Early Syphilis Patients Research Articles

Clinical and genomic diversity of Treponema pallidum subspecies pallidum to inform vaccine research: an international, molecular epidemiology study

The increase in syphilis rates worldwide necessitates development of a vaccine with global efficacy. Weaimed to explore Treponema pallidum subspecies pallidum (TPA) molecular epidemiology essential for vaccine research by analysing clinical data and specimens from early syphilis patients using whole-genome sequencing (WGS) and publicly available WGS data. In this multicentre, cross-sectional, molecular epidemiology study, we enrolled patients with primary, secondary, or early latent syphilis from clinics in China, Colombia, Malawi, and the USA between Nov 28, 2019, and May 27, 2022. Participants aged 18years or older with laboratory confirmation of syphilis by direct detection methods or serological testing, or both, were included. Patients were excluded from enrolment if they were unwilling or unable to give informed consent, did not understand the study purpose or nature of their participation, or received antibiotics active against syphilis in the past 30days. TPA detection and WGS were conducted on lesion swabs, skin biopsies, skin scrapings, whole blood, or rabbit-passaged isolates. We compared our WGS data to publicly available genomes and analysed TPA populations to identify mutations associated with lineage and geography. We screened 2802patients and enrolled 233participants, of whom 77 (33%) had primary syphilis, 154 (66%) had secondary syphilis, and two (1%) had early latent syphilis. The median age of participants was 28years (IQR22-35); 154 (66%) participants were cisgender men, 77 (33%) were cisgender women, and two (1%) were transgender women. Of the cisgender men, 66 (43%) identified as gay, bisexual, or other sexuality. Among all participants, 56(24%) had HIV co-infection. WGS data from 113participants showed a predominance of SS14-lineage strains with geographical clustering. Phylogenomic analyses confirmed that Nichols-lineage strains were more genetically diverse than SS14-lineage strains and clustered into more distinct subclades. Differences in single nucleotide variants (SNVs) were evident by TPA lineage and geography. Mapping of highly differentiated SNVs to three-dimensional protein models showed population-specific substitutions, some in outer membrane proteins (OMPs) of interest. Our study substantiates the global diversity of TPA strains. Additional analyses to explore TPA OMP variability within strains is vital for vaccine development and understanding syphilis pathogenesis on a population level. US National Institutes of Health National Institute for Allergy and Infectious Disease, the Bill & Melinda Gates Foundation, Connecticut Children's, and the Czech Republic National Institute of Virology and Bacteriology.

The Expression and Clinical Significance of Seroconversion Growth Factor in Early Syphilis Patients

The Expression and Clinical Significance of Seroconversion Growth Factor in Early Syphilis Patients

Predictors of serological cure after penicillin therapy in HIV-negative patients with early syphilis in Shenzhen, China.

BackgroundSyphilis is a common infectious disease worldwide. Serological monitoring is important for syphilis management. We currently know little about the characteristics of this seronegative response. The aim of this study was to explore the factors associated with serological cure after treatment of early syphilis.MethodsA retrospective cohort study was conducted and the data of patients with early syphilis in a clinic in Shenzhen from 2011 to 2019 were retrieved. Univariable and multiple Cox proportional hazard regression models were utilized to identify factors associated with a serological cure state among syphilis patients with early syphilis two years after treatment.ResultsA total of 346 (85.9%) syphilis patients achieved serological cure. The multivariate analysis results revealed that having a baseline TRUST titer >1:8 was associated with an increased probability of serological cure, compared with having a baseline TRUST titer ≤1:8 (HR = 1.43, 95% CI = 1.10–1.85, P<0.01); primary syphilis was positively associated with serological cure, compared with participants with latent early syphilis (HR = 1.72, 95% CI = 1.27–2.33, P<0.001).ConclusionsTwo years after treatment, a higher percentage of early syphilis patients achieved serological cure. The study indicated that the syphilis stage and baseline serum titer were crucial factors associated with serological cure.

Efficacy of minocycline in the treatment of early syphilis.

Syphilis is the third prevalent infectious disease in China, caused by the spirochete bacterium Treponema pallidum. Minocycline is a derivative of tetracycline used as an alternative treatment for syphilis, but there are few studies in this field. In this research, we compared the efficacy of benzathine penicillin and minocycline in the treatment of early syphilis patients and analyzed some of the factors affecting the efficacy of minocycline. A total of 276 eligible patients treated between January 2011 and December 2017 were retrospectively analyzed, and 158 patients received 100mg of minocycline orally, twice daily for 28days, while 118 patients received benzathine penicillin, 2.4million units intramuscular injections, once a week, 1-2 times in all. All patients accepted rapid plasma regain (RPR) serological tests and followed up for 24months to evaluate serological treatment responses. After comparison, the serological cure rate of the minocycline treatment group (85.44%) was similar to the benzathine penicillin treatment group (88.14%). Besides, patients in the minocycline treatment group with higher initial RPR titer (≥1:32) exhibited better treatment effect. In addition, during the 24-month follow-up, the serological cure rate of primary syphilis patients after minocycline treatment was significantly higher than that of secondary and early latent syphilis patients. Therefore, minocycline may be an effective alternative treatment to early syphilis when benzathine penicillin is not available.

Serological Responses to Benzathine Penicillin-G Treatment in Early Syphilis Patients with Different HIV Status.

Serological Responses to Benzathine Penicillin-G Treatment in Early Syphilis Patients with Different HIV Status.

Tinidazole: Another Therapeutic Option for Syphilis?

After the incidental observation of an almost complete resolution of maculopapular eruption in a patient having simultaneously secondary syphilis and trichomonas vaginalis infection, we extended the treatment with tinidazole (500 mg 4 times daily for 7 days) to 10 other early syphilis patients before the start of the conventional penicillin treatment. All patients showed marked improvement of their lesions in a few days. After the introduction of the conventional penicillin regimen, the lesions further improved and VDRL titers declined at least 4-fold within 6 months in all patients. Tinidazole is a 5-nitroimidazole derivative as well as metronidazole but with a longer plasma half-life. It is activated intracellularly by bacterial/parasitic enzymes to a redox cytotoxic intermediate that damages large protein molecules and inhibits repair and transcription of DNA affecting also the cell wall. With this action, tinidazole might also have a synergic action with penicillin and doxycycline, facilitating the entry of such drugs. It is possible that tinidazole has the same bactericidal action on spirochetes other than Borrelia, such as Treponema pallidum, explaining its rapid therapeutic action on the lesions of early syphilis. Whether this action could be confirmed by studies on larger series of patients, tinidazole might be considered in case of allergy to penicillin or other antibiotics usually prescribed in syphilis.

Exosomal miR-146a-5p from Treponema pallidum-stimulated macrophages reduces endothelial cells permeability and monocyte transendothelial migration by targeting JAM-C

Exosomal microRNAs (miRNAs) transferred between cells have been implicated in modulating the host immune response in microbial infections. In this study, we isolated exosomes from Treponema pallidum (T. pallidum)-stimulated macrophages and detected differential exosomal miRNA expression using both microarrays, and RT-qPCR. A total of 65 differentially expressed miRNAs (35 upregulated and 30 downregulated) were identified. Of all identified miRNAs, miR-146a-5p was one of the most significantly changed miRNAs with high expression in exosomes from T. pallidum-stimulated macrophages. Furthermore, we isolated plasma exosomes from early syphilis patients and healthy controls, and confirmed miR-146a-5p upregulation in the former group. We also show that exosomal miR-146a-5p is efficiently transported into endothelial cells, reducing monocyte transendothelial migration and endothelial permeability by targeting junctional adhesion molecule C (JAM-C). Luciferase reporter assays confirmed binding of exosomal miR-146a-5p to the 3′untranslated region (3′UTR) of JAM-C. We then demonstrated that also exosomes derived from macrophages stimulated by T. pallidum expressed high levels of miR-146a-5p which could be delivered to endothelial cells, and decreased monocyte transendothelial migration by targeting JAM-C. Overall, this work provides novel insights into the mechanism by which T. pallidum hampers inflammatory reactions of the host via a blockade of leukocytes transendothelial migration and endothelial permeability.

Is repeated retreatment necessary for HIV-negative serofast early syphilis patients?

A persistent non-treponemal serological response can be observed in patients with syphilis after treatment and is referred to as serofast. This status makes it difficult for clinicians to judge the curative effect of treatment, particularly in patients with early syphilis. In the present study, a total of 114 eligible serofast patients treated between January 2009 and June 2016 were retrospectively analyzed. All patients were subjected to rapid plasma reagin (RPR) serological tests and followed up for 24 months. The patients who remained serofast after initial therapy were given the first retreatment, and at 12 months, those who were still serofast received a second retreatment. After the first retreatment (6 months), 33.3% of the subjects (38/114) were serologically cured (≥4-fold decline in RPR titer). At 24 months, the patients that had achieved serological cure accounted for 23.7% (18/76) of the patients that received the second retreatment. Furthermore, 26.3% of subjects that achieved serological cure (10/38) and had not been further treated after the first retreatment spontaneously presented with a ≥4-fold decline in RPR titer or negative status. In conclusion, the present study indicated that in patients with early syphilis and serofast status after initial treatment, retreatments may not provide any significant benefit. The second retreatment did not significantly improve the patient's serological cure rate. There is no evidence that patients with early syphilis and serofast should receive multiple retreatments, in spite of this being commonly performed in clinical practice.

Relationship between the high frequency of 23S rRNA point mutations in Treponema pallidum and low serological response rate to azithromycin treatment in China

Objective Although azithromycin is effective against Treponema pallidum (T. pallidum), the causative agent of syphilis, recent reports indicate that the prevalence of azithromycin resistance in China is very high, which may result in the failure of treatment. In this study, we aimed to investigate the association between azithromycin resistance and therapeutic outcomes in early syphilis patients. Methods Between February 2010 and December 2014, patients aged 18-65 years with early syphilis were enrolled. T. pallidum DNA were extracted to test the presence of A2058G and A2059G mutations. Then, eligible patients were randomly assigned to receive oral azithromycin (0.5 g, once daily for 15 days) or intramuscular BPG (2.4 million units, once weekly for 3 weeks). All patients were followed up in 2 weeks and 3, 6, 9, and 12 months after treatment to collect demographic and clinical characteristics and laboratory results. The differences on serological response, serological failure and serofast rate were compared between the two groups by Chi-square test. Results Among the 187 T. pallidum-infected patients enrolled, 172 (92.0%) cases had a mutation associated with azithromycin resistance (A2058G, 153 cases; A2059G, 19 cases). During the 5-year study period, the percentage of cases enrolled with these mutations steadily increased, from 90.9% in 2010 to 95.3% in 2014. Of the 172 patients presenting with these mutations, only 78 (45.3%; all benzathine penicillin G [BPG]-treated) obtained a serological response to treatment; 32.6% and 22.1% of patients presented with serological failure and serofast results, respectively. For azithromycin-treated cases, 66.3% and 33.7% had serological failure and serofast results, respectively, in contrast with 1.1% and 11.3% of BPG-treated cases. However, among the A2058G-and A2059G-negative patients, the serological response rates between the two treatment groups were similar. In multivariate analyses, patients with lower rapid plasma reagin (RPR) titers (RPR, ≤ 1:8; odds ratio[OR], 0.23; 95% confidence interval [CI], 0.09-0.37) or who received azithromycin treatment (OR, 121.50; 95% CI, 35.38-386.17) were more likely to display serological failure and serofast results. Conclusion This prospective study found that the 23S rRNA A2058G and A2059G point mutations in T. pallidum are currently circulating with high frequency in China, suggesting a correlation between the high prevalence of macrolide resistance and a lower serolo gical response rate to azithromycin treatment. Key words: Syphilis; Azithromycin; Mutation; Serological response; Treponema pallidum

Serological response to therapy following retreatment of serofast early syphilis patients with benzathine penicillin.

Some syphilitic patients remain in a serologically positive state after the recommended therapy. Although we often retreat patients in clinical practice, the optimal treatment protocol remains uncertain due to the paucity of data regarding serological response to retreatment and long-term outcomes. We examined rapid plasma reagin serological test results of 70 serofast early syphilis cases who were retreated with 2.4 million units of benzathine penicillin weekly for 3 weeks. Serological retreatment success was defined as a minimum 4-fold decrease in baseline rapid plasma reagin test antibody titre within 6 months. Thirty-four (48.6%) of the patients who failed to achieve serological cure at 6 months after initial therapy achieved serological cure at 12 months. Patients who had higher non-treponemal titres at baseline and at 6 months were more likely to exhibit serological cure after retreatment than those with lower titres. Our results suggest that the incremental benefit of retreating serofast patients with early syphilis is moderate, considering the almost 1:1 ratio of serological response to serofast state at follow-up.

Frequency of Treponema pallidum invasion into cerebrospinal fluid in primary or secondary early-stage syphilis.

Frequency of Treponema pallidum invasion into cerebrospinal fluid (CSF) has not been clear at this present. Since it is impossible to culture T.pallidum invitro at this present, we need molecular based-approach to detect it in CSF. Additionally, neurosyphilis is usually a late sequela, however it might result in asymptomatic neurosyphilis even at primary or secondary syphilis. This study was to reveal the frequency of T.pallidum invasion into CSF especially at primary or secondary syphilis with polymerase chain reaction (PCR) test. All patients were visited the Aichi Medical University Hospital or Izumi ladies' clinic between 2016 and 2017. Clinical CSF samples were collected from patients with early and late stages of syphilis. The PCR was done using primers targeting the tpN47gene. CSF samples were collected from 9 patients (4 patients with primary syphilis, 3 with secondary syphilis, and 1 early latent syphilis and 1 with late latent syphilis). PCR showed positive reaction in 2 of 7 (28.6%) primary and secondary syphilis patients, in 1 of 1 (100%) early latent syphilis patients, and in 1 of 1 (100%) late latent syphilis patients. Despite its lack of sensitivity for use alone as a diagnostic test, this PCR test should be preferred for the diagnosis of neurosyphilis. Because, T.pallidum was detected in the 28.6% CSF of patients at primary and secondary syphilis, which indicated that they invade the central nervous system from the early stages of infection. However, studies in a larger population are required to confirm these preliminary results.

Molecular subtyping of Treponema pallidum and associated factors of serofast status in early syphilis patients: Identified novel genotype and cytokine marker.

Serofast, a persistent nontreponemal serological response observed in early syphilis patients after conventional treatment, remains a concern of clinicians and syphilis patients. No consensus has been established, however, that defines an effective treatment strategy and clarifies the pathogenesis. In this study, 517 patients with early syphilis were enrolled and treated. Twelve months after treatment, 79.3% (410/517) of patients achieved serological cure, 20.1% (104/517) were serofast, and 0.6% (3/517) were serological failures. Multivariate analysis demonstrated that older age (>40 years) and lower baseline RPR titer (≤ 1:8) were associated with serofast status. We also identified 21 T. pallidum molecular subtypes among early syphilis patients and detected a new subtype, 14i/a. We found that the proportion of 14i/a type in serofast patients was significantly higher than that in patients with serological cure, predicting an increasing risk of serofast status. Levels of chemerin were higher in the serum of serofast cases than serological cure cases, potentially indicating a novel cytokine marker for serofast in early syphilis patients after therapy. We hope that these results contribute to improve guidelines for the management of syphilis patients who experience serofast.

Serum TRSUT Titer ≥1: 16 Is a Predictor for Neurosyphilis Among HIV-Infected Patients With Concurrent Syphilis and No Neurological Symptoms.

Investigating the predictors for lumbar puncture to diagnose the asymptomatic neurosyphilis among HIV and syphilis co-infected patients in Shanghai, China. Respectively, screening the medical records from August 1, 2009 to June 30, 2015. Those HIV-infected patients with concurrent syphilis who had received lumbar puncture were selected and their clinical and demographic data were recorded. Participants comprised symptomatic and asymptomatic patients. The latter ones could be further divided into 3 groups: late syphilis, early syphilis with anti-syphilis treatment failure, and early syphilis with serum toludine red unheated serum test (TRUST) ≥1:32. Both syphilis stage and anti-syphilis treatment effect were defined by common criteria, and syphilis of unknown duration was considered as late syphilis. Asymptomatic neurosyphilis was defined as neurosyphilis without neurological symptoms such as headache, cognitive dysfunction, motor deficits, auditory or ophthalmic abnormalities, and stroke. Neurosyphilis was defined as reactive cerebrospinal fluid (CSF) TRUST and/or CSF white blood cell >20 cells/μL without other reasons. Mann-Whitney test and Fisher's exact test were used for analyzing the difference between neurosyphilis and non-neurosyphilis group. Logistic regression test was performed to analyze the risk factors for neurosyphilis. In total, 170 participants were collected, and the rate of neurosyphilis was 32.35%. Among all the 105 participants without neurological symptoms, 80 patients were with late syphilis and 25 were with early syphilis. Among the early syphilis patients, 23 had a TRUST ≥1:32 and the other 2 experienced an anti-syphilis treatment failure. The differences of clinical and demographic variables between neurosyphilis and non-neurosyphilis group were not statistically significant except the serum TRUST titer (P < 0.01). From HIV/syphilis co-infected patients with or without neurological symptom, those who had neurological symptoms, CD4 <350 per μL and serological TRUST titer ≥1:16 were 4.9-fold (95% confidence interval [CI]: 2.37-10.31), 4.3-fold (95% CI: 1.17-15.78), and 4.1-fold (95% CI: 1.58-10.76), respectively, more likely to be diagnosed with neurosyphilis. Asymptomatic patients whose serum TRUST titer ≥1:16 were 8.48-fold (95% CI: 1.08-66.63) more likely to have asymptomatic neurosyphilis. Among asymptomatic HIV-infected patients with late syphilis or early syphilis experienced an anti-syphilis treatment failure, those who have a serum TRUST titer ≥1:16 are suggested to perform lumbar puncture in order to avoid delayed diagnosis and the occurrence of severe sequelae of syphilis.

Early syphilis: serological treatment response to doxycycline/tetracycline versus benzathine penicillin

Benzathine penicillin G is the treatment of choice for syphilis, but doxycycline and tetracycline are effective second-line treatments. The objective of this study was to assess the serological response to treatment for early syphilis with benzathine penicillin compared with doxycycline or tetracycline. We examined rapid plasma regain (RPR) serological test results of all first-time early syphilis patients in Peking Union Medical College Hospital between 2000 and 2011, comparing treatment with two doses of penicillin to 14-day course of oral doxycycline (100 mg twice daily) or oral tetracycline (500 mg 4 times a day). Of the 641 early syphilis cases with available treatment outcome data, 606 (94.5%) received penicillin and 35 (5.5%) received doxycycline/tetracycline. More than half (52.1%) had secondary syphilis, 13.4% had primary syphilis, and 34.5% had early latent syphilis. A statistically similar serological treatment success rate (p = 0.157) was observed in penicillin-treated patients 91.4% (554/606), when compared with patients treated with doxycycline/tetracycline 82.9% (29/35). Doxycycline/tetracycline had a similar serological treatment success rate when compared to penicillin in the treatment of early syphilis.

O01.3 Regulatory T Cells in Peripheral Blood and Cerebrospinal Fluid of Syphilis Patients with and Without Neurological Involvement: A Comprehensive and Comparative Study

BackgroundSyphilis, a sexually transmitted disease caused by spirochetal bacterium Treponema pallidum, can progress to affect central nervous system, causing neurosyphilis. While many neurosyphilis patients may be asymptomatic, some patients can...

Response to Therapy Following Retreatment of Serofast Early Syphilis Patients With Benzathine Penicillin

Response to Therapy Following Retreatment of Serofast Early Syphilis Patients With Benzathine Penicillin

Response to Therapy Following Retreatment of Serofast Early Syphilis Patients With Benzathine Penicillin

Persistent nontreponemal titers after treatment are common among patients with early syphilis. We retreated 82 human immunodeficiency virus-negative early syphilis participants who were serofast at 6 months using benzathine penicillin. Only 27% exhibited serological response after retreatment and after an additional 6 months of follow-up.

Rapid Plasma Reagin Titer Variation in the 2 Weeks After Syphilis Therapy

Serologic tests for syphilis results at the time of diagnosis are the basis for evaluating response to syphilis therapy. After treatment, however, serologic tests for syphilis titers may continue to increase for several weeks. We evaluated rapid plasma reagin (RPR) titer variation during the 14 days after therapy using data from a recent large, prospective randomized controlled trial. Prospectively enrolled participants in North America and Madagascar with primary, secondary, or early latent syphilis were randomly assigned to penicillin, doxycycline (in the case of penicillin allergy), or azithromycin treatment. Blood for RPR analysis was drawn at days 0, 7, and 14 posttreatment. All RPR titers were determined simultaneously at a central laboratory. Four hundred and seventy patients had data available for at least 2 of 3 RPR measurements. Overall, 20% of patients showed a titer increase of at least 1 dilution in the 14 days after therapy. The greatest proportion of titer increases following therapy was observed in patients with primary syphilis. Comparing outcome of therapy using the initial (day 0) RPR titer versus the maximal RPR titer (during 14 days) resulted in outcome reclassification in 2.98% of participants. Despite the fact that about 20% of early syphilis patients had increases in RPR titers immediately after treatment, these changes rarely influenced assessment of therapeutic outcome. Only 3% of patients treated would have been reclassified.

Liver dysfunction in patients with early syphilis: a retrospective study

Syphilis is one of the unrecognized etiologies of liver dysfunction. The incidence of syphilitic hepatitis is currently unknown. We conducted a retrospective study of causative agents of liver dysfunction at the time of diagnosis of early syphilis. Our study shows that 39 % (44/112) of early syphilis patients have liver enzyme abnormalities at the time of diagnosis and that 2.7 % (3/112) of patients are diagnosed with syphilitic hepatitis. Clinicians should include syphilitic hepatitis in the differential diagnosis for those patients with sexually transmitted diseases presenting with liver enzyme abnormalities.

P3-S6.02 Is fourfold drop of the nontreponemal antibody titrestitres at three or 6 months after early syphilis treatment an effectiveness “criterion?”

BackgroundAt present the criteria for treatment effective in early syphilis is the disappearance of clinical symptoms and signs and four-fold decrease of nontreponemal antibody titres within 3 to 6 months...