow-up. Ninety-one and 271 patients in the doxycycline and penicillin group, respectively, completed 12 months or longer follow-up. Clinical characteristics were similar between the two groups, except that, compared with penicillin group, doxycycline group had a lower proportion of patients with secondary syphilis (65.4% versus 41.5%, P<0.0001) and a higher proportion of patients with early latent syphilis (25.3% versus 49.6%, P<0.0001). No statistically significant differences were found in the serological response rates to doxycycline versus benzathine penicillin at 6 months (63.4% versus 72.3%, P = 0.075) and 12 months of treatment (65.9% versus 68.3%, P = 0.681). In multivariate analysis, secondary syphilis, but not treatment regimen, was consistently associated with serological response at 6 and 12 months of follow-up.
The serological response rates to a 14-day course of doxycycline and a single dose of benzathine penicillin were similar in HIV-infected patients with early syphilis at 6 and 12 months of follow-up. Patients with secondary syphilis were more likely to achieve serological response than those with other stages.
PMCID: PMC4195693  PMID: 25310367
17.  Social determinants of syphilis in South China: the effect of sibling position on syphilis and sexual risk behaviours 
BMJ Open  2013;3(5):e002834.
This study evaluated the relationship between sibling position and sexual risk based on behavioural and syphilis infection data from sexually transmitted infection (STI) patients in South China.
A cross-sectional study examining sexual behaviours and syphilis infection.
4 STI clinics in the Pearl River Delta of South China.
1792 Chinese men and women attending STI clinics.
Primary outcome measures
STI history, syphilis infection defined as positive non-treponemal and treponemal tests.
Among all clinic patients, 824 (46.3%) were first-born, 354 (19.9%) were middle-born and 602 (33.8%) were final-born. Middle-born individuals had a higher percentage of reported STI history (44.7% compared to 34.7%, p<0.001) and syphilis infection (9.7% compared to 4.9%, p=0.01) among men (n=1163) compared to other sibling positions in bivariate analyses, but not in the final multivariate model. The relationship between sibling position and syphilis was independent of income and education level. There was no trend observed between middle-born position and female sexual risk behaviours (n=626). Higher education was significantly associated with syphilis among women and men in respective multivariate models.
This study suggests that middle-born men in China may have an increased sexual risk compared to other sibling positions. As Chinese family and social structures change, a more thorough understanding of how demographic factors influence sexual risk behaviours is needed.
PMCID: PMC3657676  PMID: 23793689
Public Health
18.  Factors Associated with Serological Cure and the Serofast State of HIV-Negative Patients with Primary, Secondary, Latent, and Tertiary Syphilis 
PLoS ONE  2013;8(7):e70102.
Some syphilis patients remain in a serologically active state after the recommended therapy. We currently know too little about the characteristics of this serological response.
We conducted a cohort study using the clinical database from Zhongshan Hospital, Medical College of Xiamen. In total, 1,327 HIV-negative patients with primary, secondary, latent, and tertiary syphilis were enrolled. Bivariate and multivariate analyses were utilised to identify factors associated with a serological cure and serofast state in syphilis patients one year after therapy. Chi-square tests were used to determine the differences in the serological cure rate across different therapy time points.
One year after the recommended therapy, 870 patients achieved a serological cure, and 457 patients (34.4%) remained in the serofast state. The serological cure rate increased only within the first 6 months. The bivariate analysis indicated that male or younger patients had a higher likelihood of a serological cure than female or older patients. Having a baseline titre ≤1∶2 or ≥1∶64 was associated with an increased likelihood of a serological cure. The serological cure rate decreased for the different disease stages in the order of primary, secondary, latent, and tertiary syphilis. A distinction should be drawn between early and late syphilis. The multivariate analysis indicated that a serological cure was significantly associated with the disease phase, gender, age, and baseline rapid plasma reagin (RPR) titre.
The serofast state is common in clinical work. After one year of the recommended therapy, quite a few syphilis patients remained RPR positive. The primary endpoint of the study indicated that disease phase, gender, age and baseline RPR titre were crucial factors associated with a serological cure.
PMCID: PMC3720935  PMID: 23894598
19.  One Dose versus Three Weekly Doses of Benzathine Penicillin G for Patients Co-Infected with HIV and Early Syphilis: A Multicenter, Prospective Observational Study 
PLoS ONE  2014;9(10):e109667.
One dose of benzathine penicillin G (BPG) has been recommended for HIV-infected patients with early syphilis (primary, secondary, and early latent syphilis) in the sexually transmitted diseases treatment guidelines, but clinical data to support such a recommendation are limited.
We prospectively observed the serological response to 1 or 3 weekly doses of BPG in HIV-infected adults who sought treatment of early syphilis at 8 hospitals around Taiwan. Rapid plasma reagin (RPR) titers were followed every 3–6 months after treatment. The serological response was defined as a 4-fold or greater decline in RPR titers at 12 months of treatment. The missing values were treated by following the last-observed-carried-forward principle. We hypothesized that 1 dose was non-inferior to 3 weekly doses of BPG with the non-inferiority margin for the difference of serological response set to 10%.
Between 2007 and 2012, 573 patients completed at least 12 months of follow-up: 295 (51.5%) receiving 1 dose of BPG (1-dose group) and 278 (48.5%) 3 doses (3-dose group). Overall, 198 patients (67.1%; 95% confidence interval [CI], 61.4–72.5%) in the 1-dose group achieved serological response at 12 months, as did 208 patients (74.8%; 95% CI, 69.3–79.8%) in the 3-dose group (one-sided 95% CI of the difference, 15.1%). In the multivariate analysis, secondary syphilis (adjusted odds ratio [AOR], 1.90; 95% CI 1.17–3.09), RPR titer ≥32 (AOR, 1.93; 95% CI, 1.38–2.69), and 3 doses of BPG (AOR, 1.68; 95% CI, 1.20–2.36) were independently associated with a serological response. The time to the first episode of treatment failure was 1184 (standard deviation [SD], 70.5) and 1436 (SD, 80.0) days for 1- and 3-dose group, respectively.
Single-dose BPG resulted in a higher serological failure rate and shorter time to treatment failure than 3 weekly doses of BPG in the treatment of early syphilis in HIV-infected patients.
PMCID: PMC4186862  PMID: 25286091
20.  Reactivity of lymphocytes from patients with syphilis towards T. pallidum antigen in the leucocyte migration and lymphocyte transformation tests. 
The reactivity of lymphocytes to Treponema pallidum antigen was studied before and after treatment in nine patients with early syphilis using a leucocyte migration test and a lymphocyte transformation test. Lymphocyte reactivity was also investigated in six patients treated for syphilis within the last 4 years, and in five untreated patients with a positive result to the T. pallidum immobilization test, but negative results to other serum tests for syphilis antibodies and without any known exposure to risk of infection by syphilis. Ten seronegative patients with different dermatological disorders served as a control group. A significant increase in lymphocyte reactivity to T. pallidum antigen was recorded in both tests in vitro after treatment. There was no difference in lymphocyte reactivity to T. pallidum antigen between the other patients studied and the control group. In early syphilis the spontaneous migration was found to be inhibited before treatment. Tuberculin skin tests were also performed and found to be suppressed in patients with primary and secondary syphilis. No difference in phytohaemagglutinin response was found between any of the groups. Plasma from patients with primary and secondary syphilis was found to change the in vitro reactivity of normal lymphocytes when stimulated with different mitogens.
PMCID: PMC1045270  PMID: 786437
21.  Treponemal antibody-absorbent enzyme immunoassay for syphilis. 
Journal of Clinical Microbiology  1986;23(5):876-880.
An enzyme immunoassay for the diagnosis of syphilis (ELISA-SY) was developed with solid-phase extracts of Treponema pallidum, specimen diluent containing Reiter treponeme absorbent, and three 30-min incubations. The ELISA-SY results were determined in comparison with a standardized positive control and reported as a percentage of strong positive control. In tests with 1,005 serum samples from a venereal disease clinic and other sources, 98.2% agreement was found with fluorescent treponemal antibody-absorption (FTA-ABS) results, and 98.3% agreement was found with T. pallidum passive hemagglutination (PHA) findings. Only 1 of 29 sera originally considered to be biologically false-positive by ELISA-SY; the latter specimen was also positive by PHA and FTA-ABS tests performed in our laboratories. Serum samples from clinically diagnosed syphilitics (16 primary-stage isolates, 7 secondary-stage isolates, and 3-latent-stage isolates) were all positive by ELISA-SY, FTA-ABS, and PHA. Serum samples from 51 newborns suspected of having syphilis on the basis of positive cardiolipin flocculation tests showed 98% agreement of ELISA-SY results with FTA-ABS and PHA findings. Sera from all 61 patients with a variety of autoimmune and other diseases known to be associated with biologically false-positive reactions for syphilis were negative by this ELISA-SY. The specificity of the ELISA procedure for T. pallidum antibody was also confirmed immunologically by blocking experiments.
PMCID: PMC268741  PMID: 3519659
22.  Impact of on-site testing for maternal syphilis on treatment delays, treatment rates, and perinatal mortality in rural South Africa: a randomised controlled trial 
Sexually Transmitted Infections  2003;79(3):208-213.
Background: Syphilis remains a significant cause of preventable perinatal death in developing countries, with many women remaining untested and thus untreated. Syphilis testing in the clinic (on-site testing) may be a useful strategy to overcome this. We studied the impact of on-site syphilis testing on treatment delays and rates, and perinatal mortality.
Methods: We conducted a cluster randomised controlled trial among seven pairs of primary healthcare clinics in rural South Africa, comparing on-site testing complemented by laboratory confirmation versus laboratory testing alone. Intervention clinics used the on-site test conducted by primary care nurses, with results and treatment available within an hour. Control clinics sent blood samples to the provincial laboratory, with results returned 2 weeks later.
Results: Of 7134 women seeking antenatal care with available test results, 793 (11.1%) tested positive for syphilis. Women at intervention clinics completed treatment 16 days sooner on average (95% confidence interval: 11 to 21), though there was no significant difference in the proportion receiving adequate treatment at intervention (64%) and control (69%) clinics. There was also no significant difference in the proportion experiencing perinatal loss (3.3% v 5.1%; adjusted risk difference: -0.9%; 95% CI -4.4 to 2.7).
Conclusions: Despite reducing treatment delays, the addition of on-site syphilis testing to existing laboratory testing services did not lead to higher treatment rates or reduce perinatal mortality. However on-site testing for syphilis may remain an important option for improving antenatal care in settings where laboratory facilities are not available.
PMCID: PMC1744662  PMID: 12794203
23.  New Syphilis Cases and Concurrent STI Screening in a Southeastern U.S. HIV Clinic: A Call to Action 
AIDS Patient Care and STDs  2010;24(1):23-29.
Syphilis outbreaks in the United States have been reported since 2000 with highest rates in the South and many cases among HIV-infected individuals. We evaluated incident syphilis cases and concurrent gonorrhea and chlamydia screening at a southern HIV clinic. A retrospective cohort study included HIV-infected patients with at least one reactive plasma reagin (test for serum reagin antibodies to cardiolipin-cholesterol-lecithin antigen) and primary care visit from July 2004 to June 2007. Primary, secondary, and early latent syphilis cases were identified as incident syphilis and evaluation for gonorrhea and chlamydia within 1 month were described. Logistic regression was performed to determine factors associated with incident syphilis. Among 1544 patients, 40 incident syphilis cases were identified (5 primary, 29 secondary, and 6 early latent). The majority of patients were not virologically suppressed and only 25% had gonorrhea and chlamydia testing. In adjusted analyses, younger age (0.57 per 10 years, 95% confidence interval [CI] 0.41–0.80) and minority race (2.26, 95% CI 1.12–4.59) were associated with incident syphilis. Among 40 incident syphilis cases, only 1 in 4 were further tested for gonorrhea and chlamydia. These low rates are concerning as concurrent sexually transmitted infections (STIs) increase risk for HIV transmission. HIV care provider education with emphasis on STI testing in the setting of incident syphilis is key in prevention.
PMCID: PMC2859761  PMID: 20095902
24.  Maternal depression and infant growth and development in British Pakistani women: a cohort study 
BMJ Open  2012;2(2):e000523.
Perinatal depression has been found to be a strong and independent risk factor for poor child growth and development in low-income South Asian populations. The authors aimed to study if there was a similar association in first and second-generation British women of Pakistani origin.
A prospective cohort study.
The study was conducted in the North-West of England, in areas with high density of Pakistani-origin population. The subjects were recruited from Central Manchester Hospital in the City of Manchester and East Lancashire Hospital in Lancashire.
704 physically healthy women were assessed in two phases (screening and detailed assessment of high scorers and a proportion of low scorers) during the third trimester of pregnancy to obtain at birth a cohort of 63 infants of depressed mothers and 173 infants of psychologically well mothers.
Primary and secondary outcome measures
All infants were weighed and measured at birth and 6 months, and their development was assessed using the Bayley Scales of Infant Development–Third Edition.
There was no difference in the birth weight or weight and height at 6 months of infants of depressed mothers versus infants of psychologically well mothers. The only significant difference between the two groups was in the infants' adaptive behaviour; infants of depressed mothers scored significantly lower than those of psychologically well mothers (mean difference 4.6, t=2.81, df 195, p=0.006). The associations remained significant after adjustment for socio-demographic factors by multivariate analyses.
Prenatal depression is not associated with impaired growth in this sample of British Pakistani women. There is, however, an association of prenatal depression with parent-reported problems in the infants' adaptive behaviour. Further research is needed to understand various pathways through which maternal depression affects infant outcomes in low- and high-income settings.
Article summary
Article focus
In South Asian countries, maternal depression has been identified as a strong risk factor for undernutrition and stunted growth in infants.
Maternal depression has also been associated with insecure attachment styles and deficiencies in cognitive development.
In a longitudinal cohort design, this article examines the potential association between prenatal maternal depression and infant development, in a sample of British women of Pakistani origin.
Key messages
The present sample of British Pakistani women show lower rates of depression as compared with the women living in Pakistan.
Prenatal depression was not found to be associated with infant undernutrition or stunted growth. On the other hand, there was a significant association between prenatal depression and the infant's adaptive behaviour, as measured by Bayley Scales of Infant Development–Third Edition.
Strengths and limitations of this study
The longitudinal prospective cohort design employed in this study was well suited to address the research question. Engaging the prospective sample through culturally appropriate channels and informants helped to achieve high follow-up rates.
Due to resource and time limitations, the required sample size for the group of depressed women could not be achieved.
PMCID: PMC3312074  PMID: 22436136
25.  Immunoglobulin G subclasses of fluorescent anti-Treponema pallidum antibodies: evidence for sequential development of specific anti-T. pallidum immunoglobulin G responses in patients with early syphilis. 
Journal of Clinical Microbiology  1986;24(3):418-423.
The development of immunoglobulin G (IgG) subclass-specific anti-Treponema pallidum antibodies during the course of syphilis in humans was studied with sera from 50 untreated male patients. The patients were divided into five diagnosis groups. In the fluorescent treponemal antibody test, which delineates the presence of cross-reacting antibodies, as well as specific antitreponema antibodies, IgG1, IgG2, and IgG3 subclass antibodies were already present during the seronegative primary stage. Specific antibodies, which were detected by the fluorescent treponemal antibody absorption test, were first present during the serotype-variable primary stage. These antibodies were almost exclusively of the IgG1 and IgG3 subclasses. In later stages, antibodies of other subclasses were detectable. Titration of IgG1 antitreponema antibodies in three electrophoretically different IgG fractions revealed an asymmetric distribution in these fractions during primary syphilis. The antibodies were largely confined to the most basic fraction during primary syphilis. A sudden change in the distribution was noted between the end of the primary stage and the secondary stage; an even distribution of IgG1 antitreponema antibodies existed in the late latent stage. These findings confirm and extend previous results from our laboratory. The development of antibodies detected by both tests is discussed in terms of a sequential stimulation of the immune system due to the presence of an extracellular layer covering the treponemas or, alternatively, in terms of a suppression of the immune response during early syphilis.
PMCID: PMC268926  PMID: 3531229

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