Arando et al. BMC Infectious Diseases (2019) 19:727 https://doi.org/10.1186/s12879-019-4269-8 RESEARCH ARTICLE Open Access Early syphilis: risk factors and clinical manifestations focusing on HIV-positive patients Maider Arando1,2* , Candela Fernandez-Naval3,4, Miriam Mota-Foix5, Desi Martinez1, Pere Armengol1, Maria Jesús Barberá1, Juliana Esperalba6 and Martí Vall-Mayans1 Abstract Background: Since 2000, substantial increases in syphilis in men who have sex with men (MSM) have been reported in many cities. Condomless anal sex (CAS) is one of the factors, along with drugs for sex and sex in group. This study identified factors and clinical manifestations as well as Treponema pallidum (T.pallidum) strains that could be related to early syphilis in Barcelona. Methods: This prospective study was conducted in a sexually transmitted infections unit in 2015. Epidemiological, behavioral, clinical and microbiological variables were collected in a structured form. Univariate and multivariate statistical analyses were performed focusing on HIV-positive patients. Results: Overall, 274 cases were classified as having early syphilis (27.5% primary, 51.3% secondary, and 21.2% early latent syphilis). In all, 94% of participants were MSM and 36.3% were HIV-positive. The median number of sexual contacts in the last 12 months was 10; 72.5% practiced CAS, 50.6% had sex in group, and 54.7% consumed drugs. HIV-positive cases had more anonymous sex contacts (p = 0.041), CAS (p = 0.002), sex in group (p < 0.001) and drugs for sex (p < 0.001). In the multivariate analysis, previous syphilis (adjusted odds ratio [aOR] 4.81 [2.88–8.15]), previous Neisseria gonorrhoeae infection (aOR 3.8 [2.28–6.43]), and serosorting (aOR 20.4 [7.99–60.96]) were associated with having syphilis. Clinically, multiple chancres were present in 31% of cases with no differences on serostatus, but anal chancre was most common in HIV-positive patients (p = 0.049). Molecular typing did not conclusively explain clinical presentation in relation to specific T.pallidum strains. Conclusion: Control of syphilis remains a challenge. Similar to prior studies, HIV-positive patients were found to engage more often in sexual behaviors associated with syphilis than HIV-negative patients. Clinical manifestations were rather similar in both groups, although anal chancre was most common in HIV-positive patients. Various strain types of syphilis were found, but no clinical associations were identified. Keywords: Syphilis, Men who have sex with men, Condomless anal sex, HIV Background Europe, there were 28,701 cases of early syphilis re- Since 2000, substantial increases in cases of early syphilis ported in 2015, yielding a rate of 6.0 per 100,000 have been reported in metropolitan areas of Western inhabitants [1]. Similarly, an increase has been described countries. These increases have been described particu- in our setting in Catalonia (Spain): in 2014, the rate of larly among men who have sex with men (MSM). In early syphilis was 12.4 per 100,000 inhabitants, a 231% increase over the figures for 2005 observed mainly in * Correspondence: marando@vhebron.net MSM [2]. 1 STI Unit Vall d’Hebron-Drassanes, Infectious Diseases Department, Hospital One of the most important factors affecting syphilis Vall d’Hebron, Av Drassanes 17-21 STI Unit Vall d’Hebron-Drassanes, Barcelona, Spain transmission is the practice of condomless anal sex 2 Medicine Department, Autonomous University of Barcelona, Barcelona, (CAS) [3]. Other factors, such as drug consumption, Spain internet use for sexual contacts, and sex in group have Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Arando et al. BMC Infectious Diseases (2019) 19:727 Page 2 of 9 also been reported [4]. In some studies, these risk fac- treponemal test (i.e. two dilutions) within the past 12 tors are directly related to syphilis, whereas, other months. Cured syphilis was defined as a four-fold de- studies have found, indirect links with CAS [5, 6]. HIV cline in the titer of a non-treponemal test within 1 coinfection has been demonstrated to be strongly year of treatment. associated with syphilis [3, 7].Clinically, some differ- ences have been described between HIV-positive and Behavioral variables HIV-negative patients, for instance, in atypical Participants completed a self-administered question- manifestations, such as multiple chancres in primary naire of demographic and sexual behavior information syphilis [8] or the persistence of chancres in secondary from the previous 12 months. Variables included how syphilis [9] in HIV-positive patients. they met their partners and practices such as sex in Molecular typing of Treponema pallidum subspe- group, drugs for sex, use of condoms, serosorting (sex cies pallidum (T. pallidum) has been used for between partners with same HIV status) and seroposi- different purposes [10–12]. Epidemiologically, use of tioning (adapting sexual practices according to one’s the technique has identified a wide distribution of HIV status). The self-administered questionnaire was strain types depending on geographic location, with based on the European MSM Internet Survey (EMIS) 14d/g being the most common in Europe [13, 14]. [16], which had been previously modified, piloted, and Some strains have been associated with clinical out- revised. An adapted version of this questionnaire was comes such as neurosyphilis in rabbits, although this used for heterosexual participants. Drugs for sex was has not been shown in humans [10]. defined as substance use 2 h before or during inter- The aim of this study was to provide updated course; chemsex was defined as the use of crystal information on syphilis in Barcelona by identifying methamphetamine, gammahydroxybutrate (GHB), and/ factors associated with early syphilis and occurrence or mephedrone before or during sexual sessions; and of these factors, focusing on HIV-positive patients. poly drug use was defined as the consumption of three An additional aim was to describe the clinical char- or more drugs, excluding alcohol or cannabis. CAS was acteristics of syphilis, exploring the role of specific defined as the absence of systematic use of a condom, strain types of T. pallidum. Altogether, the study even if used occasionally. Clinical and microbiological was intended to gain an overview of the syphilis epi- variables were completed by the attending physicians. demic that affects MSM in particular. Information on pre-exposure prophylaxis against (PrEP) HIV was not collected because it was not readily available Methods at that time. This prospective study was conducted in the Sexually If patients had more than 1 episode of syphilis during Transmitted Infections Unit Vall d’Hebron-Drassanes the study period, the epidemiological and behavioral in Barcelona, Spain (STIUVD). The STIUVD is the data were analyzed only once. To determine the risk fac- main referral sexually transmitted infections (STIs) in tors for the acquisition of syphilis according to HIV Catalonia and is located in the downtown area of Bar- status, HIV-positive patients were defined as patients celona. It provides care to patients for a total of who knew that they were HIV-positive at syphilis diag- 25000 visits per year (60% MSM) and reported around nosis, excluding patients whose diagnoses of HIV and 50% of all syphilis cases seen in Barcelona during the syphilis infection coincided. However, in the clinical ana- study period. lysis, the latter (patients with coincident diagnoses) were All patients aged 18 years or older with early syph- included in the HIV coinfection group analysis because ilis who came between 15 January and 15 October 15, the clinical manifestations and course of syphilis could 2015 were eligible to participate in the study. Syphilis be influenced by HIV. diagnosis and management were based on the Euro- pean syphilis guidelines [15]. Primary syphilis was de- Microbiological tests fined as a typical ulcer (chancre) and/or a positive test All patients were tested for syphilis following a reverse using dark-field microscopy or as polymerase chain algorithm sequence screening algorithm. Initial screen- reaction (PCR) detection of T. pallidum and/or a ing consisted of a specific test for antibodies against T. positive serological test for syphilis. Secondary syph- pallidum with any positive results a subsequently ilis was defined based on typical clinical symptoms confirmed by a non-treponemal test and another trepo- with positive treponemal and non-treponemal tests. nemal test. The tests used were the treponemal enzyme Early latent syphilis was defined as positive serological immunoassay (EIA, Siemens Healthcare Diagnostics, treponemal and non-treponemal tests with no clinical Germany), rapid plasma regain (RPR) test (Biokit, Spain), evidence of infection, with a previous negative syphilis T. pallidum particle hemagglutination assay (TPHA, serology, or a four-fold increase in the titer of a non- Biokit, Spain), and indirect immunofluorescence assay Arando et al. BMC Infectious Diseases (2019) 19:727 Page 3 of 9 (FTA-abs, BioMérieux, France). Direct diagnoses were the median CD4 count was 653 cells/μl [517–810] and made using dark-field microscopy or in-house PCR for 85 (89.5%) were on antiretroviral therapy (ART). Among T. pallidum [17]. A swab was taken in the case of ulcer, all patients, 42.8% (110) had a previous history of with a second swab taken if there were lesions in more syphilis. than one site. For typing purposes an extra swab was A total of 266 patients completed the questionnaire taken. Treponemal DNA was detected by means of a answering more than 85% of the questions (2 cases were diagnostic real-time PCR (qPCR) and molecular typing excluded from the behavioral analysis due to incomplete- was performed by the Enhanced CDC Typing, analyzing ness). Overall, in the past 12 months, the median number the arp, tpr and tp0548 genes. This typing is based on of contacts was 10 and CAS was practiced in 72.5% of three regions of T. pallidum-2 first described in 1998 by cases. Half (50.6%) of them engaged in sex in group and the Centers for Disease Control and Prevention (CDC) 54.7% used drugs for sex- 25.0% practiced chemsex and [18] and extended with tp058 in 2010 by Marra et al. 22.6% engaged in poly drug use. Two-thirds of patients [10] Participants were offered screening for N. gonor- searched for sexual partners through apps and 34.5% rhoeae (NG), C. trachomatis (CT) and HIV, as well as through the internet (Table 1). hepatitis C virus (HCV) in MSM. Clinically, in primary syphilis, genital chancre was the most common manifestation in 73.7% (56/76) of cases Statistical analysis followed by anal chancre in 22.4% (17/76). Others loca- Categorical variables were expressed as percentages and tions (such as oral or urethral) were uncommon, less comparisons were made using the chi-square test or than 4% (3/76). All (except 2 cases) were confirmed by Fisher’s exact test, as appropriate. The strength of the positive dark-field microscopy or PCR positive for T. association was measured as the odds ratio (OR) with pallidum. Oral chancre was found in 2 patients. Notably, 95% confidence intervals (95% CI). Continuous variables 31.1% had more than one chancre and 2 patients had were expressed as the mean (+/− SD) or median and genital and anal chancres simultaneously. Coexistent interquartile range [IQR]. Comparisons were performed chancres in secondary syphilis were observed in 38 using a Student t test, Mann-Whitney U test, ANOVA, (28.5%) of patients. The most frequent secondary lesions or Kruskal-Walls test with 95% CI if there were more were syphilides in the genital area (70.7%) and skin rash than two groups. Variables identified as clinically signifi- (62.1%) affecting the soles (45.0%) more often than the cant at the univariate level (p < 0.01) were tested in a palms of the hands (40.7%). The most common systemic final regression model using the Akaike information manifestations were asthenia (27.1%), sore throat criterion (AIC). The “R” program (R Foundation for (22.1%), lymph node enlargement (10.7%), and malaise Statistical Computing, Vienna, Austria), version 3.3.1, (10.7%) (Table 2). was used for all analyses. The median RPR titre at diagnosis was 1/32 [1/8; 1/64]. Ethical approval was granted by the Hospital Vall Among patients offered STI screening, 257 (94.0%) of d’Hebron Ethics Committee (PR(AG)297/2014) and all them received NG and CT / lymphogranuloma venereum patients provided written informed consent obtained by tests, with a prevalence of 9.3 and 16.0%, respectively. HIV the attending physician. was tested in 148 patients with 8.8% (13/148) being newly diagnosed while 5 (2.7%) of 189 patients tested positive for Results HCV (Table 3). Among patients diagnosed with early syphilis during the The majority of patients were treated with benzathine study period, 33 patients declined to participate while penicillin G 2.4 million units IM as a single dose (93.0%) another 3 were < 18 years old. In total, 270 patients with and 14 (5.2%) were treated with oral doxycycline 100 mg 274 episodes (4 patients had 2 episodes during this twice daily for 14 days. About a year after treatment, a period) were included. In terms of episodes, 76 (27.7%) four-fold decrease in the non-treponemal test titre was were primary syphilis, 140 (51.1%) were secondary syph- observed in all but 14 patients (2 patients were rein- ilis and 58 (21.2%) were early latent syphilis. Most pa- fected, 1 had a serological failure and 11 were missing). tients (257 [95%]) were MSM including bisexuals; there Five patients became HIV-positive and 4 new cases of were 2 (0.75%) women and 11 (4.0%) heterosexual men. HCV occurred during the first year after syphilis diagno- The median age was 36 [30–44] years, 60.5% were au- sis. Furthermore, 14 new syphilis reinfection cases tochthonous, 65.0% had university-level education, occurred, 5 of them in HIV-positive patients. 73.5% were employed, and 7.0% were students. A total Molecular typing was performed in 78 anogenital ul- of 95 (36.0%) patients knew they were HIV-positive at cers samples (16 samples could be typed only partially): the time of syphilis diagnosis. Four patients had never 55 were from genital ulcers and 23 from anal ulcers. A undergone an HIV test (these patients were excluded high variety of strains was found making clinical associa- from the comparative study). In HIV-positive patients, tions unreliable. The strain type distribution (compared Arando et al. BMC Infectious Diseases (2019) 19:727 Page 4 of 9 Table 1 Risk factors related to early syphilis, overall and by HIV serostatus. Barcelona 2015 HIV negative HIV positive ALL p aOR N = 167 N = 95 N = 266a Value (95% CI) % % % 95%CI 95%CI Sexual practices and condomless anal sex CAS 104 75 183 0.002 (CAS) 65.5 84.3 72.5 (57.4, 72.7) (75.0, 91.1) Receptive anal sex 107 77 185 0.011 67.3 82.8 72.3 (59.4, 74.5) (73.5, 89.8) Receptive CAS 40 46 88 0.005 39.6 62.2 49.7 (30.0, 49.8) (50.1, 73.2) Number of casual partners 10 10 10 0.041 [4-5] [5.75–32.8] [4-20] Number of casual partners with anal 5 6.5 6 0.039 sex [2-12] [4–21.5] [2-15] Number of casual partners with CAS 1 3 1 0.001 [0–2.25] [1-7] [0-4] Sexual risk behaviors Serosorting 4 28 32 < 0.001 20.4 3 43.1 16 [7.99– 60.96] (0.8, 7.6) (30.8, 55.9) Seroposition 10 15 25 0.004 8.4 25.4 13.8 (4.1, 14.9) (14.9, 38.4) Contact through App 99 65 166 0.164 61 70.7 64.3 (53.1, 68.6) (60.2, 79.7) Contact through internet 55 34 89 0.729 34 37 34.5 (26.7, 41.8) (27.1, 47.6) Club sex 27 27 54 0.027 16.7 29.3 20.9 (11.2, 23.3) (20.3, 39.7) Sauna 33 17 50 0.841 20.4 18.5 19.5 (14.4, 27.4) (11.1, 27.9) Fisting 28 21 50 0.232 18.1 25.6 20.7 (12.3, 25.0) (16.6, 36.4) Sex in group 66 59 125 < 0.001 41.8 69.4 50.6 (34.0, 49.8) (58.4, 78.9) Toys 53 39 93 0.06 33.3 46.4 37.7 (26.0, 41.2) (35.4, 57.6) Arando et al. BMC Infectious Diseases (2019) 19:727 Page 5 of 9 Table 1 Risk factors related to early syphilis, overall and by HIV serostatus. Barcelona 2015 (Continued) HIV negative HIV positive ALL p aOR N = 167 N = 95 N = 266a Value (95% CI) % % % 95%CI 95%CI Drugs for sex 78 66 145 < 0.001 46.7 71 54.7 (38.9, 54.5) (60.6, 79.9) Cocaine 21 27 49 0.096 26.4 41.5 34 (17.5, 38.1) (29.4, 54.4) Mephedrone 4 12 16 0.024 5 18.5 11 (1.4, 12.6) (9.9, 30.0) GHB 22 35 58 0.003 28.2 53.8 40.3 (18.6, 39.5) (41.0, 66.3) Sildenafil 20 29 49 0.028 25.6 44.6 34 (16.4, 36.8) (32.2, 57.4) Crystal methamphetamine 9 19 28 0.015 11.5 29.2 19.5 (5.4, 20.7) (18.6, 41.8) Poly drug use 27 34 61 0.05 16 37 22.6 (10.9, 22.6) (23.2, 46.2) Chemsex 26 40 67 0.001 15.5 42 25 (10.4, 21.9) (32.0, 52.6) +in italics: median with interquartile range in brackets a four cases with HIV unknown serostatus by proportions and graphics) between genital and anal the past 12 months (87.0% vs 91%) with a median of chancre was similar, with 14d/g isolated most often in 10 [5.75–32.8],3 [1-7]of which were CAS. There was both (12.7% in genital chancre; 30.4% in anal chancre), no difference between the group in insertive anal sex; followed by 14f/g (9.0% in genital chancre; 17.3% in anal however, HIV-positive patients had more receptive chancre). In multiple chancres, 14d/g was also most anal sex (82.8% vs. 67.3%; p = 0.011) (Table 1). common (20.0%). One patient with concomitant genital Concerning condom use for anal sex, HIV-positive and anal chancres had different types in anal chancre patients were more likely to practice CAS (84.3%) (14f/g) compared with genital chancre (−p/g partial than HIV-negative patients (65.5%; p = 0.002). result). Remarkably, 43.1% of HIV-positive patients practiced serosorting and 25.4% practiced seropositioning, while HIV-negative patients more frequently had CAS after Comparative study by HIV status having been tested for HIV (Table 1). Other risk All HIV-positive patients were MSM. Compared with factors were also more common in HIV-positive patients, HIV-negative patients, HIV-positive patients were such as having sex in group (69.4%), use of toys (46.4%), older (39 [34–44] vs 34[29–43] years, p = 0.01), and and drugs for sex (71.0%), mainly involving cocaine, GHB, were more likely to have had previous episodes of mephedrone, sildenafil, and crystal methamphetamine. NG, CT, and syphilis, as well as HCV coinfection Poly drug use was reported by 34 HIV-positive patients (Table 4). They also had more anonymous contacts in (35.7%) and chemsex by 40 (42.1%). Among HIV-negative Arando et al. BMC Infectious Diseases (2019) 19:727 Page 6 of 9 Table 2 Clinical manifestation of early syphilis. Barcelona 2015 HIV-negative HIV-positiveb All P Value a N = 59 N = 17 N = 76 Primary syphilis % % % Genital chancre 46 10 56 0.129 78 58.8 73.7 Anal chancre 10 7 17 0.049 17 41.2 22.4 Multiples chancres 17 6 23 0.553 29.3 37.5 31.1 Secondary syphilis N = 75 N = 65 N = 140 % % % Skin eruption 51 36 87 0.174 68.0 55.4 62.1 Palm lesion 30 27 57 0.99 40.0 41.5 40.7 Sole lesion 36 27 63 0.551 48.0 41.5 45 Genital syphilides 54 45 99 0.863 72.0 69.2 70.7 Sore throat 16 15 31 0.965 21.3 23.1 22.1 Asthenia 18 20 38 0.479 24.0 30.8 27.1 Malaise 8 7 15 1 10.7 10.8 10.7 Lymph node enlargement 11 4 15 0.1 14.7 6.15 10.7 a including 3 other cases with oral and urethral chancres b including patients diagnosed coinciding with syphilis infection patients, 27 (16.1%) reported poly drug use (p = 0.05), often in HIV-positive patients without a previous history of and 26 (15.5%) reported chemsex (p = 0.001). Four pa- syphilis. Anal chancres were more common in HIV-positive tients, all HIV-positive, reported IV drug use. The patients than in HIV-negative patients (41.2% vs. 17.0%; final regression model showed that HIV-positive pa- p = 0.04). In secondary syphilis, there were no signifi- tients with syphilis were more likely to have previous cant difference between these two groups (Table 2), syphilis (adjusted-OR, (ad-OR) 4.81 [2.88–8.15)] and even in terms of coexistent chancres. Median RPR ti- previous NG infection (ad-OR 3.8 [2.28–6.43)]. Al- ters were higher in HIV-positive patients at 1/64 [1/ though mainly related with people with HIV, sero- 32–1/64] than in HIV-negative patients at 1/16 [1/4– sorting (ad-OR 20.4 [7.99–60.96)] was strongly 1/64] p < 0.001 (Table 3). RPR titres stratified by associated with syphilis in HIV-positive patients. previous history of syphilis showed that this difference Clinically, in HIV-positive patients, secondary syphilis persisted among patients without a previous history was the most common stage (61.9%). Primary syphilis was of syphilis. When RPR titers were stratified by stage seen less often (15.2%), with a similar proportion to early the difference disappeared in secondary syphilis, in latent syphilis (22.6%) compared with HIV-negative contrast with primary and early latent syphilis where patients (early latent syphilis in 20.2%,secondary syphilis in RPR titers were higher in HIV-positive patients. There 44.5%, primary in 35%; p = 0.002). After stratifying for pre- were no differences between the two groups in treat- vious syphilis as a possible confounding factor, the differ- ment received, evolution of RPR or cure of syphilis ence was still significant, secondary syphilis occurred more after 1 year of treatment (p = 0.2). Arando et al. BMC Infectious Diseases (2019) 19:727 Page 7 of 9 Table 3 Microbiological results (RPR and coinfection) of early syphilis. Barcelona 2015 HIV negative HIV positivea All P Value N = 168 N = 106 N = 274 61.3% 38.3% 100% RPR 1/16 1/64 1/32 < 0.001 [1/4–1/64] [1/32–1/64] [1/8;1/64] STI coinfectionb Neisseria gonorrhoeae 12 12 24 0.378 7.69 11.9 9.3 Chlamydia trachomatis 24 17 41 0.949 15.4 16.8 15.9 Lymphogranuloma venereum 4 6 10 0.267 18.2 37.5 26.3 Hepatitis C virus 3 2 5 0.637 2.29 3.64 2.67 + in italics: median with interquartile range in brackets a including patients diagnosed coinciding with syphilis infection STI screening done in 257 patients for N. gonorrhoeae and C. trachomatis/L. venerum and 189 patients for hepatitis C b Discussion and 8.5% were newly diagnosed concomitantly with In our study the dominant profile of the epidemic syphilis. HIV and syphilis are related to each other [21, was MSM. Globally in high-income settings, MSM 22], and syphilis itself could increase the risk of HIV infec- accounts for a disproportionate burden of syphilis tion [23]. However, this increased risk could also be asso- infections [19]. This study shows that this cohort of ciated with sexual behavior, as HIV-positive patients patients with early syphilis, especially HIV-positive engage in more high-risk behaviors than HIV-negative patients, engage in high-risk sexual behaviors. At our patients as we report here, similarly to others researches clinic we had previously found an HIV coinfection [24–27]. Factors such as sex in group, multiple sex part- rate of 30% in a study conducted between 2003 and ners, CAS and use of drugs for sex, could also each raise 2013 [20]. In this study, we show that this relation- the risk of syphilis [3, 7]. However, these factors are mutu- ship has persisted over time, as we have now found ally linked, a fact that might increase the probability of that 36% of patients with syphilis were HIV-positive infection. An example of this interrelationship is chemsex, Table 4 Previous STI related to early syphilis, overall and by HIV serostatus. Barcelona 2015 HIV negative HIV positive All p Value aOR N = 167 N = 95 N = 266a (95% CI) % % % (95% CI) (95% CI) Previous STI Syphilis 42 68 110 < 0.001 4.81 26.4 72.3 42.8 [2.88–8.15] (19.7, 33.9) (62.1, 81.0) N. Gonorrhoeae 42 59 101 < 0.001 3.8 26.8 66.3 40 [2.28–6.43] (20.0, 34.4) (55.5, 75.9) C. Trachomatis 20 31 51 < 0.001 13.3 38.3 21.5 (8.3, 19.8) (27.7, 49.7) HCV coinfection 3 13 16 < 0.001 1.8 13.7 6 (0.3, 5.1) (7.5, 22.2) a four cases with HIV unknown serostatus Arando et al. BMC Infectious Diseases (2019) 19:727 Page 8 of 9 a growing global phenomenon which has been associated patients with high-risk sexual behaviors and the main with a higher number of partners and CAS, situations in findings are in line with those reported by others else- which patients more likely to be diagnosed with acute rec- where. Another limitation is the use of self-reporting, tal or bacterial STIs, and HCV [28]. sometimes with partial information, an approach that From a clinical perspective, HIV may modify the clin- could have influenced some of the results. Apart from the ical presentation [22] and course of syphilis. After inherent constraints of this method, the limited number adjusting for a previous history of syphilis, we found that of samples for molecular typing made it impossible to there were still differences in the stage depending on gather relevant information on the clinical manifestations HIV status, with secondary syphilis being more common of syphilis. Further results on microbiological typing in among HIV-positive patients, similar to the findings of syphilis obtained in this study will be published elsewhere Hutchinson et al. [9] An atypical presentation of syphilis, (Fernandez-Naval C. et al, submitted). Last, the sample such as multiple chancres and concurrent primary chan- size is underpowered to make multiple comparisons be- cres in secondary syphilis, had been described more tween groups but the results are consistent with those of often in HIV-positive patients [8, 22]. In our study we other studies. found no such differences with the exception that HIV- positive patients had more anal chancres. This could be Conclusion explained by seropositioning, in addition to the fact that In conclusion, HIV-positive MSM patients are more likely HIV-positive patients practiced receptive anal sex more than HIV-negative patients to have risk factors for syphilis, often than HIV-negative patients. When taking into ac- such as anonymous contacts, CAS, and chemsex. These count T. pallidum typing, molecular studies have associ- factors facilitate syphilis acquisition and and have been ated some strain types with clinical outcomes, such as found to contribute to the syphilis epidemic in Western neurosyphilis [10], ocular involvement [11], or serofast countries. HIV-positive patients practicing receptive anal status [12]. Following this methodology, we explored sex and seropositioning may cause them to have anal chan- whether or not multiple chancres and other clinical cres more often than HIV-negative patients. HIV could in- manifestations of early syphilis could be related to a spe- fluence the natural course of syphilis as secondary syphilis cific strain. We found a high diversity of strains in a lim- has been found to be more common in HIV-positive pa- ited sample size, precluding any associations. More tients. These findings are an updated report on syphilis in refined molecular methods such as multilocus sequence Barcelona and provide important information to be consid- typing (MLST) or whole genome sequencing could per- ered for public health interventions, including STI screen- haps be more conclusive [29]. We speculate that HIV ing and, access to health services and risk-reduction could influence the clinical presentation of syphilis in a programs targeting high-risk groups. way similar to how immunological factors affect the manifestation of syphilis in patients with a history of Abbreviations syphilis [30]. ART: Antiretroviral therapy; CAS: Condomless anal sex; CI: Confidence interval; CT: Chlamydia trachomatis; GHB: Gammahydroxybutrate; HCV: Hepatitis C Factors that influence the natural course of an infection virus; HIV: Human immunodeficiency virus; IQR: Interquartile range; include host susceptibility, bacterial characteristic and MSM: Men who have sex with men; NG: Neisseria gonorrhoeae; OR: Odds transmissibility, and host immunity [31]. Rekart et al. [32] ratio; PCR: Polymerase chain reaction; RPR: Rapid plasma reagin; SD: Standard deviation; STIs: Sexually transmitted infections suggested that ART could increase the susceptibility to syphilis due to changes in the innate and adaptive immune Acknowledgements responses to T. pallidum by suppressing mitochondrial Not applicable. function, proinflammatory response, and macrophage acti- vation. They concluded that the immunological effects of Author’s contributions ART and ART-induced behavioral changes could act syner- MA and MV contributed to the study design and conduct and to manuscript preparation. MM contributed to the statistical analysis MA, CF, DM, PA, MJB, gistically to increase susceptibility to syphilis. Could this be JE and MV contributed to the acquisition of clinical and microbiological data the reason why HIV-positive patients are more likely to of patients. MM, CF, DM, PA, MJB and JE reviewed the article. All authors have secondary syphilis than HIV-negative patients? In view read and approved the final manuscript. of our findings on risk behaviors in HIV-positive patients Funding compared with HIV-negative patients, we suggest that sex- This research received no specific grant from any funding agency, whether ual behavior probably has a much greater effect than other commercial or not-for-profit sectors. factors, as Tuddenhem et al. [33] argued. This study did have several limitations. First, it was car- Availability of data and materials ried out at a single center in Barcelona and, therefore, the The datasets generated and/or analyzed during the current study are not publicly available due to the sensitivity of the topic and hence to ensure findings could not be generalized. Nevertheless, the clinic confidentiality of the information but are available from the corresponding is a known referral center attending a large number of author on reasonable request. Arando et al. BMC Infectious Diseases (2019) 19:727 Page 9 of 9 Ethics approval and consent to participate 14. Grange PA, Allix-Beguec C, Chanal J, Benhaddou N, Gerhardt P, Morini JP, et Ethical approval was granted by the Hospital Vall d’Hebron Ethics al. Molecular subtyping of Treponema pallidum in Paris, France. Sex Transm Committee. All patients provided written informed consent. Dis. 2013;40:641–4. 15. Janier Á, Hegyi V, Dupin N, Unemo M, Tiplica GS, Potočnik M, et al. 2014 European guideline on the management of syphilis. J Eur Acad Dermatol Consent for publication Venereol. 2014;28:1581–93. Not applicable. 16. The EMIS Network. EMIS 2010: The European Men-Who-Have-Sex-With-Men Internet Survey. Findings from 38 countries. Stockholm: European Centre for Competing interests Disease Prevention and Control; 2013. [Accessed 14 June 2017]. Available The authors declare that they have no competing interests. from: http://ecdc.europa.eu/en/publications/Publications/EMIS-2010- european-men-who-have-sex-with-men-survey.pdf. Author details 17. Orle KA, Gates CA, Martin DH, Body BA, Weiss JB. Simultaneous PCR detection 1 of Haemophilus ducreyi, Treponema pallidum, and herpes simplex virus types STI Unit Vall d’Hebron-Drassanes, Infectious Diseases Department, Hospital Vall d’Hebron, Av Drassanes 17-21 STI Unit Vall d’Hebron-Drassanes, 1 and 2 from genital ulcers. J Clin Microbiol. 1996;34:49–54. Barcelona, Spain. 2Medicine Department, Autonomous University of 18. Pillay A, Liu H, Chen CY, Holloway B, Sturm AW, Steiner B, Morse SA. Barcelona, Barcelona, Spain. 3Vall d’Hebron Institute of Research, Barcelona, Molecular subtyping of Treponema pallidum subespecies pallidum. Sex Spain. 4Genetics and Microbiology Department, Autonomous University of Transm Dis. 1998;25:404–14. Barcelona, Barcelona, Spain. 5Statistics and Bioinformatics Unit, Vall d’Hebron 19. Abara WE, Hess KL, Neblett Fanfair R, Bernstein KT, Paz-Bailey G. Syphilis trends Institute of Research, Barcelona, Spain. 6Microbiology Department, Hospital among men who have sex with men in the United States and Western Vall d’Hebron, Barcelona, Spain. Europe: a systematic review of trend studies published between 2004 and 2015. PLoS One. 2016;11(7):1–19. https://doi.org/10.1371/journal.pone.0159309. Received: 11 April 2019 Accepted: 8 July 2019 20. Arando M, Caballero E, Curran A, Armengol P, Barberá MJ, Vall-Mayans M. The epidemiological and clinical characteristics of the epidemic of syphilis in Barcelona. Actas dermato-sifiliográficas. Accepted. 21. Hook EW 3rd. Syphilis. Lancet. 2017;389:1550–7. References 22. Lynn WA, Lightman S. Syphilis and HIV: a dangerous combination. Lancet 1. European Centre for Disease Prevention and Control. Syphilis. In: ECDC Infect Dis. 2004;4:456–66. Annual Epidemiological Report for 2015. Stockholm: ECDC; 2017. [Accessed 23. Fleming DT, Wasserheit JN. From epidemiological synergy to public 5 Feb 2018]. Available from: https://ecdc.europa.eu/sites/portal/files/ health policy and practice: the contribution of other sexually documents/AER_for_2015-syphilis.pdf. transmitted diseases to sexual transmission of HIV infection. Sex 2. Centre d'Estudi Epidemiològics sobre Infeccions de Transmissió Sexual i Transm Infect. 1999;75:3–17. Sida de Catalunya (CEEISCAT). CEEISCAT Epidemiological Report 2015. 24. Klitzman RL, Pope HG, Hudson JI. MDMA (“ecstasy”) abuse and high-risk Integrated Surveillance System for STI and HIV in Catalonia (SIVES) Technical sexual behaviors among 169 gay and bisexual men. Am J Psychiatry. Document N° 22. Barcelona: CEEISCAT; 2015. [Accessed 5 Feb 2018]. 2000;157:1162–4. Available from https://scientiasalut.gencat.cat/bitstream/handle/11351/3418/ 25. Hirshfield S, Schrimshaw EW, Stall RD, Margolis AD, Downing MJ Jr, informe_SIVES_2015_informe_epidemiologic_CEEISCAT_2015.pdf. Chiasson MA. Drug use, sexual risk, and syndemic production among men pdf?sequence=1. who have sex with men who engage in group sexual encounters. Am J 3. Paz-Bailey G, Meyers A, Blank S, Brown J, Rubin S, Braxton J, et al. A case–control Public Health. 2015;105:1849–58. study of syphilis among men who have sex with men in new York City 26. Grov C, Rendina HJ, Breslow AS, Ventuneac A, Adelson S, Parsons JT. association with HIV infection. Sex Transm Dis. 2004;31:581–7. Characteristics of men who have sex with men (MSM) who attend sex 4. Wong W, Chaw KJ, Kent CK, Klausner JD. Risk factors for early syphilis parties: Results from a national online sample in the U.S. Sex Transm Infect. among gay and bisexual men seen in an STD clinic: San Francisco, 2014;90:26–32. 2002-2003. Sex Transm Dis. 2005;32:458–63. 27. Friedman SR, Bolyard M, Khan M, Maslow C, Sandoval M, Mateu-Gelabert P, et 5. Taylor MM, Aynalem G, Smith LV, MontoyaJ KP. Methamphetamine use and al. Group sex events and HIV/STI risk in an urban network. J Acquir Immune sexual risk behaviours among men who have sex with men diagnosed with Defic Syndr. 2008;49(4):440–6. https://doi.org/10.1097/QAI.0b013e3181893f31. early syphilis in Los Angeles County. Int J STD AIDS. 2007;18:93–7. 28. Pakianathan M. 2nd European Chem Sex Forum Report. Panel 1. Berlin; 2018. 6. Lewnard JA, Berrang-Ford L. Internet-based partner selection and risk for [Accessed 28 May 2019]. Available from: https://es.slideshare.net/ unprotected anal intercourse in sexual encounters among men who have Checkpoints14/european-chemsex-forum-report-2018 sex with men: a meta-analysis of observational studies. Sex Transm Infect. 29. Grillová L, Bawa T, Mikalová L, Gayet-Ageron A, Nieselt K, Strouhal M. 2014;90:290–6. Molecular characterization of Treponema pallidum subsp. pallidum in 7. Simms I, Fenton KA, Ashton M, Turner KM, Crawley-Boevey EE, Gorton R, et Switzerland and France with a new multilocus sequence typing scheme. al. The re-emergence of syphilis in the United Kingdom: the new epidemic PLoS One. 2018;13(7):e0200773. phases. Sex Transm Dis. 2005;32:220–6. 30. Courjon J, Hubiche T, Dupin N, Grange PA, Del Giudice P. Clinical aspects of 8. Rompalo M, Lawlor J, Seaman P, Quinn TC, Zenilman JM, Hook EW 3rd. syphilis reinfection in HIV-infected patients. Dermatology. 2015;230:302–7. Modification of syphilitic genital ulcer manifestations by coexistent HIV 31. Stoltey JE, Cohen SE. Syphilis transmission: a review of the current evidence. infection. Sex Transm Dis. 2001;28:448–54. Sex Health. 2015;12:103–9. 9. Hutchinson CM, Hook EW 3rd, Shepherd M, Verley J, Rompalo AM. Altered 32. Rekart ML, Ndifon W, Brunham RC, Dushoff J, Park SW, Rawat S, et al. A clinical presentation of early syphilis in patients with human double-edged sword: does highly active antiretroviral therapy contribute to immunodeficiency virus infection. Ann Intern Med. 1994;121:94–100. syphilis incidence by impairing immunity to Treponema pallidum? Sex 10. Marra CM, Sahi SK, Tantalo LC, Godornes C, Reid T, Behets F, et al. Enhanced Transm Infect. 2017;93:374–8. molecular typing of Treponema Pallidum: geographical distribution of strain 33. Tuddenham S, Shah M, Ghanem KG. Syphilis and HIV: is HAART at the heart tupes and association with neurosyphilis. J Infect Dis. 2011;202:1380–8. of this epidemic? Sex Transm Infect. 2017;93:311–2. 11. Oliver S, Sahi SK, Tantalo LC, Godornes C, Neblett Fanfair R, Markowitz LE, et al. Molecular typing of Treponema pallidum in ocular syphilis. Sex Transm Dis. 2016;43:524–7. Publisher’s Note 12. Zhang RL, Wang QQ, Zhang JP, Yang LJ. Molecular subtyping of Springer Nature remains neutral with regard to jurisdictional claims in Treponema pallidum and associated factors of serofast status in early published maps and institutional affiliations. syphilis patients: identified novel genotype and cytokine marker. PLoS One. 2017;12:e0175477. 13. Salado-Rasmussen K, Cowan S, Gerstoft J, Larsen HK, Hoffmann S, Knudsen TB, et al. Molecular typing of Treponema pallidum in Denmark: a Nationwide study of syphilis. Acta Derm Venereol. 2016;96:202–6.