research article on syphilis

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• Published: 14 July 2023

Evaluating the global, regional, and national impact of syphilis: results from the global burden of disease study 2019

• Tao Chen 1   na1 ,
• Bo Wan 1 , 2   na1 ,
• Mingfang Wang 3 , 4 , 5 ,
• Su Lin 3 , 4 , 5 ,
• Yinlian Wu 3 , 4 , 5 &
• Jiaofeng Huang 3 , 4 , 5  

Scientific Reports volume  13 , Article number:  11386 ( 2023 ) Cite this article

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• HIV infections
• Infectious diseases

Syphilis is a global public health concern. This study aimed to assess the global and regional burden of syphilis from 1990 to 2019. Disease burden was evaluated using disability-adjusted life-years (DALYs) and prevalence. Data were extracted from the 2019 global burden of disease Study, an open database available for download. Age-standardized rates (ASR) and estimated annual percentage changes (EAPC) were calculated to evaluate the syphilis burden over time. In 2019, the total number of prevalent cases of syphilis was 49.71 million worldwide. The ASR of prevalence was stable from 1990 to 2019 with an EAPC of 0.00 (95% CI − 0.10–0.11). The number of DALYs caused by syphilis was 7.36 million in 2019, reflecting a reduction of 16.38% compared with that in 1990 (8.80 million). The ASR of DALYs exhibited a decreasing trend from 1990 to 2019 (EAPC =  − 1.01; 95% CI − 1.19 to − 0.84), with the highest rates observed in the younger age group (< 14 years old). In 2019, the highest ASR of DALYs was found in low sociodemographic index (SDI) regions (239.21/100,000), and the lowest in high SDI regions (3.14/100,000). Generally, the ASR of DALYs decreased as the SDI increased. The top three countries with the highest ASR of DALYs for syphilis were the Solomon Islands, Equatorial Guinea, and Liberia. While the global prevalence of syphilis remained persistently high from 1990 to 2019, there has been a recent decrease in the ASR of DALYs. Increased attention should be dedicated to younger populations and regions characterized by low SDIs.

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Introduction.

Syphilis is a sexually transmitted infection (STIs) caused by Treponema pallidum that has imposed a significant global burden in the past few decades 1 . Syphilis not only affects the genitourinary system 2 but also impairs other systems, including the neurological, cardiovascular, ocular, or liver systems 3 , 4 . Patients diagnosed with syphilis may experience discrimination, stigma, exclusion, and pressure from society and family 5 . During the 69th World Health Assembly in 2016, a target was set to reduce the global incidence of syphilis by 90% from 2018 to 2030 6 . Nevertheless, there has been a recent indication of an increase in the global prevalence of syphilis. To achieve the target set by the 69th World Health Assembly, countries need to revise their policies regarding syphilis and especially focus on high-risk populations.

The burden and rate of syphilis show variations based on time, location, and population. There has been a discernable rise in the prevalence of syphilis in Europe and Australia 7 , 8 . Additionally, syphilis has extended its reach beyond urban areas and is spreading to rural or remote areas 8 . A report from South–East Asia revealed the emergence of a subsequent wave of syphilis in the past 15 years 9 . Most studies have focused on examining the burden of syphilis within specific regions and did not extend their investigation to encompass global changes 7 , 8 , 9 . A recent systematic review revealed that the frequency of maternal and congenital syphilis in indigenous people varies but tends to be higher compared to that in their non-indigenous counterparts. Data from China indicated a substantial increase in syphilis diagnoses over time, particularly among less developed cities and older women 10 . These groups had received comparatively less attention. In a study conducted in the United States, a similar finding was reported, revealing an increase in the burden of syphilis among older adults; notably, this population has always been overlooked or neglected 11 .

Previous studies have indicated that the prevention of mother-to-child transmission (MTCT) could be key to reducing the burden of syphilis. In 2008, an estimated 1.36 million pregnant women were reported to have active syphilis, resulting in serious complications, including pelvic inflammatory disease, premature birth, low birth weight, stillbirth, and neonatal infection 12 . Antenatal screening and treatment of syphilis have played a crucial role in safeguarding the well-being of both the mother and newborn, as well as promoting child health 13 . However, the association between syphilis, economic status, and age group is not well established. Identifying the groups most affected by the disease and formulating effective programs and policies that specifically target these populations are essential for syphilis control.

The global burden of disease study (GBD) is an open database providing a systematic scientific assessment of the prevalence and disability-adjusted life-years (DALYs) of 369 diseases worldwide 14 . Based on this database, studies have been conducted to assess the burden of HIV and acute viral hepatitis. These studies have consistently demonstrated that HIV and acute viral hepatitis remain significant contributors to the loss of healthy life 15 , 16 . A systematic analysis of the burden of syphilis is still lacking. In this study, we used the 2019 GBD data to analyze the temporal trends and burden of syphilis. The results of our study will enhance our knowledge of the burden of syphilis and will assist in the formulation of strategies for effective prevention and control of the disease.

Syphilis data from 1990 to 2019 were obtained from the Global Health Data Exchange query tool ( http://ghdx.healthdata.org/gbd-results-tool ). In the GBD 2019 study, all statistics are presented as values with 95% uncertainty intervals (UI) after 100,000 simulations. The following selection criteria were applied to select the data for analysis. First, the study period was set to 1990–2019. Second, the location name was set to include “Global”, “the 21 geographic locations”, “sociodemographic index (SDI) areas”, and “the 204 countries or territories” 17 . Third, the cause was set to “syphilis”. Fourth, “prevalence” and “DALYs” were chosen as the evaluation index of syphilis burden. Finally, age was segregated into four categories: up to 14, 15–49, 50–69, and 70 + years.

Definitions

Age-standardized rate (asr) 18.

Age-standardized rate (ASR) was based on the GBD 2019 global age (standard population). The ASR in this study mainly included the ASR of prevalence and ASR of DALYs.

Disability-adjusted life-years (DALYs)

The global burden of syphilis was estimated in terms of disability-adjusted life years (DALYs) in the GBD 2019 study, which was defined as the sum of years of life lost and years lived with a disability 18 .

Sociodemographic index (SDI)

The sociodemographic index (SDI) is a summary indicator of economic and societal development and was constructed using education, average income, and overall fertility rate under the age of 25 19 . In the GBD 2019, countries and territories were grouped into five SDI quintiles: low, low-middle, middle, high-middle, and high.

Estimated annual percentage change (EAPC)

The estimated annual percentage change (EAPC) and 95% confidence intervals (CI) were calculated as the average annual percentage change in ASR from 1990 to 2019. If the EAPC and lower 95% CI limit were both positive, the ASR was considered to have an upward trend. Conversely, if the EAPC and the upper 95% CI limit were both negative, the ASR was considered to have a decreasing trend. Otherwise, ASR was regarded to be consistent over time.

Joinpoint regression analysis

Joinpoint regression analyses were performed using Joinpoint software version 5.0, which was obtained from the US National Cancer Institute ( https://surveillance.cancer.gov/joinpoint/ ). This software was used to calculate the annual percent change (APC) and average annual percentage change (AAPC). The Joinpoint regression technique has the advantage of characterizing the trend of disease burden changes at many stages.

Statistical analysis

Data were downloaded from the GBD database and statistical analyses were performed using R software version 4.2.2 ( https://www.R-project.org/ ). Subgroup analysis was performed according to sex, age, SDI, and the 21 geographic locations.

Worldwide burden estimates of syphilis

Globally, the number of prevalent cases of syphilis was 30.91 million in 1990 and 49.71 million in 2019, with an increase of 60.83% from 1990 to 2019. (Table 1 ) The ASR of prevalence was stable from 1990 to 2019 (Fig.  1 A), with an EAPC of 0.00 (95% CI − 0.10–0.11). The prevalence of ASR in 2019 was 766.41/100,000 for men and 473.81/100,000 for women (male/female = 1.62). The number of DALYs caused by syphilis was 7.36 million in 2019, a reduction of 16.38% compared to that in 1990 (8.80 million) (Table 2 ). The ASR of DALYs showed a decreasing trend from 1990 to 2019 (EAPC =  − 1.01; 95% CI − 1.19 to − 0.84) (Fig.  1 B). A similar downward trend was observed in both men and women. The highest ASR prevalence was observed among those aged 15–49 years (1113.54/100,000), followed by the 50–69 years age group (364.20/100,000), and was the lowest in the < 14 years age group (31.53/100,000) (Fig.  1 C). The highest ASR of DALYs was found in the < 14 years age group, which increased with increasing age. A reduction in DALYs over time was observed in all age-stratified subgroups (Fig.  1 D). Joinpoint analysis was applied to divide the temporal trends into four time periods and estimate the APC by sex. The results showed that the ASR of prevalence increased slightly (AAPC = 0.24) between 1990 and 2019. The three periods of prevalence from 1990 to 2001, 2001 to 2010, and 2015 to 2019 showed an upward trend (APC > 0), whereas the period from 2001 to 2004 showed a downward trend (APC < 0). The upward trend in men was more pronounced than that in women (Fig.  2 A). Joinpoint regression analysis revealed that the ASR of DALYs showed a downward trend in all four time periods (APC < 0 and AAPC < 0), and this trend was similar between men and women (Fig.  2 B).

Trend of ASR of syphilis from 1990 to 2019. ( A ) ASR of prevalence grouped by sex; ( B ) ASR of DALYs grouped by sex; ( C ) ASR of prevalence grouped by age, age 15–49 and 50–69 groups are depicted on the left axis, while other age groups are depicted on the right Y-axis; ( D ) ASR of DALYs grouped by age, age 15–49, 50–69, and ≥ 70 groups are depicted on the left axis, while age group < 14 years is depicted on the right Y-axis; ( E ) ASR of prevalence grouped by SDI levels, and low and low middle SDI groups are depicted on the left axis, while other SDI groups are depicted on the right Y-axis. ( F ) ASR of DALYs grouped by SDI levels, and low and low middle SDI groups are depicted on the left axis, while other SDI groups are depicted on the right Y-axis. DALYs disability-adjusted life years, ASR age-standardized rate, SDI sociodemographic index.

Results of Joinpoint regression analysis grouped by sex. ( A ) ASR of prevalence; ( B ) ASR of DALYs. APC annual percent change, AAPC average annual percent change.

Prevalence in different regions

The ASR of syphilis prevalence has been investigated in different regions worldwide and is reported to be negatively associated with the SDI level. In 2019, the highest ASR of prevalence was observed in the low SDI regions (1459.13/100,000) and lowest in the high SDI regions (246.75/100,000) (Fig.  1 E). There was an increasing trend in the ASR of prevalence in high SDI regions (EAPC: 0.15, 95% CI 0.10–0.20) and high-middle SDI regions (EAPC: 0.12, 95% CI 0.01–0.23), whereas the incidence decreased in low SDI regions (EAPC: − 1.03, − 1.13 to − 0.93).

The highest observed ASR of prevalence in 2019 was in Central Sub-Saharan Africa, followed by Southern Sub-Saharan Africa and Eastern Sub-Saharan Africa (Fig.  3 A). In addition, among the 204 countries or territories, the Central African Republic (4883.08/100,000), Equatorial Guinea (4429.62/100,000), and Angola (3892.36/100,000) exhibited the highest ASR of prevalence in 2019 (Supplementary Table 1 , Fig.  4 A). However, the ASR of prevalence decreased significantly over time among the three regions. The three countries and territories with the highest increase in ASR of prevalence were Greece, Mongolia, and Paraguay, with EAPCs of 3.59, 3.31, and 1.38, respectively.

ASR of syphilis in 21 geographical regions in 2019. ( A ) ASR of prevalence; ( B ) ASR of DALYs. DALYs disability‐adjusted life years, ASR age-standardized rate.

ASR of syphilis in 204 countries or territories in 2019. ( A ) ASR of prevalence; ( B ) ASR of DALYs. The world map chart was built using the R statistical software (version 4.2.2). Prevalence and DALYs of syphilis worldwide was mapped using the “sf” R package and “.shp file”. DALYs disability‐adjusted life years, ASR age-standardized rate.

DALYs in different regions

The highest ASR of DALYs occurred in low-SDI regions (239.21/100,000) and the lowest occurred in high-SDI regions (3.14/100,000). Generally, the ASR of DALYs decreased as the SDI increased. (Fig.  1 F). We also found decreasing trends of DALYs in all SDI areas, particularly in low SDI areas (EAPC =  − 2.10; 95% CI − 2.24 to − 1.95). In 2019, the highest observed ASR of DALYs was in Oceania, followed by Central Sub-Saharan Africa and Eastern Sub-Saharan Africa (Fig.  3 B). The ASR of DALYs showed decreasing trends in most regions, particularly Eastern Europe (EAPC =  − 8.12; 95% CI − 9.79 to − 6.45) and Southern Latin America (EAPC =  − 3.85; 95% CI − 4.47 to − 3.22). An upward trend in the ASR of DALYs was observed exclusively in the Caribbean and Southeast Asia, with EAPCs of 0.64 (95% CI 0.30–0.99) and 0.52 (95% CI 0.31–0.74), respectively.

The top three countries and territories with the highest ASR of DALYs due to syphilis were the Solomon Islands (920.93/100,000), Equatorial Guinea (727.02/100,000), and Liberia (717.24/100,000), while those with the lowest were Slovenia, Lithuania, and Hungary (Fig.  4 B). The details are listed in Supplementary Table 2 . Overall, the ASR of DALYs exhibited a predominantly declining trend across most regions worldwide. Additionally, Turkmenistan (EAPC =  − 9.58 95% CI − 11.48 to − 7.68) and Panama (EAPC = 3.51, 95% CI 2.46–4.56) exhibited the most significant downward and upward trend in ASR of DALYs, respectively.

This study provides a comprehensive estimation of the global prevalence of syphilis and its associated DALYs, over the past three decades. The main findings were as follows: (1) The ASR of the prevalence of syphilis remained stable from 1990 to 2019, whereas the ASR of the DALYs due to syphilis decreased globally. (2) The highest ASR of the DALYs was observed among individuals younger than 14 years. (3) The burden of syphilis decreased with an increase in the SDI. Solomon Islands, Equatorial Guinea, and Liberia exhibited the highest age-standardized DALYs rates in 2019 among 204 countries or territories investigated.

Several regional studies have provided evidence that affirms the persistently high prevalence of syphilis 7 , 8 , 9 , 20 . The reason may be due to the development of diagnostic capacity in the countries studied, which has led to an increase in the number of declared cases. Additionally, the increased numbers of men engaging in same-sex sexual activity 21 , and the patterns of sexual behavior among adolescents may play a relatively crucial role 22 . Furthermore, an increase in the frequency of travel may be attributed to the transmission of syphilis 23 . While pre-exposure and post-exposure prevention measures are available to mitigate the risk of STIs 24 , 25 , insufficient awareness of syphilis may be a probable reason for its persistence in certain regions 26 . The use of condoms is the most economical and simple way to prevent the spread of syphilis and other STIs 27 . Several governments have implemented a series of measures and efforts to promote the use of condoms and prevent the spread of STIs 28 . For instance, government initiatives provide free or affordable condoms, while family planning and healthcare organizations distribute free condoms to individuals, concurrently promoting safe sex education. Volunteers are additionally mobilized within the community to raise awareness and educate people about condoms and safe sex practices. Furthermore, governments have actively promoted the implementation of comprehensive sex education programs in schools and communities. These initiatives aim to educate young individuals and adults about contraception, safe sexual practices, and the importance of understanding their own physical and sexual behaviors. The objective is to help individuals develop realistic reproductive health plans 29 , 30 .

Although syphilis has a high prevalence, the ASR of the DALYs has decreased over the past three decades. This may have been due to the effectiveness of the current therapy. Furthermore, the declining trend in syphilis cases may be attributed to the expanding diagnostic capabilities and improved access to health services, particularly in terms of antimicrobial agent treatment. Antibiotics are the most effective treatment for syphilis 31 and can significantly reduce the morbidity and mortality of syphilis in humans 32 . However, antimicrobial resistance has increased worldwide as a consequence of the widespread use of antimicrobial agents. At present, many countries are experiencing an increase in antibiotic resistance, which poses a growing threat to the burden of syphilis 33 , 34 . Appropriate use of antibiotics is indispensable to minimize the burden of antibiotic resistance in syphilis 35 . In addition, there is an urgent need for the development of novel antibiotics 36 . Finally, syphilis has a wide variety of clinical manifestations and can be easily misdiagnosed if the specific antibody is not tested 37 . In addition to causing damage to the genitourinary system, syphilis has to potential to harm other organs, including the cardiovascular, nervous, and ocular systems 38 , 39 . If left untreated, syphilis can pose life-threatening risks.

Additionally, we observed a paradoxical phenomenon, in which the age group aged under 14 years exhibited the lowest prevalence but the highest rate of DALYs. This indicates that early exposure to syphilis can lead to adverse outcomes. Therefore, there is a critical need for sexual protection for syphilis among younger individuals 40 . Another important reason for the high burden of DALYs in this age group may be the vertical transmission of syphilis, which may contribute to poorer outcomes in younger individuals 41 . Congenital syphilis due to vertical transmission can cause neonatal death, as well as cutaneous and visceral manifestations. Early diagnosis and treatment are effective measures to reduce prevalence and mortality 42 . Therefore, it is crucial to strengthen the existing screening practices for pregnant women and establish thorough follow-up evaluations for women who have contracted syphilis 43 , 44 .

Another important finding of our study was that the burden of syphilis decreased with the increase in SDI level. This is consistent with the cross-sectional study by Costa et al., which showed a significant association between family income and STIs 45 . Additionally, the present study highlights the substantial disease burden of STIs in developing countries, particularly in Sub-Saharan Africa, Oceania, and the Caribbean. Hence, extensive strategies for the effective control and management of syphilis should be extensively implemented in developing countries for screening, education, and treatment 46 , 47 . The Solomon Islands, Equatorial Guinea, and Liberia were among the less developed countries in the world 48 , 49 that exhibited the highest ASR of DALYs.

Limitations

The study is subject to certain inherent limitations. First, data from the GBD database primarily focuses on economically developed countries, and there may be a lack of comprehensive health data for certain poorer or developing countries. As a result, the health situation in these regions may not be fully represented 50 . Furthermore, the collection and update of data may have certain delays, particularly during emergencies or large-scale outbreaks. As a result, there could be some lag in the availability of updated data. There are several suggestions for future research in this field. With the advancement of technology and the development of data collection methods, more accurate data can be obtained by enhancing the speed of data updates. Furthermore conducting data analysis from multiple perspectives through the integration of different data sources, analysis methods, and disease classification standards can improve the accuracy and precision of the data.

The ASR of the prevalence of syphilis remained persistently high from 1990 to 2019 worldwide, with no significant changes observed. Conversely, the ASR of DALYs attributed to syphilis exhibited a decrease over the same period. There was an inverse relationship between the syphilis burden and SDI levels. Individuals under the age of 14 and regions with a low SDI require greater attention in addressing the burden of syphilis.

Data availability

The data used in this study were publicly accessed. To download the dataset, please visit the Global Health Data Exchange at http://ghdx.healthdata.org/gbd-results-tool .

Abbreviations

Sexually transmitted infections

Disability‐adjusted life years

Age-standardized rate

Estimated annual percentage changes

Global burden of diseases

Sociodemographic index

Uncertainty intervals

Confidence interval

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Acknowledgements

We thank all contributors to the global burden of diseases 2019 Study.

This research is supported by Joint Funds for the Innovation of Science and Technology, Fujian Province (No. 2020Y9105), Natural Science Fundation of Fujian Province (No. 2022J01700).

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These authors contributed equally: Tao Chen and Bo Wan.

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Department of Hepatology, Hepatology Research Institute, The First Affiliated Hospital, Fujian Medical University, No. 20, Chazhong Road, Taijiang District, Fuzhou, 350005, Fujian, China

Mingfang Wang, Su Lin, Yinlian Wu & Jiaofeng Huang

Fujian Clinical Research Center for Liver and Intestinal Diseases, The First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China

Department of Hepatology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China

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C.T. and W.B. made the study design and wrote the paper. H.J.F. did the study design and data analysis. W.Y.L. and W.M.F. were involved in manuscript preparation and data collection. H.J.F. and C.T. constructed the tables and figures. H.J.F., W.B. and L.S. revised the final article for important intellectual content.

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Chen, T., Wan, B., Wang, M. et al. Evaluating the global, regional, and national impact of syphilis: results from the global burden of disease study 2019. Sci Rep 13 , 11386 (2023). https://doi.org/10.1038/s41598-023-38294-4

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Evidence reviews for the US Preventive Services Task Force (USPSTF) use an analytic framework to visually display the key questions that the review will address to allow the USPSTF to evaluate the effectiveness and safety of a preventive service. The questions are depicted by linkages that relate to interventions and outcomes. Further details are available from the USPSTF Procedure Manual ( https://www.uspreventiveservicestaskforce.org/uspstf/procedure-manual ).

• USPSTF Recommendation: Syphilis Screening in Nonpregnant Adolescents and Adults JAMA US Preventive Services Task Force September 27, 2022 This 2022 Recommendation Statement from the US Preventive Services Task Force recommends screening for syphilis infection in persons who are at increased risk for infection (A recommendation). US Preventive Services Task Force; Carol M. Mangione, MD, MSPH; Michael J. Barry, MD; Wanda K. Nicholson, MD, MPH, MBA; Michael Cabana, MD, MA, MPH; David Chelmow, MD; Tumaini Rucker Coker, MD, MBA; Esa M. Davis, MD, MPH; Katrina E. Donahue, MD, MPH; Carlos Roberto Jaén, MD, PhD, MS; Martha Kubik, PhD, RN; Li Li, MD, PhD, MPH; Gbenga Ogedegbe, MD, MPH; Lori Pbert, PhD; John M. Ruiz, PhD; James Stevermer, MD, MSPH; John B. Wong, MD
• The Critical Need to Modernize Syphilis Screening JAMA Editorial September 27, 2022 Susan Tuddenham, MD, MPH; Khalil G. Ghanem, MD, PhD
• Patient Information: Screening for Syphilis JAMA JAMA Patient Page September 27, 2022 This JAMA Patient Page summarizes the US Preventive Services Task Force’s recent recommendations on screening for syphilis infection in adults and adolescents who are at increased risk for syphilis infection. Jill Jin, MD, MPH
• Screening for Syphilis in Nonpregnant Adults and Adolescents JAMA Network Open Editorial September 27, 2022 Ronnie M. Gravett, MD; Jeanne Marrazzo, MD, MPH
• Resurgence of Syphilis in the US—USPSTF Reaffirms Screening Guidelines JAMA Dermatology Editorial November 1, 2022 Erin H. Amerson, MD; Herbert B. Castillo Valladares, MD, MHS; Kieron S. Leslie, MD

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Henninger ML , Bean SI , Lin JS. Screening for Syphilis Infection in Nonpregnant Adults and Adolescents : Updated Evidence Report and Systematic Review for the US Preventive Services Task Force . JAMA. 2022;328(12):1250–1252. doi:10.1001/jama.2022.8612

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Screening for Syphilis Infection in Nonpregnant Adults and Adolescents : Updated Evidence Report and Systematic Review for the US Preventive Services Task Force

• 1 Kaiser Permanente Evidence-based Practice Center, Portland, Oregon
• Editorial The Critical Need to Modernize Syphilis Screening Susan Tuddenham, MD, MPH; Khalil G. Ghanem, MD, PhD JAMA
• Editorial Screening for Syphilis in Nonpregnant Adults and Adolescents Ronnie M. Gravett, MD; Jeanne Marrazzo, MD, MPH JAMA Network Open
• Editorial Resurgence of Syphilis in the US—USPSTF Reaffirms Screening Guidelines Erin H. Amerson, MD; Herbert B. Castillo Valladares, MD, MHS; Kieron S. Leslie, MD JAMA Dermatology
• US Preventive Services Task Force USPSTF Recommendation: Syphilis Screening in Nonpregnant Adolescents and Adults US Preventive Services Task Force; Carol M. Mangione, MD, MSPH; Michael J. Barry, MD; Wanda K. Nicholson, MD, MPH, MBA; Michael Cabana, MD, MA, MPH; David Chelmow, MD; Tumaini Rucker Coker, MD, MBA; Esa M. Davis, MD, MPH; Katrina E. Donahue, MD, MPH; Carlos Roberto Jaén, MD, PhD, MS; Martha Kubik, PhD, RN; Li Li, MD, PhD, MPH; Gbenga Ogedegbe, MD, MPH; Lori Pbert, PhD; John M. Ruiz, PhD; James Stevermer, MD, MSPH; John B. Wong, MD JAMA
• JAMA Patient Page Patient Information: Screening for Syphilis Jill Jin, MD, MPH JAMA

Syphilis is a sexually transmitted infection (STI) caused by the bacterium Treponema pallidum . In 2019, the reported incidence of syphilis was 39.7 cases per 100 000 population, increasing 75% from 2015. 1

In 2016, the US Preventive Services Task Force (USPSTF) recommended screening for syphilis infection in asymptomatic, nonpregnant adults and adolescents at increased risk for syphilis infection (A recommendation). 2 High-risk groups included men who have sex with men (MSM), persons living with HIV, and persons living in communities with a high prevalence of infection. This targeted evidence update was conducted to inform the USPSTF for an updated recommendation statement and focused solely on the new evidence since the 2016 recommendation.

An analytic framework and 3 key questions (KQs) guided the evidence update ( Figure ). Detailed methods are available in the full evidence report. 3 A literature search of MEDLINE and the Cochrane Central Register of Controlled Trials was conducted from January 1, 2016, to June 3, 2021. Ongoing surveillance in targeted publications was conducted through April 6, 2022. We included studies of asymptomatic, nonpregnant adolescents and adults who were not known to have current syphilis infection. We excluded studies conducted exclusively in populations with HIV and studies conducted in low- to middle-income countries. Two investigators independently evaluated articles for inclusion criteria and quality.

A summary of the evidence is presented in the Table . A total of 2780 titles and abstracts and 40 full-text articles were screened. One fair-quality cohort study (n = 117 387) addressed the association between screening for syphilis and complications of the disease (KQ1). 4 Chow et al reported that the proportion of MSM screened annually and the mean number of tests per MSM performed annually increased between 2007 and 2014. In addition, in HIV-negative MSM, a 17% increase (from 27% of total syphilis diagnoses in 2007 to 44% in 2014) in the proportion of early latent syphilis infections was identified, as well as a 5% decrease (from 24% of total diagnoses in 2007 to 19% in 2014) in the proportion of secondary syphilis infections, suggesting an interruption of disease progression. Similar although more pronounced trends were found among HIV-positive MSM. No studies reported on other outcomes of interest, such as acquisition or transmission of other STIs or complications of tertiary syphilis or neurosyphilis.

One fair-quality study (n = 361) addressed the performance of risk assessment methods (KQ2). 5 Allan-Blitz et al developed and evaluated an online risk calculator for predicting future syphilis among high-risk individuals (eg, individuals living with HIV or who have a history of syphilis infection) seeking STI testing or treatment. The final model for predicting syphilis incidence within the next 3 months demonstrated an area under the curve of 0.69 and included the following risk factors: current HIV infection, history of syphilis infection, number of male sex partners, and receptive sex role in anal sex in the past 3 months.

One fair-quality study (n = 1097) addressed potential harms of screening for syphilis (KQ3). 6 Reynolds et al examined factors associated with emotional stress just before and after syphilis testing. Factors that were associated with stress at pretest were injection drug use, Black race, and less than a high school education. Factors associated with stress at posttest included less than a high school education and single marital status. The results suggested that emotional stress may be a common experience for individuals, although the study did not directly compare changes in levels of emotional stress pretest vs posttest.

The findings of this targeted evidence update are generally consistent with those from the prior systematic review that supported the USPSTF 2016 statement recommending screening for syphilis in at-risk adolescents and adults. Limitations of this review include that only studies in English, conducted in very high-income and high-income countries, and conducted in settings and with tests applicable to current practice in the US were included. Further research on novel screening approaches, how to best identify persons most likely to benefit from screening, and the effectiveness of specific screening intervals among different risk populations is still needed.

Accepted for Publication: May 5, 2022.

Corresponding Author: Michelle L. Henninger, PhD, Kaiser Permanente Evidence-based Practice Center, Center for Health Research, Kaiser Permanente Northwest, 3800 N Interstate Ave, Portland, OR 97227 ( [email protected] ).

Author Contributions: Dr Henninger had full access to all of the data in the study and takes full responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Henninger, Lin.

Acquisition, analysis, or interpretation of data: Henninger, Bean.

Drafting of the manuscript: Henninger, Bean.

Critical revision of the manuscript for important intellectual content: Lin.

Obtained funding: Lin.

Administrative, technical, or material support: Henninger, Bean.

Supervision: Henninger, Lin.

Conflict of Interest Disclosures: None reported.

Funding/Support: This research was funded under HHSA75Q80120D00004, Task Order 75Q80120F32001, from the Agency for Healthcare Research and Quality (AHRQ), US Department of Health and Human Services, under a contract to support the US Preventive Services Task Force (USPSTF).

Role of the Funder/Sponsor: Investigators worked with USPSTF members and AHRQ staff to develop the scope, analytic framework, and key questions for this review. AHRQ had no role in study selection, quality assessment, or synthesis. AHRQ staff provided project oversight, reviewed the report to ensure that the analysis met methodological standards, and distributed the draft for peer review. Otherwise, AHRQ had no role in the conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. The opinions expressed in this document are those of the authors and do not reflect the official position of AHRQ or the US Department of Health and Human Services.

Additional Contributions: We gratefully acknowledge the following individuals for their contributions to this project: Brandy Peaker, MD, MPH, and Tina Fan, MD, MPH (AHRQ); current and former members of the USPSTF who contributed to topic deliberations; Michael Barry, MD, Katrina Donahue, MD, MPH, Carol Mangione, MD, MSPH, Melissa Simon, MD, MPH, and James Stevermer, MD, MSPH; and Melinda Davies, MAIS, and Jill Pope, BA, for technical and editorial assistance at the Center for Health Research. The USPSTF members, peer reviewers, and federal partner reviewers did not receive financial compensation for their contributions.

Additional Information: A draft version of this evidence report underwent external peer review from 2 content experts (Kahlil Ghanem, MD, PhD, John Hopkins University; Elitza Theel, PhD, Mayo Clinic) and 4 federal partners (Centers for Disease Control and Prevention, US Food and Drug Administration, National Institute of Allergy and Infectious Diseases, and Eunice Kennedy Shriver National Institute of Child Health and Human Development). Comments were presented to the USPSTF during its deliberation of the evidence and were considered in preparing the final evidence review.

Editorial Disclaimer: This evidence report is presented as a document in support of the accompanying USPSTF recommendation statement. It did not undergo additional peer review after submission to JAMA .

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NIAID-Supported Research is Advancing the Response to Surging Syphilis Rates

NIAID Now | August 29, 2023

Colorized electron micrograph of Treponema pallidum, the bacteria that cause syphilis. Several spiral-shaped bacteria have been highlighted in gold.

Syphilis , a common sexually transmitted infection (STI) caused by the bacteria Treponema pallidum, is a centuries-old STI that can result in adult neurological and organ damage, as well as congenital abnormalities, stillbirths, and neonatal deaths. Benzathine penicillin G (BPG) was introduced as syphilis treatment in the middle of the 20 th century and led to a precipitous drop in disease burden, but T. pallidum continues to circulate in the global population, including in the United States. U.S. syphilis incidence has increased since 2000, marked by a sharp rise in reported adult and congenital cases since 2019 and, notably, an escalating toll in medically underserved populations. There is currently a shortage of BPG, which is still one of only a few antibiotics known to effectively treat syphilis. There is no preventive vaccine and most syphilis testing is done in a laboratory setting, which prevents people from learning their status conveniently and in real time. More research is urgently needed to diversify the diagnostic, preventive, and therapeutic options available to alter the course of the growing public health threat of syphilis. NIAID supports a research portfolio to help address these areas of need, including studies featured at the recent STI & HIV World Congress in Chicago.  

Updates from STI & HIV World Congress

The STI & HIV World Congress hosted presentations on new STI research, policy, and public health implementation issues, and was attended by a global community of scientists, policymakers, healthcare providers, advocates and community organizations. NIAID-supported studies and research priorities presented at the meeting included an update on syphilis vaccine development, an overview of strategies for enhanced penicillin allergy screening, exploratory research to identify new syphilis therapeutics, and the latest data and next steps to explore the utility of the antibiotic doxycycline as post-exposure prophylaxis for syphilis and other STIs —an approach commonly referred to as DoxyPEP:

• Lorenzo Giacani, Ph.D., from the University of Washington as well as Alloysius Gomez, B.Sc. and Simon Houston, Ph.D., from the University of Victoria described results from NIAID-supported syphilis vaccine studies, including preclinical (animal) research showing a vaccine containing three different antigens —a protein and peptides from the surface of T. pallidum bacteria—enabled animals to mount an immune response when they subsequently acquired syphilis, experiencing reduced severity of disease, but not full protection from infection. Dr. Houston shared how a laboratory team identified 95% of the approximately 1,000 proteins in T. pallidum . This discovery may enable scientists to select one or more of those proteins as targets for future vaccine candidates.
• Approximately 15% of people attending STI clinics report an allergy to penicillin, which prevents them from using the preferred BPG treatment. However, previous studies have shown more than 95% of people who self-reported penicillin allergy could safely use the antibiotic, according to allergy test results. Rebecca Lillis, M.D., from the Louisiana State University School of Medicine, shared a validated process for determining penicillin allergy status in an STI care setting, which would enable providers to safely clear people who previously reported penicillin allergy for use of BPG.
• Given the limited known treatments for syphilis, Virginia Tech Ph.D. candidate Kathryn Hayes presented results of a study to screen more than 100 β-lactams—antibiotics in the same class as penicillin—for their ability to kill T. pallidum bacteria or slow their growth. The team identified multiple β-lactams showing higher efficacy than BPG against T. pallidum in the laboratory, which may inform future research to develop new syphilis therapeutics.
• Multiple presenters addressed emerging NIAID-supported science on the use of DoxyPEP for STIs, including Connie Celum, M.D., M.P.H., from the University of Washington-Fred Hutch, Annie Luetkemeyer, M.D., from the University of California San Francisco, and Jenell Stewart, D.O., M.P.H., from the University of Minnesota. Presenters reviewed the high efficacy of DoxyPEP in preventing syphilis, gonorrhea, and chlamydia among men who have sex with men and transgender women, as well as the need to understand whether the lower efficacy observed in cisgender women to date may be due to lower acceptability of DoxyPEP in that population, which could pose a barrier to taking doxycycline as prescribed. Presenters underscored the need for further research and vigilance with respect to antimicrobial resistance and STI testing, the latter due to the potential for a false negative test result while someone is taking DoxyPEP.

Current and Future NIAID Syphilis Research

In addition to the latest findings presented at the conference, new and ongoing NIAID-supported studies are helping to close gaps in the current syphilis response. To address the complicated and limited diagnostic tools currently available for syphilis, a new NIAID-supported study is enrolling volunteers at all stages of infection to provide laboratory samples for a biorepository of syphilis specimens. This biorepository will safely avail high-quality syphilis specimens for laboratories to use as they create new diagnostics. A new complementary funding opportunity will advance development of promising diagnostic technologies for congenital and adult syphilis.

The new Syphilis in Pregnancy Study (SIPS) is monitoring the outcomes of pregnant people diagnosed with and treated for syphilis, as well as the health outcomes of their infants. SIPS is expected to shed light on how adult and infant immune systems respond with effective treatment. Results may inform development of future vaccine concepts that could stimulate a similar immune response when a person is initially exposed to syphilis, thereby preventing infection.

In addition, NIAID funds STI cooperative research centers (CRCs) to advance the science related to numerous STIs, including development of syphilis vaccine concepts. In their pursuit of a syphilis vaccine, the CRCs are investigating the structure of proteins on the outer membrane (layer) of T. pallidum bacteria as potential vaccine targets and developing the tri-antigen vaccine that was featured at the STI & HIV World Congress. NIAID plans to fund new CRC awards in 2024.

Finally, in recognition of the limited treatment options for syphilis, the low-but-significant prevalence of penicillin allergy, and the current drug shortage, NIAID is soliciting small business contract proposals for identification of alternatives to BPG for syphilis treatment.

Syphilis is a serious public health challenge. Scientific discovery, research and development will continue to play a critical role in enabling an equitable and effective response to the syphilis surge.

References:

C Celum. STI biomedical prevention in 2023: Doxy PEP and Beyond. Presentation at the STI & HIV 2023 World Congress in Chicago, Illinois. Wednesday, July 26, 2023.

L Giacani. State of syphilis vaccine development. Presentation at the STI & HIV 2023 World Congress in Chicago, Illinois. Tuesday, July 25, 2023.

A Gomez. Syphilis vaccine development: Generating a stable and efficacious multi-epitope vaccine chimera through protein engineering. Presentation at the STI & HIV 2023 World Congress in Chicago, Illinois. Wednesday, July 26, 2023.

KA Hayes. A large-scale drug screen identifies novel therapeutics that target the syphilis pathogen Treponema pallidum. Presentation at the STI & HIV 2023 World Congress in Chicago, Illinois. Wednesday, July 26, 2023.

S Houston. Treponema pallidum Proteomic Analysis to Inform Syphilis Vaccine Development. Presentation at the STI & HIV 2023 World Congress in Chicago, Illinois. Wednesday, July 26, 2023.

A Luetkemeyer. Doxycycline Post-exposure prophylaxis (PEP) & PrEP for Syphilis Prevention. Presentation at the STI & HIV 2023 World Congress in Chicago, Illinois. Thursday, July 27, 2023.

RA Lillis. Validation of an Easy to Administer Algorithm to Define Penicillin Allergy Status in STI Clinic Outpatients. Presentation at the STI & HIV 2023 World Congress in Chicago, Illinois. Wednesday, July 26, 2023.

J Stewart. Self-reported adherence to event-driven doxycycline postexposure prophylaxis for sexually transmitted infection prevention among cisgender women. Presentation at the STI & HIV 2023 World Congress in Chicago, Illinois. Tuesday, July 25, 2023.

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An Update on the Global Epidemiology of Syphilis

• Infectious Disease Epidemiology (A Reingold, Section Editor)
• Published: 19 February 2018
• Volume 5 , pages 24–38, ( 2018 )

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• Noah Kojima 1 &
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Purpose of Review

Syphilis continues to cause morbidity and mortality worldwide. While syphilis infection is easily identifiable and treatable, rates of syphilis infection continue to increase among select populations in high-income countries and remain at endemic levels in low- and middle-income countries.

Recent Findings

World Health Organization recommended strategies have led to the dual elimination of mother-to-child transmission of syphilis and HIV in several countries; however, outbreaks among select populations need to be adequately addressed.

Continued vigilance and investment are needed to address syphilis worldwide. The epidemiology of syphilis differs in high-, and low- and middle-income countries.

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New Caledonia was included under the France sub-section because it is a special collectivity of France in the southwest Pacific Ocean.

Papers of particular interest, published recently, and have been highlighted as: • of importance •• of major importance

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Acknowledgements

We would like to thank Mr. Maanda Mudau for comments. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the University of California Global Health Institute.

Time for literature review and manuscript preparation was supported in part by NIH/FIC D43TW009343 (Fogarty International Center of the NIH and the University of California Global Health Institute Training Program), NIH P30MH058107 (The Center for HIV Identification, Prevention, and Treatment Services), and NIH/NIAID AI028697 (UCLA Center for AIDS Research). No funding bodies had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NK is supported by the Fogarty International Center of the National Institutes of Health (NIH) under award number D43TW009343 and the University of California Global Health Institute (UCGHI).

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Kojima, N., Klausner, J.D. An Update on the Global Epidemiology of Syphilis. Curr Epidemiol Rep 5 , 24–38 (2018). https://doi.org/10.1007/s40471-018-0138-z

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A 2021 update on syphilis: taking stock from pathogenesis to vaccines.

1. Introduction

2. etiology and pathogenesis, 3. clinical manifestation, 4. diagnosis, 4.1. indirect methods.

• Biological false positive, although uncommon, must be considered during pregnancy or autoimmune illnesses as well as other infectious diseases. Currently, NTT are manually performed and several attempts to automate these tests have been described [ 42 ].
• Evaluate treatment response ( Table 3 ) Titer tends to wane over time even without treatment, but successful therapy accelerates the pace of antibody decline. A serological cure is defined as a seroconversion (from positive to negative) or as a 4-fold (or two dilutions) decline in NNT antibody titer 6 to 12 months after therapy for early syphilis and 12 to 24 months for late syphilis [ 44 ]. A 4-fold or greater titer decline is generally associated with younger age, higher baseline nontreponemal titers, and earlier syphilis stage. Treatment failure is defined as a ≥4-fold rise in nontreponemal titers after treatment in the absence of reinfection [ 44 ]. Patients correctly treated, with a ≤4-fold titer decrease and unlikely to have a new infection, are known as serological non-responders . Serofast status concerns patients with a persistently reactive NTT despite adequate treatment without seroconversion after an initial ≥4-fold decline [ 44 , 45 ].
• Evaluate reinfection An individual with a previous serological cure might be considered as “re-infected” if a new seroconversion (from negative to positive) or a 4-fold or greater increase in antibody titer occurs ( Table 3 and Table 4 ).

4.2. Direct Methods

4.3. neurosyphilis diagnosis, 4.4. syphilis reinfections diagnosis, 5. treatment, follow up after treatment, 6. syphilis prevention and vaccines, 7. conclusions, 8. research strategy and selection criteria, author contributions, institutional review board statement, informed consent statement, data availability statement, conflicts of interest.

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Share and Cite

Tiecco, G.; Degli Antoni, M.; Storti, S.; Marchese, V.; Focà, E.; Torti, C.; Castelli, F.; Quiros-Roldan, E. A 2021 Update on Syphilis: Taking Stock from Pathogenesis to Vaccines. Pathogens 2021 , 10 , 1364. https://doi.org/10.3390/pathogens10111364

Tiecco G, Degli Antoni M, Storti S, Marchese V, Focà E, Torti C, Castelli F, Quiros-Roldan E. A 2021 Update on Syphilis: Taking Stock from Pathogenesis to Vaccines. Pathogens . 2021; 10(11):1364. https://doi.org/10.3390/pathogens10111364

Tiecco, Giorgio, Melania Degli Antoni, Samuele Storti, Valentina Marchese, Emanuele Focà, Carlo Torti, Francesco Castelli, and Eugenia Quiros-Roldan. 2021. "A 2021 Update on Syphilis: Taking Stock from Pathogenesis to Vaccines" Pathogens 10, no. 11: 1364. https://doi.org/10.3390/pathogens10111364

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The U.S. Syphilis Spike Has Been Brewing for Decades

Annalies Winny

Syphilis cases in the U.S. are skyrocketing even as rates for other STIs like gonorrhea and chlamydia are flat or declining.

Alarming numbers released by the CDC are the latest marker in a decades-long rise of the disease, showing the highest case numbers since the 1950s.

From 2018 to 2022, reported cases rose 80% in the U.S . In 2022, cases of congenital syphilis among newborns were 10 times higher than in 2012, at 3,700 cases. Black and American Indian populations bear a disproportionate share of the burden—and women are making up a rising share of cases.

Left untreated, the disease can be devastating, causing serious heart and brain damage, blindness, deafness, and paralysis. Congenital cases can cause miscarriage, lifelong medical issues, and infant death.

Khalil Ghanem , MD, PhD ’08, a professor of Medicine with a joint appointment in Population, Family and Reproductive Health, discusses how the country—which just decades ago seemed on the brink of defeating syphilis—lost momentum.

How is syphilis transmitted, and what are the symptoms?

Syphilis can be transmitted through sexual contact (anal, genital, or oral), from mother to fetus, and in very rare cases, through blood transfusion or organ transplantation. Only during its early stages—around the first four months—can it be transmitted sexually, but it can be passed to a fetus at any stage.

The first clinical signs are known as primary syphilis, which usually don’t show up until two to six weeks after infection. In sexually transmitted syphilis, the first symptoms are ulcers at the site of exposure. They are generally painless, and therefore much harder to detect inside the vagina or anus than on the penis.

The immune system usually kicks in and clears those symptoms—but it doesn’t cure the disease—and eventually it escalates to secondary syphilis. At this stage, the organism is replicating very quickly and affecting many organs in the body. It can bring on fevers, skin lesions, mucosal lesions, and even hepatitis. Again, the immune system can clear these symptoms and the infection reaches its next stage: latent syphilis.

Sixty percent of people with latent syphilis will never have symptoms again. The other 40% suffer devastating complications including neurological problems, cardiovascular issues, and inflammatory masses all over the body. Overall, 10% of patients who are not treated for syphilis wind up dying from this infection.

Currently, there’s no way of knowing who will fall into what category.  

How are congenital cases different from adult cases?

It's the same [disease] process, but in a tiny person whose immune system is not yet functional.

The disease can lead to miscarriage or stillbirth, and up to 40% of babies born to women with untreated syphilis die from the infection. 

If the infant is born, early manifestations include horrifying skin peeling, enlarged liver and spleen, and impacts on the blood and central nervous system.

A newborn with syphilis may only present symptoms years later, when the disease can cause incredibly brittle bones that essentially break when the child begins to put on weight. And there’s nothing you can do about it if the disease reaches that stage without prior treatment.

Every case of congenital syphilis in this country is a black mark on public health. The reality is that a lot of pregnant patients are not seeking care until late or don’t have access to care—and the later you wait, the more likely you are to have transmission to the fetus.

How is syphilis treated?

Syphilis is a cruel disease. Left untreated, it can affect any and every organ system and evade the immune response. Penicillin and other antibiotics can cure it, but it’s essential to treat it early when the least damage has been done.

There is only one drug recommended for the treatment of uncomplicated syphilis during pregnancy: benzathine penicillin G (BPG), and we are experiencing a national shortage of it. The FDA has temporarily approved the importation and sale of the nearly identical French version of the drug to shore up supplies—but this episode highlights the country’s dependence on a single manufacturer for BPG and the dire implications when that manufacturer experiences production issues.

Why is syphilis on the rise in the U.S. now?

The syphilis rates in the U.S. started going up in 2000 and have not stopped.

Initially, this increase was mainly among men who have sex with men. Today, we have parallel epidemics in two sexual networks: one in MSM, and one among heterosexuals, which has been linked to drug use. The rise of syphilis cases among women is now surpassing the rise among men.

It’s harder to break down by region. We have good data from cities but very poor data from rural areas, where there’s less access to health care and more missed diagnoses. But there have been multiple outbreaks reported in rural areas.

What changed in 2000?

In the late 1990s, there was a belief that the U.S. was on track to beat syphilis—in 1999 we achieved the lowest rates of syphilis recorded in the country.

During that time, people were scared of HIV—it was a death sentence—and that helped change sexual behaviors. Now you can treat HIV as a chronic disease, and you can prevent it with pre-exposure prophylaxis. That has impacted sexual behavior and taken some of the pressure off of syphilis prevention overall, which has been deprioritized and underfunded.

Why hasn’t the U.S. been able to beat syphilis?

We should be able to eradicate this entirely preventable disease through the basic tenets of infection control: widespread screening, testing, finding the sexual partners of infected individuals, treating those who have the disease, and educating the public.

We have good diagnostics, we know how it’s transmitted, there’s no animal reservoir, and we know how to treat it. 

But there are wider public health challenges. Screening is inadequate: While some women get routinely tested for STIs at their annual exam, men are far less likely to get routine screenings. And because many people with syphilis have no symptoms, they won’t seek out screening. Plus, many at-risk patients don’t have access to health care, and a lot of sexual health clinics have closed over the last decade.

Also, the stigma of STIs doesn’t just happen from the patient side, it also comes from clinicians —many physicians think, “my patient doesn’t have syphilis.”

Finding patients’ partners has also become more difficult in the online dating era—partners are often identified with an online handle, not a physical location.

What’s the global picture?

Any place where you look, syphilis rates are going up. The only place that I know is seeing some declines in rates in some populations is China, which in the last 15 years had a massive outbreak in both gay and heterosexual populations. In recent years they’ve seen steady declines after spending a lot of money screening, testing, and treating the disease.

What can the U.S. learn from that? Has this outbreak drawn more attention to the issue?

I gave a talk on syphilis at a conference 10 years ago, and there were about 40 people in the room. They just reinvited me to speak at that same meeting, and there were over 700 people in the room. There is more interest because we’re seeing a lot more patients, and clinicians need to relearn how to treat them.

The one major thing that has an impact on the rate is money. The U.S. government through the CDC has had relatively flat spending on STD prevention over the last 20 years—and with inflation, that amounts to a significant decrease in spending.

The problem with public health is that when disease rates go down, we have to take the limited funds we have, and move them somewhere else.  

Annalies Winny is a writer and producer at the Johns Hopkins Bloomberg School of Public Health

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Syphilis cases rise to their highest levels since the 1950s, CDC says

Diba Mohtasham

This 1966 microscope photo made available by the Centers for Disease Control and Prevention shows a tissue sample with the presence of numerous, corkscrew-shaped, darkly-stained, Treponema pallidum spirochetes, the bacterium responsible for causing syphilis. Skip Van Orden/AP hide caption

This 1966 microscope photo made available by the Centers for Disease Control and Prevention shows a tissue sample with the presence of numerous, corkscrew-shaped, darkly-stained, Treponema pallidum spirochetes, the bacterium responsible for causing syphilis.

The number of syphilis cases in the U.S. are on the rise. According to a new report from the Centers for Disease Control and Prevention, cases increased by nearly 80% to more than 207,000 between 2018 and 2022.

Rates increased among all age groups, including newborns, and in all regions of the country. In 2022, 3,755 cases of babies born with syphilis in the U.S. were reported, which reflects an alarming 937% increase in the past decade, the CDC said .

The report continued that racial and ethnic minorities are most disproportionately affected due to "long standing social inequities that often lead to health inequalities."

Shots - Health News

Syphilis among newborns continues to rise. pregnant moms need treatment, cdc says.

Experts point to various reasons for the increase, including increases in substance abuse tied to risky sexual behavior, decrease in condom use, ongoing social and economic conditions and reduction in sexually transmitted infections (STI) services at the state and local level.

"Because STIs often do not show symptoms, and screening is necessary for timely diagnosis and treatment, changes in access to sexual health care can affect the number of infections diagnosed and reported," the CDC said .

The stigma surrounding STIs can also keep people from seeking care, and "buries the truth that all people deserve quality sexual health care," said Laura Bachmann, acting director of the CDC's Division of STD Prevention, in an interview with NPR. "It also can cause issues at the provider level when it comes to talking with people about these issues."

The CDC said that its findings signal an urgent need for a closer look at public health efforts and prevention strategies.

"Some people face tremendous barriers to STI prevention and health services," said Bachmann in a statement . "So, the most important work is often outside the clinic, whether it be reaching out to communities with testing, interviewing patients to offer services to their partners, or delivering treatment directly to someone."

She added that there is still a need for more innovation around diagnosis, treatment and prevention.

"In the United States, syphilis was close to elimination in the 1990s, so we know it's possible to reverse this epidemic," said Jonathan Mermin, director of CDC's National Center for HIV, Viral Hepatitis, STD, and TB Prevention, in a statement . "I have hope for innovative prevention tools – such as a pill after sex that prevents STIs, and better tests for syphilis – but they will only be successful if they reach the people who will benefit. And that is going to require coordinated and sustained efforts at the federal, state, and local levels."

There's an effective morning-after pill for STIs but it's not clear it works in women

The U.S Department of Health and Human Services is also continuing to address the issue through the establishment of a federal task force last year.

"Addressing the resurgence of syphilis and congenital syphilis requires a concerted effort," said Admiral Rachel Levine, assistant secretary for health and chair of the National Syphilis and Congenital Syphilis Syndemic Federal Task Force, in a statement . "We can collectively work towards reducing the incidence of syphilis and its devastating consequences, and we will turn the tide on the syphilis epidemic."

Without the appropriate funding however, it's difficult for communities to follow through with the recommendations by government officials, said Elizabeth Finley, director of communications at the National Coalition of STD Directors .

Over the past year, there has been a shortage of Bicillin , an antibiotic used to treat syphilis. In addition, last year states lost funding for STD prevention , affecting their ability to respond to syphilis.

"The 2022 data is devastating to see, but it's already a year old," said Finley. As a result, she said that "we have every reason to believe that the 2023 numbers will be much worse."

The CDC report also included data on other sexually transmitted infections, stating that "reported gonorrhea cases declined for the first time in at least a decade while reported chlamydia cases were level."

There were more than 2.5 million cases of syphilis, gonorrhea, and chlamydia reported in the U.S. in 2022 alone.

Without treatment, syphilis can cause serious health problems including damage to the heart and brain, and can cause blindness, deafness and paralysis. If transmitted during pregnancy, it can cause miscarriage, infant death and lifelong medical issues. With the right antibiotics, the STI is curable.

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Is Syphilis Curable? Learn About Treatment Options and Prevention

• Transmission

Syphilis, a sexually transmitted infection (STI) caused by the Treponema pallidum ( T. pallidum ) bacterium, is curable at all stages of infection. The antibiotic drug penicillin G is the treatment of choice, given in one or more injections, depending on whether you have primary, secondary, latent, or tertiary syphilis.

The treatment of syphilis remains crucial as infection rates continue to soar in the United States, reaching their highest level since the 1950s. This includes syphilis cases among newborns, the number of which has increased by more than tenfold from 2014 to 2024.

This photo contains content that some people may find graphic or disturbing.

Reproduced with permission from © DermNet dermnetnz.org 2023.

Understanding Syphilis Transmission

The Treponema pallidum bacterium that causes syphilis is spiral-shaped and can pass through tiny breaks in the skin or intact (unbroken) mucous membranes of the mouth, genitals, and anus.

Syphilis is mainly transmitted (passed) through oral, vaginal, or anal sex. This generally occurs when you come into contact with a syphilis sore or rash. The odds of infection from someone with early syphilis run anywhere from 51% to 64%.

Though uncommon, it is also possible to get syphilis by kissing someone who has a syphilis sore on the lip.

Another common mode of T. pallidum transmission is from a pregnant person to the fetus during pregnancy. Congenital (present at birth) syphilis mainly occurs when T. pallidum is passed to the fetus via the placenta . It can also happen during childbirth if the baby comes into contact with a syphilis sore in the vaginal canal.

Cases of syphilis have been linked to blood transfusions and organ transplants, but these are considered rare.

How Common Is Syphilis Today?

According to the Centers for Disease Control and Prevention (CDC), there were 203,500 reported cases of syphilis in the United States in 2022—an increase of nearly 80% since 2018. The number of congenital syphilis cases also rose from 1,325 in 2018 to 3,755 in 2022—an almost threefold increase over five years.

Reproduced with permission from © DermNet dermnetnz.org 2023

What Are the Symptoms Associated With Syphilis?

The symptoms of syphilis vary by the stage of infection. If left untreated, syphilis can progress through four characteristic stages—called the primary, secondary, latent, and tertiary stages—and affect multiple organ systems, often years or decades after the original infection.

Syphilis is often called the "great imitator" because the symptoms are so diverse that they can easily be mistaken for other diseases or medical conditions.

Primary Stage

Primary syphilis happens two to 12 weeks after exposure to T. pallidum. During this stage, a smooth, hard sore called a chancre will develop on your genitals, anus, or mouth. Most cases involve just a single sore, but it is possible to have more than one.

Because chancres are generally painless, you may not even know that you have the infection. This is especially true if the sore is in the vagina or anus or under the foreskin, where it may go unnoticed.

The chancre will eventually clear on its own within a few weeks or months. However, this doesn’t mean that the infection is clear; you are still highly contagious and can transmit the infection to others.

It is important to get treatment , even if your sore goes away. Left untreated, around 1 in 4 people with primary syphilis will progress to secondary syphilis.

Secondary Stage

Secondary syphilis occurs four to 10 weeks after the syphilis sore disappears, leading to the spontaneous outbreak of a bumpy, red to reddish-brown rash. The rash can cover the entire body, including the palms of your hands and the soles of your feet. The rash is usually non-itchy.

Other symptoms of secondary syphilis may include:

• Muscle aches
• Patchy hair loss
• Sore throat
• Swollen lymph nodes
• Unintended weight loss
• Wartlike skin patches

These symptoms may persist for 12 weeks or even longer before spontaneously disappearing. Even so, you are still contagious during the secondary stage and can readily transmit the infection to others.

The symptoms will resolve whether or not you get treatment, but getting treated is the only way to prevent the disease from progressing to the next stage.

Latent Stage

If syphilis is not treated during the primary or secondary stages, it can go into an extended period of low disease activity—called latency—that can last up to 20 years or longer. Although there may be no outward signs or symptoms, the disease can progressively damage your heart, bones, nerves, and other organs.

Latent syphilis is largely silent, but roughly 1 in 4 people will experience an occasional flare-up of symptoms, which can easily be mistaken for an allergy or drug reaction.

During the early-latent stage (defined as up to one year following the initial infection), you can still transmit the infection to others. Thereafter, your risk of transmission rapidly declines. After two years, it is rare for transmission to occur.

Tertiary Stage

Around 1 in 3 untreated people will progress to the most advanced stage of infection, called tertiary syphilis . Tertiary syphilis tends to develop 10 to 30 years after the initial infection by which time the heart, kidney, and other organs may be severely—and sometimes irreversibly—damaged.

While tertiary syphilis can affect any organ system, it most commonly manifests as:

• Cardiovascular syphilis : This is a complication that causes the swelling and weakening of the heart and blood vessels. Severe cases can lead to an aortic aneurysm  (swelling of the blood vessel) and rupture.
• Gummatous syphilis : This is a complication in which soft, tumor-like lesions (called gummas ) form on the skin, bones, liver, and other organs, causing major damage.
• Neurosyphilis : This is when syphilis affects the  central nervous system , causing seizures, personality changes, hallucinations,  dementia , paralysis, and even stroke.

Neurosyphilis, Ocular Syphilis, and Otosyphilis May Occur at Any Stage

Without treatment, syphilis may spread to the nervous system eyes, or ears at any stage of the disease:

• Neurosyphilis symptoms can include severe headache, muscle weakness, and changes in mental state.
• Ocular syphilis symptoms can include eye pain, red eyes, and changes in vision.
• Otosyphilis symptoms can include hearing loss, tinnitus (noises in the ear), and dizziness or vertigo (feeling like everything is spinning around you).

Congenital Syphilis

Congenital syphilis occurs when a pregnant person passes the infection to the fetus during pregnancy or the baby during childbirth. Up to half of all babies infected with syphilis die shortly before or after birth.

Most babies born with congenital syphilis have no initial symptoms and may only develop signs by the age of 2, such as:

• Failure to gain weight
• Fluid discharge from the nose
• Irritability
• Irritated, cracking skin around the mouth, anus, and genitals
• Painful leg or arm joints
• Secondary syphilis rash
• Swollen abdomen (caused by an enlarged liver or spleen)

If left untreated, congenital syphilis can lead to hearing loss, blindness, bone pain, and deformity of the nose, bones, and teeth.

A Word From Verywell

Prevention is the cornerstone of managing syphilis. Regular screening, safe sexual practices, and prompt treatment of any detected infections are essential strategies to curb the spread of this disease.

Is Syphilis Curable?

Syphilis is curable at all stages. It is far easier to treat during the early stages of infection, often with a single dose of penicillin G . During the primary, secondary, and early-latent stages, between 94.5% and 100% of treated individuals will experience complete clearance of the infection.

After that, response rates steadily decline. By late latency, a single shot of penicillin G will deliver a response (cure) rate of only 56% to 63%. Because of this, multiple doses of penicillin G are needed over several weeks to ensure a complete cure.

Early detection is key to protecting yourself and others from this widespread and increasingly complicated STI.

Due to the high rates of infection and reinfection, syphilis has begun to develop resistance to some antibiotic drugs. As a result, penicillin G is today the only antibiotic recommended by the CDC for all stages of infection.

Syphilis Treatment Options

Penicillin G is the preferred antibiotic for syphilis. Also known as penicillin G potassium or benzylpenicillin , this long-acting antibiotic is given by intramuscular (IM) injection into a large muscle.

Penicillin G is preferred over other types of penicillin because it can reach parts of the body, such as the brain and spinal cord, that other forms of penicillin cannot.

The type used in the United States is called Bicillin L-A (benzathine penicillin G). Bicillin L-A is slowly absorbed after the injection, providing antibiotic action for as long as two to four weeks.

Depending on the stage of infection, the CDC recommends penicillin G in the following dosages:

Common side effects of penicillin G include injection site pain, nausea, and diarrhea.

Alternatives to Penicillin G

Other antibiotic drugs may be used if you are allergic to penicillin, some of which are highly active against T. pallidum. These include:

• Doxycycline : 100 milligrams given orally (by mouth) once daily for 14 days
• Ceftriaxone : 1 to 2 grams given by IM or intravenous (IV) injection once daily for 10 to 15 days

Doxycycline was reported to have a response rate of between 83% and 100% in people with early syphilis, while ceftriaxone was reported to have a response rate of between 65% and 100%.

Even so, penicillin G remains the gold standard of treatment, particularly for people with tertiary syphilis. If a person with tertiary syphilis has a penicillin allergy, they should be treated in consultation with an infectious disease specialist.

Does My Sex Partner Need Treatment?

If you have been treated for syphilis (primary, secondary, or early latent), your sex partners may likely need to be treated as well. The following factors determine the decision to treat or not treat:

• Sexual contacts within the past 90 days should be treated even if their test results are negative.
• Sexual contacts made more than 90 days ago should be treated if their results are unavailable and the chances of their returning for testing are low. If their results are negative, treatment is not needed.
• Long-term sex partners of someone with late latent syphilis should be treated based on the results of syphilis testing.

Syphilis Prevention and Management

Despite ongoing public awareness campaigns, syphilis rates continue to climb in the United States. By 2023, the rate of new infections had become so high that shortages of Bicillin L-A were reported nationwide. This led to the temporary importation of an alternative form of benzathine penicillin G called Extencilline.

To help reduce the spread of syphilis and protect yourself and others from infection:

• Use condoms consistently and correctly, including for oral sex .
• Reduce your number of sex partners.
• Get tested regularly for syphilis if you are sexually active. The CDC advises that sexually active men who have sex with men and people with human immunodeficiency virus (HIV) should be screened at least once yearly.
• Ask a new or prospective sex partner to get tested.
• Get tested for syphilis during your first prenatal visit if you are pregnant.
• Advise sex partners if you get syphilis so they can get tested and treated, too.

Is Syphilis a Reportable Disease?

Syphilis is a reportable disease in every state, although reporting requirements vary. In some states, sex partners are advised by a provider, clinic, or lab; in others, public health officials are tasked with notification.

With that said, don't assume that these systems are infallible. Consider contacting your partners yourself and explaining the situation without accusation or blame. If you feel too uncomfortable or embarrassed to do so, ask your healthcare provider to notify them for you (or with you).

Syphilis is a curable sexually transmitted infection caused by the Treponema pallidum bacteria. It is mainly transmitted through oral, vaginal, or anal sex but can also be passed from pregnant person to fetus or child during pregnancy or childbirth.

Penicillin G is the treatment of choice for all stages of syphilis. Primary, secondary, and early-latent syphilis can usually be cured with one intramuscular injection. Late-latent and tertiary syphilis can usually be resolved with three intramuscular injections given over three weeks. Congenital syphilis may be treated with IV or IM penicillin for 10 days.

Sexual partners should also be tested and treated.

Centers for Disease Control and Prevention. Sexually transmitted infections treatment guidelines, 2021: syphilis .

Department of Health and Human Services. Syphilis is a public health priority .

Peeling RW, Mabey D, Kamb ML, et al. Syphilis . Nat Rev Dis Primers. 2017;3:17073. doi:10.1038/nrdp.2017.73

Stoltey JE, Cohen SE. Syphilis transmission: a review of the current evidence . Sex Health. 2015;12(2):103–109. doi:10.1071/SH14174

Yu X, Zheng H. Syphilitic chancre of the lips transmitted by kissing: a case report and review of the literature . Medicine (Baltimore). 2016;95(14):e3303. doi:10.1097/MD.0000000000003303

Centers for Disease Control and Prevention. CDC’s 2022 STI Surveillance Report underscores that STIs must be a public health priority .

Nyatsanza F, Tipple C. Syphilis: presentations in general medicine . Clin Med (Lond). 2016;16(2):184–188. doi:10.7861/clinmedicine.16-2-184

Klausner JD.  The great imitator revealed: syphilis .  Top Antivir Med.  2019;27(2):71–74.

New York State Department of Health.  Syphilis .

MedlinePlus.  Gumma .

Centers for Disease Control and Prevention. Neurosyphilis, ocular syphilis, and otosyphilis .

Mount Sinai. Congenital syphilis .

Clement ME, Okeke NL, Hicks CB. Treatment of syphilis: a systematic review . JAMA . 2014;312(18):1905–1917. doi:10.1001/jama.2014.13259

Orbe-Orihuela YC, Sánchez-Alemán MÁ, Hernández-Pliego A, Medina-García CV, Vergara-Ortega DN. Syphilis as re-emerging disease, antibiotic resistance, and vulnerable population: global systematic review and meta-analysis . Pathogens . 2022;11(12):1546. doi:10.3390/pathogens11121546

Correia de Almeida V, Donalisio MR, Cordeiro R. Factors associated with reinfection of syphilis in reference centers for sexually transmitted infections . Rev Saude Publica. 2017;51:64. doi:10.1590/S1518-8787.2017051006432

DailyMed.  Penicillin G potassium .

World Health Organization. Notes on the design of bioequivalence study: benzathine benzylpenicillin .

Centers for Disease Control and Prevention. Sexually transmitted infections treatment guidelines, 2021: tertiary syphilis .

Centers for Disease Control and Prevention. Sexually transmitted infections treatment guidelines, 2021: latent syphilis .

Centers for Disease Control and Prevention. Sexually transmitted infections treatment guidelines, 2021: primary & secondary syphilis .

California Department of Public Health. Special considerations for the treatment of syphilis using alternative therapies in non-pregnant persons .

Centers for Disease Control and Prevention. Screening recommendations and considerations are referenced in treatment guidelines and original sources .

Centers for Disease Control and Prevention. Reporting and confidentiality .

By James Myhre & Dennis Sifris, MD Dr. Sifris is an HIV specialist and Medical Director of LifeSense Disease Management. Myhre is a journalist and HIV educator.

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Rosanna W. Peeling

1 London School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT, UK

David Mabey

Mary l. kamb.

2 Division of STD Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia, USA

Xiang-Sheng Chen

3 National Center for STD Control, Chinese Academy of Medical Sciences and Peking Union Medical College Institute of Dermatology, Nanjing, China

Justin David Radolf

4 Department of Medicine, UConn Health, Farmington, Connecticut, USA

Adele Schwartz Benzaken

5 Department of Surveillance, Prevention and Control of STI, HIV/AIDS and Viral Hepatitis, Ministry of Health, Brasília, Brazil

Treponema pallidum subspecies pallidum ( T. pallidum ) causes syphilis via sexual exposure or vertical transmission during pregnancy . T. pallidum is renowned for its invasiveness and immune-evasiveness; its clinical manifestations result from local inflammatory responses to replicating spirochetes and often imitate those of other diseases. The spirochete has a long latent period during which patients have no signs or symptoms, but can remain infectious. Despite the availability of simple diagnostic tests and the effectiveness of treatment with a single dose of long-acting penicillin, syphilis is re-emerging as a global public health problem, particularly among men who have sex with men (MSM) in high-income and middle-income countries. Syphilis also causes several hundred thousand stillbirths and neonatal deaths every year in developing nations. Although several low-income countries have achieved WHO targets for the elimination of congenital syphilis, an alarming increase of syphilis in HIV-infected MSM serves as a strong reminder of the tenacity of T. pallidum as a pathogen. Strong advocacy and community involvement is needed to ensure that syphilis is given high priority on the global health agenda. More investment in research is needed on the interaction between HIV and syphilis in MSM, as well as into improved diagnostics, a better test of cure, intensified public health measures and, ultimately, a vaccine.

Introduction

Syphilis is a sexually and vertically transmitted infection (STI) caused by the spirochaete Treponema pallidum subspecies pallidum (order Spirochaetales) ( Fig. 1 ). Three other organisms within this genus are causes of nonvenereal or endemic treponematoses. T. pallidum subspecies pertenue is the causative agent of yaws, T. pallidum subspecies endemicum causes endemic (non-venereal) syphilis and T. carateum causes pinta. These pathogens are morphologically and antigenically indistinguishable. They can, however, be differentiated by their age of acquisition, principal mode of transmission, clinical manifestations, capacity for invasion of the central nervous system and placenta, and genomic sequences, although the accuracy of these differences remains a subject of debate 1 . Analyses based on the mutation rates of genomic sequences suggest that the causative agents of yaws and venereal syphilis diverged several thousand years ago from a common progenitor originating in Africa 2 . These estimates argue against the so-called Columbian hypothesis — the notion that shipmates of Christopher Columbus imported a newly evolved spirochete causing venereal syphilis from the New World into Western Europe in the late 15 th century 3 .

A | Like all spirochetes, T. pallidum consists of a protoplasmic cylinder and cytoplasmic membrane bounded by a thin peptidoglycan sacculus and outer membrane 239 , 240 . Usually described as spiral-shaped, T. pallidum is actually a thin planar wave similar to Borrelia burgdorferi , the agent of Lyme borreliosis 239 . The bacterium replicates slowly and poorly tolerates desiccation, elevated temperatures and high oxygen tensions 55 . B | Periplasmic flagellar filaments, a defining morphological feature of spirochetes, originate from nanomotors situated at each pole and wind around the cylinder atop the peptidoglycan, overlapping at mid-cell. Force exerted by the rigid filaments against the elastic peptidoglycan deforms the sacculus to create the flat wave morphology of the spirochete 100 . Panel B used with permission from Ref. 239 C | Ultra-thin section of T. pallidum showing the outer and cytoplasmic membranes and flagellar filaments (endoflagella) within the periplasmic space 9 . D | Surface rendering of a flagellar motor based on cryoelectron tomograms. Panel D used permission from Ref. 240 . E | Darkfield micrograph showing the flat-wave morphology of Tpallidum . The arrow and arrowhead indicate segments that are oriented 90° from each other. The different appearances of the helical wave at 90° to the viewer can be explained only by a flat wave morphology; a corkscrew would appear the same from any angle. Panel E used permission from Ref 239 .

T. pallidum is an obligate human pathogen renowned for its invasiveness and immunoevasiveness 4 – 7 ; clinical manifestations result from the local inflammatory response elicited by spirochetes replicating within tissues 8 – 10 . Infected individuals typically follow a disease course divided into primary, secondary, latent and tertiary stages over a period of ≥10 years. Different guidelines define early latency as starting 1–2 years after exposure. Typically, ‘early syphilis’ refers to infections that can be transmitted sexually (including primary, secondary and early latent infections) and is synonymous with active (infectious) syphilis; the WHO defines ‘early syphilis’ as infection of <2 years duration 11 , whereas the guidelines from the United States 12 and Europe 13 define it as infection <1 year in duration. These differences in definition can affect interpretation of results and in therapeutic regimens used in some circumstances.

Owing to its varied and often subtle manifestations that can mimic other infections, syphilis has earned the names of the Great Imitator or Great Mimicker 14 . Patients with primary syphilis present with a single ulcer (chancre) or multiple lesions on the genitals or other body sites involved in sexual contact and regional lymphadenopathy ~3 weeks post-infection; these are typically painless and resolve spontaneously. Resolution of primary lesions is followed 6–8 weeks later by secondary manifestations, which can include fever, headache and a maculopapular rash on the flank, shoulders, arm, chest or back and that often involves the palms of the hands and soles of the feet. As signs and symptoms subside, patients enter a latent phase, which can last many years. A patient in the first 1–2 years of latency are still considered infectious owing to a 25% risk of secondary syphilis-like relapses 15 . Historical literature suggests that 15–40% of untreated individuals will develop tertiary syphilis, which can manifest as destructive cardiac or neurological conditions, severe skin or visceral lesions (gummas) or bony involvement 9 . More-recent data suggest tertiary syphilis may be less common today, perhaps owing to wide use of antibiotics. Numerous case reports and small series suggest that HIV infection predisposes to neuro-ophthalmological complications in those with syphilis 16 . Importantly, neurosyphilis is typically described as a late manifestation but can occur in early syphilis. Indeed, T. pallidum can be frequently identified in the cerebral spinal fluid (CSF) of patients with early disease 9 , 15 , 17 . However, the majority of patients with early syphilis who have CSF abnormalities do not demonstrate central nervous system symptoms and do not require therapy for neurosyphilis 12 . Symptomatic manifestations of neurosyphilis include chronic meningitis, meningovascular stroke-like syndromes and manifestations common in the neurological forms of tertiary syphilis (namely, tabes dorsalis and general paresis, a progressive dementia mimicking a variety of psychotic syndromes) 9 .

Sexual transmission of syphilis occurs during the first 1–2 years after exposure (that is, during primary, secondary and early latent stages of infection) 9 . The risk of mother-to-child transmission (MTCT) is highest in primary and secondary stages, followed by early latent syphilis. However, transmission risk continues during the first 4 years after exposure, after which vertical transmission risk declines over time 18 . The rate of fetal infection depends on stage of maternal infection, with approximately 30% of pregnancies resulting in fetal death in utero , stillbirth (late second and third trimester fetal death) or death shortly after delivery 19 – 21 . Infants born to infected mothers are often preterm, of low birth weight or with clinical signs that mimic neonatal sepsis (that is, poor feeding, lethargy, rash, jaundice, hepatosplenomegaly and anaemia).

Given that T. pallidum has a relatively long generation time of 30–33 hours 22 , long-acting penicillin preparations such as benzathine penicillin G is the preferred therapy for most patients with syphilis. Since the 1940s (when penicillin became widely available), syphilis prevalence continued decline in regions able to appropriately test and treat the infection. However, syphilis outbreaks continue to occur throughout the world. In particular, with declining AIDS-related mortality related to effective HIV treatment over the past two decades, syphilis has re-emerged in urban settings among men who have sex with men (MSM). High-income and middle-income countries have observed rises in syphilis case rates as well as increased case rates of neurosyphilis (such as ocular syphilis) and, in some countries, congenital syphilis. In low income countries where syphilis prevalence remains high, MTCT of syphilis continues to be the most common cause of STI-related mortality outside of HIV 23 , 24 , with perinatal deaths owing to untreated syphilis exceeding those of HIV or malaria 25 . Syphilis is now the second leading cause of preventable stillbirths worldwide, following malaria 25 .

Syphilis should be an ideal disease for elimination as it has no known animal reservoir, can usually be diagnosed with simple inexpensive tests and can be cured 9 , 16 . Nevertheless, syphilis remains a continuing public health challenge globally 26 . In this Primer, we describe recent discoveries that have improved our understanding of the biological and genetic structure of the pathogen, novel diagnostic tests and testing approaches that can improve disease detection, as well as current, evidence-based management recommendations. We also draw attention to the call for global elimination of MTCT of syphilis and HIV and recent success in elimination in in low and middle income countries (LMICs), particularly through fundamental public health strategies such as ensuring quality antenatal care that includes testing for syphilis early in pregnancy and providing prompt treatment of women and their partners. We also report on the rising numbers of syphilis cases in MSM, ongoing work supporting improved interventions against syphilis in marginalized populations and, ultimately, development of an effective vaccine.

Epidemiology

According to the most recent estimation of the WHO, approximately 17.7 million individuals 15–49 years of age globally had syphilis in 2012, with an estimated 5.6 million new cases every year 27 ( Fig. 2 ). The estimated prevalence and incidence of syphilis varied substantially by region or country, with the highest prevalence in Africa and >60% of new cases occurring in LMICs 27 . The greatest burden of maternal syphilis occurs in Africa, representing >60% of the global estimate 23 , 24 .

The WHO estimates of incident cases of syphilis by region in 2012 are shown for the different geographical regions. Data from Ref. 27

Prevalence and incidence

In LMICs, heterosexual spread of syphilis has declined in the general population but remains problematic in some high-risk sub-populations, such as female sex workers (FSWs) and their male clients. A recent study of FSWs in Johannesburg, South Africa, showed that 21% of participating women had antibodies that suggested past or current infection and 3% had active (infectious) infection 28 . Another study of FSWs in 14 zones in Sudan showed high seroprevalence (median 4.1%), with the highest value of 8.9% in the eastern zone of the country 29 . A large study of >1,000 FSWs in Kampala, Uganda, showed 21% were seropositive for syphilis and 10% had active infection 30 . Studies in emerging economies, such as China, indicate that syphilis is increasing among ‘mobile men with money’ 31 . Although syphilis case rates are low in the general population in China, syphilis prevalence is ~5% among FSWs and 3% among their male clients 31 , 32 . Risk of infection varies among FSWs working in different venues, with the highest prevalence (~10%) among street-based FSWs and lower prevalence (~2%) among venue-based FSWs 33 .

By contrast, higher-income countries have had declining syphilis prevalence among heterosexual men and women. However, a resurgence of syphilis that disproportionately affects MSM has been noted. Syphilis is associated with high-risk sexual behaviours and substantially increased HIV transmission and acquisition. Indeed, the numbers and rates of reported cases of syphilis among MSM in the United States and Western Europe have been increasing since 1998 (Ref. 34 ). In 2015, the case rates for primary and secondary syphilis among MSM (309 per 100,000) in the United States were 221-times the rate for women (1.4 per 100,000) and 106 times the rate for heterosexual men (2.9 per 100,000) 35 . In Canada, compared with reported cases in the general male population, the incidence of syphilis was >300-times greater among HIV-positive MSM 36 . Syphilis infection has been associated with certain behavioural and other factors, including incarceration; multiple or anonymous sex partners; sexual activity connected with illicit drug use; seeking sex partners through the internet and other high-risk sexual network dynamics 37 – 41 . Risk factors for syphilis are frequently overlapping 40 . Reports of unusual presentations and rapid progression of syphilis in patients with concurrent HIV infection has led to the hypothesis that infection with or treatment for HIV alters the natural history of syphilis 42 .

Adverse birth outcomes caused by fetal exposure to syphilis are preventable if women are screened for syphilis and treated before the end of the second trimester of pregnancy 21 . However, MTCT of syphilis continued to cause such perinatal and infant mortality that, in 2007, the WHO and partners launched a global initiative to eliminate it as a public health problem 43 – 45 . At the time of the campaign launch, an estimated 1.4 million pregnant women had active syphilis infections, of whom 80% had attended at least one antenatal visit — suggesting missed opportunities for testing and treatment 23 . At that time, untreated maternal syphilis infection was estimated to have resulted in >500,000 adverse pregnancy outcomes, including more than 300,000 perinatal deaths (stillbirths and early neonatal deaths).

Syphilis testing and treatment during pregnancy is highly effective and was included in the Lives Saved Tools of effective maternal–child health interventions 46 . Furthermore, studies have shown that prenatal syphilis screening, treatment support testing and treatment during pregnancy are highly cost-effective in most countries regardless of prevalence or availability of resources, and can even be cost-saving in LMICs with syphilis prevalence ≥3% in pregnant women 47 – 50 . In China, where syphilis and HIV prevalence in pregnant women is low but rising, integration of prenatal syphilis and HIV screening was found to be highly cost-effective 51 .

Since 2007, an increasing number of countries have implemented regional and national initiatives to prevent MTCT of syphilis 52 , improving guidance documents, using point-of-care (POC) tests as a means of improving access to testing and treatment and integrating behavioural and medical interventions into HIV prevention and control programmes 53 . By 2012, these efforts had contributed to a reduction in global adverse pregnancy outcomes due to MTCT of syphilis to 350,000, including 210,000 perinatal deaths, and decreased the rates of maternal and congenital syphilis decreased by 38% and 39%, respectively 23 , 24 . In 2015, Cuba became the first country to be validated for having achieved elimination of MTCT of HIV and syphilis 54 . Subsequently, Thailand, Belarus and four United Kingdom Overseas Territories (Bermuda, the Cayman Islands, Montserrat and Antigua) was validated for elimination of MTCT of HIV and syphilis, Moldova was validated for elimination of MTCT of syphilis, and Armenia was validated for elimination of MTCT of HIV. However, these gains were mostly in Asia and the Americas — maternal prevalence in Africa has remained largely unchanged 23 , 24 .

Mechanisms/pathophysiology

Although a local inflammatory response elicited by spirochetes is thought to be the root cause of all clinical manifestations of syphilis 9 , the mechanisms that cause tissue damage, as well as the host defences that eventually gain a measure of control over the bacterium, are ill defined. The recalcitrance of T. pallidum to in vitro culture and the consequent inability to harness genetic techniques to delineate its virulence determinants remains the primary obstacle to progress 55 . Additionally, the fragility and low protein content of its outer membrane have confounded efforts to characterize surface-exposed molecules 56 , 57 . Finally, facile murine models to dissect the host response and the components of protective immunity are also lacking 58 . Outbred rabbits are essential for isolating T. pallidum strains from clinical specimens 59 and routine propagation in the laboratory 60 . Because rabbits are highly susceptible to T. pallidum infection, develop lesions grossly and histopathologically resembling chancres following intradermal inoculation and generate antibody responses similar to those in humans, the rabbit is the model of choice for studying endogenous and exogenous protective immunity 61 , 62 . However, the rabbit model poorly recapitulates many clinical and immunological facets of human disease 63 . Not surprisingly, even in the post-genomics era, our understanding of pathogenic mechanisms in syphilis lags well behind other common bacterial diseases 63 .

Molecular Features

The morphological features of T. pallidum are described in Figure 1 . Because of its double-membrane structure, the spirochete is often described as a Gram-negative bacterium. However, this analogy is phylogenetically, biochemically and ultrastructurally inaccurate 63 , 64 . The T. pallidum outer membrane lacks lipopolysaccharide 65 and has a markedly different phospholipid composition than the outer membranes of typical Gram-negative bacteria 66 . Although T. pallidum expresses abundant lipoproteins, these molecules reside predominantly below the surface 5 , 63 , 67 . Accordingly, this paucity of surface-exposed pathogen-associated molecular patterns (PAMPs) enables the spirochete to avoid triggering host innate surveillance mechanisms, facilitating local replication and early dissemination. Its limited surface antigenicity promotes evasion of adaptive immune responses (that is, antibodies), facilitating persistence 5 , 56 , 68 , 69 . Collectively, these attributes have earned T. pallidum its designation as ‘the stealth pathogen’ 63 , 69 . Understanding events unfolding at the host–pathogen interface requires a detailed knowledge of the T. pallidum repertoire of surface-exposed proteins. However, characterization of the protein constituents of the outer membrane has been, and continues to be, daunting 8 , 55 , 57 , 63 .

Lipoproteins

In the 1980s, investigators screened E. coli recombinant libraries with syphilitic sera and murine monoclonal antibodies based upon the unproven (and, as it turned out, immunologically incorrect) assumption that immunoreactive proteins ought to be surface-exposed in T. pallidum 57 . Biochemical and genetic analyses subsequently revealed that most of the antigens identified by these screens are lipoproteins 70 – 72 tethered by their N-terminal lipids to the cytoplasmic membrane (hence, the protein moieties are in the periplasmic space) 67 , 73 – 75 . However, convincing evidence now shows that the spirochete displays small amounts of lipoproteins on its surface that have the potential to enhance infectivity ( Fig. 3 ). For example, TP0751 (also known as pallilysin) is a laminin-binding lipoprotein and zinc-dependent metalloproteinase capable of degrading clots and extracellular matrix 76 – 78 . Although expressed by T. pallidum in minute quantities, surface exposure of TP0751 has been demonstrated by knock-in experiments in Borrelia burgdorferi (the spirochete that causes Lyme borreliosis 79 ), and the cultivatable commensal treponeme T. phagedenis 80 , opsonophagocytosis assays in T. pallidum 77 and, most recently, protection of immunized rabbits against dissemination of spirochetes following intradermal challenge 81 . The X-ray structure of TP0751, demonstrating an unusual lipocalin fold, should inform efforts to clarify its multi-functionality 79 . Additionally, the lipoprotein Tpp17 (also known as TP0435) has been shown to be at least partially surface-exposed and can function as a cytadhesin 82 . The structurally characterized lipoprotein TP0453 attaches to the inner leaflet of the outer membrane via its N-terminal lipids and two amphipathic helices within its protein moiety 83 .

Shown in the outer membrane are TP0751 (as known as pallilysin) 79 , 81 and Tpp17 (also known as TP0435) 82 , 241 — two surface-exposed lipoproteins; TP0453, a lipoprotein attached to the inner leaflet of the outer membrane 83 ; BamA (also known as TP0326) 84 , 94 ; a full-length T. pallidum repeat (Tpr) attached by its N-terminal portion to the peptidoglycan 93 , 94 ; and a generic β-barrel that represents other non-Tpr outer-membrane proteins identified by computational mining of the T. pallidum genome 112 . Substrates and nutrients present in high concentration in the extracellular milieu (such as, glucose) traverse the outer membrane through porins, such as TprC. At the cytoplasmic membrane, prototypic ABC-like transporters (such as RfuABCD, a riboflavin transporter) use a periplasmic substrate-binding protein (SBP), usually lipoproteins, and components with transmembrane and ATP-binding domains to bind nutrients that have traversed the outer membrane for transport across the cytoplasmic membrane. The energy coupling factor (ECF)-type ABC transporters use a transmembrane ligand-binding protein in place of a separate periplasmic SBP for binding of ligands (BioMNY is thought to transport biotin) 242 . Symporter permeases (for example, TP0265) use the chemiosmotic or electrochemical gradient across the cytoplasmic membrane to drive substrate transport 243 . The tripartite ATP-independent periplasmic (TRAP)-type transporters also use transmembrane electrochemical gradients to drive substrate transport; the periplasmic component protein TatT (also known as TP0956) likely associates with the SBP TatP (also known as TP0957) that binds ligands (perhaps hydrophobic molecules, such as long chain fatty acids), uptake of which is probably is facilitated by the permease TatQ-M (also known as TP0958) 244 , 245 . Figure adapted from Ref. 63 with permission.

With the publication of the T. pallidum genome in 1998 (Ref. 65 ), only one protein with sequence relatedness to an outer membrane protein of Gram-negative bacteria was identified: TP0326 (also known as β-barrel assembly machinery A; BamA) 84 , 85 . BamA has a dual domain architecture consisting of a 16-stranded, outer membrane-inserted, C-terminal β-barrel and five tandem polypeptide transport-associated (POTRA) repeats within the periplasm 84 , 85 . The opening of the channel is covered by a ‘dome’ comprising three extracellular loops, one of which contains an opsonic target that is sequence variable among T. pallidum strains 85 . BamA is the essential central component of the molecular machine that catalyses insertion of newly exported outer membrane proteins to the outer membrane 86 .

Tpr proteins

The T. pallidum repeat (Tpr) proteins, a 12-member paralogous family with sequence homology to the major outer sheath protein of the oral commensal T. denticola, were also identified by the T. pallidum genomic sequence 65 . Of these, TprK (TP0897) has received the greatest attention because of its presumed role in immune evasion by the spirochete 87 , 88 ; it has been shown to undergo antigenic variation in seven regions believed to be extracellular loops harbouring B-cell epitopes 89 – 92 . DNA sequence cassettes that correspond to V-region sequences in an area of the T. pallidum chromosome located away from the tprK gene have been proposed to serve as unidirectional donor sites for the generation of variable regions by nonreciprocal gene conversion 89 . Two other Tpr proteins, TprC and TprI, have met stringent experimental criteria for rare outer membrane proteins. They form trimeric β-barrels when refolded in vitro , cause large increases in permeability upon insertion into liposomes and are surface-exposed opsonic targets in T. pallidum 93 , 94 . Unlike classic porins, for which the entire polypeptide forms a β-barrel, TprC and TprI are bipartite. As with BamA, the C-terminal domain forms the surface-exposed β-barrel, whereas the N-terminal half anchors the barrel to the peptidoglycan sacculus. These results collectively imply that Tprs serve as functional orthologs of Gram-negative porins, using variations in substrate specificities of their channel-forming β-barrels, probably along with differential expression, to import the spirochete’s nutritional requirements into the periplasmic space from blood and body fluids 95 , 96 . These proteins also furnish a topological template for efforts to understand how antibody responses to Tprs promote bacterial clearance.

Biosynthetic machinery

T. pallidum has evolved to dispense with a vast amount of the biosynthetic machinery found in other bacterial pathogens 55 , 63 – 65 . To compensate for its loss of biosynthetic capacity, the spirochete maintains a complex assortment of ABC transporters and symporters (totalling ~5% of its 1.14 MB circular genome) to transfer the broad spectrum of molecules essential for viability from periplasm to cytosol ( Fig. 3 ). T. pallidum relies on an optimized conventional glycolytic pathway as its primary means for generating ATP. By dispensing with oxidative phosphorylation, the spirochete has no need for cytochromes and the iron required to synthesize them. Accordingly, the spirochete maintains a complex, yet parsimonious, assortment of ABC transporters and symporters (totalling ~5% of its 1.14 MB circular genome) to transfer essential molecules from the periplasmic space to the cytosol ( Fig. 3 ). Whereas many pathogens have highly redundant systems for uptake of transition metals across the cytoplasmic membrane, T. pallidum accomplishes this task with just two ABC transporters (Tro, which imports zinc, manganese and iron, and Znu, which is zinc-specific). A small, but powerful arsenal of enzymes neutralize superoxides and peroxides to fend off host responses to infection. Lastly, the spirochete possesses novel and surprisingly intricate mechanisms ostensibly to redirect transcription and fine-tune metabolism in response to environmental cues and nutrient flux 63 .

Transmission and dissemination

Transmission of venereal syphilis occurs during sexual contact with an actively infected partner; exudate containing as few as 10 organisms can transmit disease 8 , 68 . Spirochetes directly penetrate mucous membranes or enter through abrasions in skin, which is less heavily keratinized in peri-genital and peri-anal areas than skin elsewhere 8 , 68 . To establish infection, T. pallidum must adhere to epithelial cells and extracellular matrix components; in vitro binding studies suggest that fibronectin and laminin are key substrates for these interaction 76 , 97 – 99 . Once below the epithelium, organisms multiply locally and begin to disseminate through the lymphatics and bloodstream. Spirochetes penetrate extracellular matrix and intercellular junctions by ‘stop and go’ movements that coordinate adherence with motility, powered by front-to-back undulating waves generated by flagellar rotation and presumably assisted by the proteolytic activity of TP0751 77 , 100 . Ex vivo studies using cultured human umbilical vein endothelial cells ( Fig. 4A ) suggest that spirochetes invade tissues using direct motility to negotiate their way through intercellular junctions, so-called inter-junctional penetration 7 , 101 . The infection rapidly becomes systemic 9 , 16 , 100 . Profuse spirochetes within the epidermis and superficial dermis in secondary syphilitic lesions ( Fig. 4B ) enable tiny abrasions created during sexual activity to transmit infection 10 , 102 . Penetration of the blood–brain barrier, occurring in as many as 40% of individuals with untreated early syphilis, can cause devastating neurological complications 9 , 16 .

A | Transmission electron micrograph of T. pallidum (arrowheads) penetrating the junctions between cultured umbilical vein endothelial cells. ‘Inter-junctional invasion’ following attachment to vascular endothelium is thought to provide T. pallidum access to tissue parenchyma during haematogenous dissemination. Reprinted with permission from Reference 101 . B | Immunohistochemical staining (using commercial anti- T. pallidum antibodies) of a secondary syphilis skin lesion reveals abundant spirochetes embedded within a mixed cellular inflammatory infiltrate in the papillary dermis. The inflammatory response elicited by spirochetes replicating in tissues is widely thought to be the cause of clinical manifestations in all stages of syphilis. Reprinted with permission from 10 . C | Human syphilitic serum (HSS) dramatically enhances opsonophagocytosis of T. pallidum by purified human peripheral blood monocytes compared with D | normal human serum (NHS). Arrowheads indicate treponemes being degraded within phagolysosomes.

Adaptive immune response and inflammation

Although the paucity of PAMPs in the T. pallidum outer membrane enables the bacterium to replicate locally and undergo repeated bouts of dissemination, pathogen sensing in the host is eventually triggered. The organisms are taken up by dendritic cells 103 , which then traffic to draining lymph nodes to present cognate treponemal antigens to naive B cells and T cells. The production of opsonic antibodies markedly enhances the uptake and degradation of spirochetes by phagocytes ( Fig. 4C,D ), liberating lipopeptides and other PAMPs for binding to Toll-like receptors lining the interior of the phagosome and antigenic peptides for presentation to locally recruited T cells 62 , 104 , 105 . Activated lesional T cells secrete IFN-γ, promoting clearance by macrophages, but also bolstering the production of tissue-damaging cytokines, such as tumor necrosis factor (TNF) and IL-6 10 , 106 , 107 . Immunohistochemical analysis has identified CD4+ and CD8+ T cells 10 , 106 , 108 , 109 , natural killer cells 10 and activated macrophages in early syphilis lesions 10 , 109 . Perivascular infiltration of lymphocytes, histiocytes (phagocytic cells in connective tissues) and plasma cells with endothelial cell swelling and proliferation are characteristic histopathological findings in all stages of syphilis and can progress to frank endarteritis obliterans (leading to occlusion of arteries and severe clinical manifestations, such as the stroke syndromes of meningovascular syphilis) 9 , 110 .

Antibody avoidance

T. pallidum is widely regarded as an extracellular bacterium 61 . Thus, a question of paramount importance is why, unlike ‘classic’ extracellular pathogens, syphilis spirochetes not only fail to be cleared rapidly but can replicate and circulate in the midst of a prolific antibody response 8 , 68 , 69 . Immunolabelling, opsonophagocytosis, and complement-dependent neutralization assays have shown that T. pallidum populations consist of antibody-binding and non-binding subpopulations; the minority of organisms that bind antibodies do so in minute amounts and with delayed kinetics 10 , 111 – 114 . Accordingly, one can envision a scenario whereby nonbinders replenish the spirochetes that bind and are cleared 63 .

Understanding the basis for the heterogeneity of T. pallidum ’s surface antigenicity is critical to unravelling its strategy for antibody avoidance. The picture emerging from our evolving concepts of the spirochete’s molecular architecture is multi-factorial and likely involves copious production of antibodies against subsurface lipoprotein ‘decoys’ 57 , 110 ; poor target availability owing to low copy numbers of outer membrane proteins and surface-exposed lipoproteins 67 , 77 , 82 , 84 , 93 ; in the case of bipartite outer membrane proteins, limited production of antibodies against surface-exposed epitopes along with skewed production of antibodies against periplasmic domain 84 , 93 ; organism-to-organism variation in the levels of expression of outer membrane proteins and outer surface lipoproteins through a variety of mechanisms, including phase variation 82 , 92 , 115 , 116 ; and, in the case of TprK, antigenic variation as a result of intra-genomic recombination 89 , 92 , 117 . Additionally, the ability of motile spirochetes to ‘outrun’ infiltrating phagocytes and reach sequestered locations, including the epidermis, could be an under-appreciated aspect of immune evasion 10 , 102 . As infection proceeds, the antibody repertoire possibly broadens and intensifies to the point where the antigen-poor surface of the spirochete is overwhelmed and its capacity for antigenic variation is exhausted, ushering in the asymptomatic period called latency. Once in the latent state, the organism can survive for years in untreated individuals, establishing niduses of inflammation in skin, bones, the thoracic aorta, the posterior uveal tract and the central nervous system, that set the stage for recrudescent disease — collectively referred to as tertiary syphilis. How immune containment mechanisms decline and enable the balance to shift back in favour of the pathogen in tertiary syphilis is inclear 9 , although a hyper-intense cellular response to the spirochete is generally believed to be the cause of the highly destructive lesions of tertiary syphilis 9 . Numerous case reports and small series suggest that HIV infection predisposes to neuro-ophthalmological complications in those with syphilis 16 . Cardiovascular syphilis, typically involving the aortic arch and leading to aneurysmal dilatation, usually occurs 10–30 years after the initial infection 9 .

Congenital infection

Although MTCT of syphilis can occur at the time of delivery, the overwhelming majority of cases are caused by to in utero transmission. Studies have shown spirochetes in placenta and umbilical cord samples, supporting transplacental passage of the organism to the fetus, as early as 9–10 weeks of gestation 118 . Although fetal syphilis infection was not thought to occur prior to the second trimester, the fetus can indeed be infected very early in pregnancy but may be unable to mount a characteristic immune response until development of the embryonic immune system at 18–20 weeks gestation.

Transmission risk is directly related to stage of syphilis in the pregnant woman (that is, the extent and duration of fetal exposure to spirochetes). Small case series have found highest MTCT risk in primary and secondary stages, during which transmission probability may be ≥80%. In latent (asymptomatic) infections during pregnancy, probability of transmission to the fetus is highest during the first 4 years after infection, after which risk declines 18 , 45 . Systematic reviews assessing women with predominantly asymptomatic infections are consistent in showing that delayed or lack of adequate treatment results in stillbirth, early neonatal death, prematurity, low birth weight or congenital infection in infants (more than half of syphilis-exposed pregnancies); syphilitic stillbirth was the most commonly observed adverse outcomes in syphilis-exposed pregnancies 21 , 45 , 119 .

Diagnosis, screening and prevention

Syphilis has varied and often subtle manifestations that make clinical diagnosis difficult and lead to many infections being unrecognized. The classically painless lesions of primary syphilis can be missed, especially in hidden sites of exposure such as the cervix or rectum. The rash ( Fig. 5 ) and other symptoms of secondary syphilis can be faint or mistaken for other conditions. A syphilis diagnosis is often based on a suggestive clinical history and supportive laboratory 9 , 16 (that is, serodiagnostic) tests. Serological testing has become the most common means to diagnose syphilis whether in people with symptoms of syphilis, or in those who have no symptoms but are detected through screening. A limitation of all syphilis serological tests is their inability to distinguish between infection with T. pallidum subsp. pallidum and the non-venereal T. pallidum subspecies that cause yaws, pinta or bejel.

A | Primary chancre. B | Primary chancre with rash of secondary syphilis. C | Secondary syphilis in a pregnant woman, who has palmar rash. D | Secondary syphilis as palmar rash. E | 3-month old baby with congenital syphilis, showing hepatosplenomegaly and desquamating rash. The child also presented with nasal discharge. F | Typical palmar desquamating rash in baby with congenital syphilis.

Ensuring accuracy and reliability of syphilis testing is important, especially in nonspecialized laboratories where most patients are tested 120 . Syphilis-specific quality assurance strategies include training of technologists on specific techniques, internal quality control systems; test evaluation; and interassay standardization of commercially available test kits on a regular basis 37 , 120 . It is especially important to provide adequate training and regular external quality assessment or proficiency testing with corrective action to ensure the quality of tests and testing for health care providers who perform rapid tests in clinic based or outreach settings 121 – 124 . Because many parts of the world lack laboratory capacity for accurate diagnosis, the requirement for laboratory testing has greatly constrained syphilis control and congenital syphilis elimination. However, development of inexpensive rapid tests that can be performed at the POC has greatly increased access to prenatal screening and diagnosis, even in low-resourced and remote settings.

Definitive diagnosis by direct detection

The choice of method for diagnosing syphilis depends on the stage of disease and the clinical presentation 125 . In patients presenting with primary syphilitic ulcers, condyloma lata (genital lesions of secondary syphilis) or lesions of congenital syphilis, direct detection methods — which include darkfield microscopy, fluorescent antibody staining, immunohistochemistry and PCR — may be used to make a microbiological diagnosis. However, with the exception of PCR, these methods are insensitive and require fresh lesions from which swab or biopsy material can be collected as well as well-experienced technologists ( Table 1 ).

Direct detection methods for Treponema pallidum

Microscopy had been used for direct detection and diagnosis since 1920, but is now used infrequently. A 2014 survey of national reference and large clinical laboratories in Latin America and the Caribbean found that only two of 69 participating facilities, of which half were reference laboratories, still performed darkfield or direct fluorescent antibody staining for T. pallidum (DFA-TP) 126 . The most recent European guidelines recommended against DFA-TP testing in clinical settings, and the reagents are no longer available 13 . PCR techniques are increasingly used; however, there is as yet no commercially available or internationally approved test for T. pallidum 13 . Species-specific and subspecies-specific T. pallidum PCR testing is a developing technology that is still primarily available in research laboratories 127 , 128 , although these tests are anticipated to be more widely available in the near future. A systematic review and meta-analysis concluded that T. pallidum PCR was more efficient for confirmation than to exclude syphilis diagnosis in lesions 129 . Recent research indicates that this technology may be helpful for the diagnosis of neurosyphilis by the detection of T. pallidum DNA in the cerebrospinal fluid (CSF) of patients with syphilis, particularly among HIV-infected individuals 130 , 131 .

Diagnosis using serology

Serodiagnostic tests are the only means for screening asymptomatic individuals and are the most commonly used methods to diagnose patients presenting with signs and symptoms suggestive of syphilis. Serodiagnostic tests for syphilis can be broadly categorized into non-treponemal tests (NTTs) and treponemal tests (TTs).

NTTs measure immunoglobulins (IgM and IgG) produced in response to lipoidal material released from the bacterium and/or dying host cells. The most commonly used NTTs — the Rapid Plasma Reagin (RPR) test, the Toluidine Red Unheated Serum Test (TRUST) and the Venereal Disease Research Laboratory (VDRL) test — are flocculation (precipitation) tests that detect antibodies to a suspension of lecithin (including phosphatidylcholine and phosphatidylethanolamine), cholesterol and cardiolipin. NTTs are useful in detecting active syphilis. However, because they do not become positive until 10–15 days after onset of the primary lesion, 25–30% of primary syphilis cases may be missed ( Fig. 6 ) 132 , 133 . Although relatively simple and inexpensive, NTTs must be performed manually on serum, and rely on subjective interpretation ( Table 2 ). These tests also require trained laboratory personnel and specialized reagents and equipment and, therefore, do not fulfil the ASSURED (Affordable, Sensitive, Specific, User-friendly, Rapid and robust, equipment-free and Deliverable to those who need them) criteria for tests that can be used at the point of care 134 .

Diagnosis of syphilis can be made by measuring a patient’s serological response to infection. IgM antibodies against Treponema pallidum proteins are the first to appear, followed a few weeks later by IgG antibodies. Both IgM and IgG antibodies can be measured using treponemal tests such as the T. pallidum Haemagglutination Assay (TPHA), T. pallidum Particle Assay (TPPA), Fluorescent Treponemal Antibody Absorption assay (FTA-ABS), enzyme immunoassays (EIA) and Chemilluminescent immunoassays (CIA). IgM and IgG antibodies against proteins that are not specific to T. pallidum (non-treponemal antibodies) can be detected using the Rapid Plasma Reagin (RPR), Venereal Disease Research Laboratory (VDRL) or toluidine red unheated serum (TRUST) tests and usually appear 2–3 week after treponemal antibodies. With effective treatment (which is arbitrarily shown here at 6 months), the non-treponemal antibody levels decline whereas the treponemal antibodies remain high for many years. In ~20% of patients, non-trepnemal antibodies persist 6 months after treatment; these individuals are labelled as having a serofast status. Despite repeated treatment, ~11% of patients remain serofast 187 . Here, we show early syphilis (including primary, secondary and early latent infections; infectious syphilis) and late syphilis (including late latent and tertiary infections) as being ≤1 year in duration and >1 year in duration, respectively, in line with US and European guidelines. However, the WHO guidelines place this demarcation at 2 years. Beyond primary and secondary syphilis, the pattern of serological response over time is less well defined and is accordingly not shown.

Serological tests for Treponema pallidum

The data on sensitivity and specificity of each test with respect to disease stage are reported in the WHO Manual on Laboratory Diagnosis of Sexually Transmitted Infections, including HIV 252 .

Without treatment, titres peak at 1–2 years after infection and remain positive even in late disease (usually at a low titre). After treatment, titres generally decline and in most immunocompetent individuals become nonreactive within 6 months. However, up to 20% of syphilis-infected individuals have a persistently reactive (albeit low-titre) NTT even after treatment, possibly related to a less robust pro-inflammatory immune response 135 . These patients are labelled as having a serofast status and are observed more commonly with treatment for late latent than early syphilis 37 , 136 . Biologic false positive results can occur in ~2–5% of the population, regardless of the NTT test used— although the proportion is difficult to estimate with certainty because it is influenced by the population studied 137 . These low-titre reactions might be of limited duration if related to acute factors (such as febrile illness, immunization or pregnancy) or longer duration if related to chronic conditions (such as autoimmune diseases, hepatitis C infection or leprosy) 136 , 138 . By contrast, false-negative results can occur in sera with very high titres (such as those with secondary syphilis) that are not diluted before testing, a phenomenon known as a Prozone effect. Pre-dilution of sera re-establishes the concentration needed for optimal antibody–antigen interaction and avoids this problem.

In contrast to NTTs, TTs detect antibodies directed against T. pallidum proteins and are theoretically highly specific. However, as most syphilis-infected individuals develop treponemal antibodies that persist throughout life, TTs cannot be used to distinguish an active from a past or previously treated infection and are not useful in evaluating treatment efficacy. TTs are used as confirmatory assays following a positive NTT result.

TTs become positive 6–14 days after the primary chancre appears (~5 weeks after infection) and, therefore, may be useful to detect early syphilis missed by NTT testing. These tests are usually laboratory based and include the fluorescent treponemal antibody absorbed (FTA-ABS) test, the microhaemagglutination assay for antibodies to T. pallidum (MHA-TP), the T. pallidum passive particle agglutination (TPPA) and T. pallidum haemagglutination (TPHA) assays ( Table 2 ). These tests also require trained personnel in a laboratory setting, are more expensive and technically more complex than NTTs and involve specialized reagents and equipment. For these reasons, in the developing world, laboratory-based TTs are not widely available in primary care settings, hence limiting their utility as confirmatory assays for NTTs.

In recent years, TTs using recombinant T. pallidum antigens in enzyme and chemiluminescence immunoassay (EIA and CIA, respectively) formats have been commercialized. These assays are useful for large-scale screening as they are automated or semi-automated and, because they are read spectrophotometrically, are not subjective 13 , 139 – 142 . In higher income countries, many health care institutions depend upon high throughput screening and have adopted ‘reverse’ algorithms that screen with an automated treponemal EIA or CIA and confirm with a NTT rather than the opposite, traditional approach ( Fig. 7 ). Few studies as yet have addressed the accuracy of these ‘reverse testing’ algorithms 40 , 143 . The traditional and reverse approaches should theoretically produce the same result. However, the reverse alogorithm results in the detection of early syphilis cases (TT-positive, NTT-negative) that would not detected by the conventional approach 144 . As this pattern of serological reactivity occurs in very early primary syphilis, in previously treated disease and late infection, considerable attention should be given to a thorough physical examination of the patient, previous history and recent sexual risk before initiating any treatment and partner notification activities.

A | The traditional algorithm begins with a qualitative non-treponemal test (NTT) that is confirmed with a treponemal test (TT). This algorithm has a high positive predictive value when both tests are reactive, although early primary and previously treated infections can be missed owing to the lower sensitivity of NTTs 136 . Importantly, this algorithm is less costly than reverse screening algorithms, and does not require highly specialized laboratory equipment, but is limited by subjective interpretation of the technologist. Additionally, false negative NTT results can arise from the prozone effect (when there is an excess of antibody). Finally, because the traditional algorithm is not always followed by a confirmatory TT, previously treated, early untreated and late latent cases can be missed and biologically false-positive cases can be overtreated. B | The reverse screening algorithm uses a TT with recombinant T. pallidum antigens in enzyme immunoassay (EIA) or chemiluminescence immunoassay (CIA) formats that, when reactive, is followed by an NTT. This approach is associated with higher initial setup costs and ongoing operational costs than the traditional algorithm, but the algorithm permits treatment of 99% of syphilis cases, compared to the traditional algorithm in a low-prevalence setting 246 . Also, because TTs are not flocculation assays, false negative tests due to the Prozone effect do not occur. However, in high-risk populations, screening with a TT can result in a high rate of positive results due to previously treated infections, leading to increased clinician workload needed to review cases and determine appropriate management. Some guidelines recommend further evaluation of reactive TT with a quantitative NTT and, if results of the latter are nonreactive, a second (different) TT to help resolve the discordant results 143 , 247 , 248 . The European Centre for Disease Prevention and Control uses a variation of this approach: a reactive TT immunoassay is followed by a second (different) TT of any kind (that is, not followed by an NTT) 249 . Ideally, a positive TT should be supplemented by another TT or an NTT. However, in most developing countries, and in particular given the serious consequences of syphilis in pregnancy, treatment is recommended in a patient with a positive TT result.

Rapid tests

POC rapid TTs are a recent technology that enable onsite screening and treatment, and are particularly useful in settings with limited laboratory capacity. Rapid syphilis use a finger-prick whole blood sample and are are typically immuno-chromatographic strip-based TT assays that can be stored at room temperature, require no equipment and minimal training, and give a result in <20 minutes 145 ( Table 2 ). Various rapid tests have been evaluated in a range of clinical and community settings and shown to fulfil the ASSURED criteria 134 , 146 – 154 . Like other TTs, most POC diagnostics have the limitation of being unable to distinguish between recent and previously treated syphilis infection and, therefore, could lead to overtreatment. Ideally, patients found to have a reactive POC TT would be further evaluated with an NTT to support management decisions; however, this is often not possible in settings with limited laboratory capacity as is the case in many antenatal care clinics and outreach programmes for high-risk populations. POC rapid tests play an important part when delayed diagnosis is problematic, such as in pregnant women in whom delayed or no treatment poses significant risks to the fetus that far outweigh the risks of overtreatment for the mother 45 , 155 . In non-pregnant individuals, treatment is recommended in those who test positive if they have no prior history of treatment, and to refer those with a prior history to have an NTT 11 .

At least one test has been developed that enables simultaneous detection of non-treponemal and treponemal antibodies in a single POC device 156 – 158 . Additionally, dual syphilis/HIV rapid tests are available to screen for HIV and treponemal antibodies using a single lateral flow immunochromatographic strip. These are an increasingly important tool in the global elimination of MTCT of HIV and syphilis in settings in which laboratory capacity is limited 159 .

Tests useful in special situations

Neurosyphilis.

The diagnosis of neurosyphilis is challenging. The CSF is frequently abnormal in patients with neurosyphilis with both pleocytosis (lymphocyte accumulation) and a raised protein concentration. The Venereal Disease Research Laboratory (VDRL) assay performed on CSF is considered the gold standard for specificity but is recognized to have limited sensitivity 160 , 161 . Other CSF tests, including serological assays — such as the Rapid Plasma Reagin (RPR) 162 , FTA-ABS 163 and TPHA 164 — and molecular assays including PCR 165 have all been assessed for CSF and have variable specificity and sensitivity for the diagnosis of neurosyphilis. Difficulties in interpretation of CSF pleocytosis in individuals co-infected with HIV and syphilis challenge the evaluation of the relationship between the two diseases. CSF pleocytosis occurs in individuals with either infection alone 37 , 165 ; thus, discerning the cause of pleocytosis in co-infected individuals is not always possible.

Congenital syphilis

Diagnosis of congenital syphilis in exposed, asymptomatic infants is another area in testing can be improved. Because maternal nontreponemal and treponemal IgG antibodies can be transferred from mother to child, treponemal testing of infant serum is difficult to interpret and is not recommended 37 . An infant with a reactive RPR or VDRL serum titre that is ≥4-times than those of the mother is highly suggestive of congenital syphilis, but its absence does not exclude the diagnosis. A clinical examination, reactive infant CSF VDRL, abnormal complete blood count or liver function tests or suggestive long-bone radiographs (that, for example, show retarded ossification or dislocation of epiphyses and radiolucencies, especially of long bones) can support a diagnosis of congenital syphilis. Use of IgM immunoblots is controversial owing to limited availability of tests and inconclusive data thus far on sensitivity; their use in diagnosing congenital syphilis is recommended in some guidelines 11 , 13 but not others 37 . Maternal syphilis infection is highly correlated with fetal loss, therefore, evaluation of a stillborn infant should include evaluation of maternal tests for syphilis 11 .

The wide availability of effective treatment and resulting decline in syphilis prevalence has led to low yield of screening in low prevalence settings; thus, screening in low-risk adults (for example, premarital adults or those admitted to hospital) has been abandoned in most places. However, systematic reviews provide convincing evidence in favour of syphilis screening in pregnant women 13 , 166 , adults and adolescents at increased risk for infection 13 , 40 and individuals donating blood, blood products or solid organs 13 , 167 – 169 . Several countries also recommend syphilis testing in people with unexplained sudden visual loss, deafness or meningitis as these may be manifestations of early neurosyphilis 13 , 37 .

Prenatal screening

Syphilis screening is universally recommended for pregnant women, regardless of previous exposure, because of the high risk of MTCT during pregnancy and the availability of a highly effective preventive intervention against adverse pregnancy outcomes 11 , 37 , 41 , 46 . Global normative authorities and most national guidelines recommend syphilis screening at the first prenatal visit, ideally during the first trimester 11 , 37 , 41 , 170 . Some countries recommend that women at high risk have repeat screening in the third trimester and again at delivery to identify new infections 37 . Women should be tested in each pregnancy, even if they have tested negatively in a previous pregnancy. When access to prenatal care is not optimal or laboratory capacity is limited, rapid tests have been found beneficial in detecting and treating syphilis in pregnancy 148 . Guidelines recommend that, post-delivery, neonates should not be discharged from the health facility unless the serological status of the mother had been determined at least once during pregnancy and preferably again at delivery 11 , 37 .

The importance of universal syphilis screening in pregnancy to prevent perinatal and infant morbidity and mortality is highlighted in the current WHO global initiative to eliminate congenital syphilis 43 , 44 and justified by the continuing high global burden of congenital syphilis, availability of an effective and affordable preventive intervention and wider availability of low cost POC rapid tests that can be used when laboratory capacity is lacking 23 , 43 , 44 , 46 , 145 . A systematic review of studies (most of which were conducted in low-income countries) reporting on antenatal programmes initiating or expanding syphilis screening, compared with various local control conditions, found that enhanced screening reduced syphilis-associated adverse birth outcomes by >50% 171 . Integration of syphilis testing with other prenatal interventions, including HIV testing, has been shown to be cost-effective across settings, even when syphilis prevalence is low 48 – 51 . Strategies that enhance screening coverage, such as increased use of POC rapid testing and integrating syphilis and HIV screening, will further support global elimination of congenital syphilis 145 , 172 – 174 .

Screening at-risk populations

Increased risk for infection can be related to personal or partner behaviours leading to syphilis infection or living in a community with high syphilis prevalence 37 , 40 . In many countries, syphilis testing is recommended for all attendees at STI or sexual health centres and as part of integrated services targeted to high-risk groups (such as HIV testing centres or drug treatment centres) 13 , 37 . The optimal screening interval for individuals at increased risk for infection is not well established; however, some guidelines suggest that MSM or people with HIV may benefit from more frequent screening than others at risk for syphilis (for example, 3 monthly rather than annual screening) 37 , 40 , 175 , 176 .

At-risk communities are often marginalized from care and experience discrimination and stigma when using traditional STI services 177 . Innovations in promoting uptake of testing and developing user-friendly services are important in the control of syphilis in these communities to reduce transmission. Social entrepreneurship and crowdsourcing approaches have been shown as innovative approaches to improve HIV and syphilis testing coverage rates and accelerate linkage to care, two fundamental elements within the cascade of STI service delivery 178 , 179 . Evaluation studies of other interventions, such as pre-exposure prophylaxis (PrEP) for syphilis, are also underway 180 . One option in the future might be to simultaneously administer PrEP for syphilis and HIV 181 .

Blood bank screening

Although syphilis was among the first identified infectious risks for blood donation and s transmission through blood has been documented 182 – 184 , reports of transfusion-transmitted syphilis have become exceedingly rare over the past 60 years as increasingly more countries adopt donor selection processes, universal serological screening of donors and use of refrigerated products rather than fresh blood components 183 , 185 . Survival of T. pallidum in different blood components has been shown to vary according to storage conditions, with fresh blood or blood components stored for <5 days more infectious than blood stored for longer periods 183 . Syphilis screening of blood, blood components or solid organs remains a recommendation in many countries 13 , 169 . Occasional cases of transfusion-transmitted syphilis are still reported in settings with high syphilis prevalence, particularly with transfusion of fresh blood 167 .

There is as yet no vaccine against syphilis, and the most effective mode of prevention is prompt treatment to avoid continued transmission of the disease sexually or vertically from mother-to-child, and treatment of all sex partners to avoid reinfection. Other prevention modalities against venereal transmission of syphilis are latex condom use, male circumcision and avoiding sex with infected partners 37 . Treatment of exposed sex partners is important to avoid reinfection 37 .

Important factors in managing syphilis are early detection, prompt treatment with an effective antibiotic regimen and treatment of sex partners of a person with infectious syphilis (primary, secondary or early latent infections). The WHO guidelines 11 ( Box 1 ) and European guidelines 13 for the management of early syphilis in adults are the same. The CDC guidelines do not offer procaine penicillin as a treatment, but are otherwise identical 12 . Patients with late syphilis are no longer infectious. Thus, the objective of treatment is to prevent complications in persons who are asymptomatic (that is, have late latent syphilis) or arrest their development if the patient has manifestations of tertiary disease. Treatment of late syphilis requires longer courses of antimicrobial therapy than early disease.

WHO guidelines for the treatment of syphilis

Early syphilis.

• Intramuscular benzathine penicillin G (single dose)
• Or intramuscular procaine penicillin (daily doses for 10–14 days)
• If penicillin-based treatment cannot be used, oral doxycycline (twice daily doses for 10–14 days)* or intramuscular ceftriaxone (daily doses for 10–14 days)

Late syphilis

• Intramuscular benzathine penicillin G (weekly doses for 3 weeks)
• Or intramuscular procaine penicillin (daily doses for 20 days)
• If penicillin-based treatment cannot be used, oral doxycycline (daily doses for 30 days)*
• Intravenous aqueous benzyl penicillin six hourly (for 10–15 days)
• Or intramuscular procaine penicillin daily (for 10–15 days)

*Contraindicated in pregnancy. From Ref. 11

Penicillin has been the mainstay of treatment for syphilis since it first became widely available in the late 1940s. Although its efficacy was never demonstrated in a randomized controlled trial, it was clearly far superior to all previous treatments, and T. pallidum resistance to penicillin has never been reported. As T. pallidum divides slower than most bacteria, it is necessary to maintain penicillin levels in the blood above the minimum inhibitory concentration (MIC) for at least 10 days; this can be achieved by giving a single intramuscular injection of long-acting benzathine penicillin G (which benefits from not requiring patient adherence to a prolonged drug regimen). The first-line treatments for early syphilis recommended by the CDC and European (authored by the International Union Against Sexually Transmitted Infections) guidelines are very similar 12 , 13 as are recommendations for treatment of exposed sex partners. Patients with late syphilis, or with syphilis of unknown duration, should receive longer courses of treatment ( Box 1 ). Those with symptoms suggestive of neurosyphilis or ocular involvement should undergo lumbar puncture to confirm or rule out the presence of neurosyphilis, which requires more intensive treatment. However, CDC and European guidelines define latent syphilis as occurring beginning at 1 year after infection, whereas the WHO defines latent syphilis to occur beginning at 2 years, resulting in some differences in management; that is, longer treatment duration is required for some patients in the United States and Europe.

Given that confirmation or exclusion of the presence of viable T. pallidum after treatment is not possible, treatment efficacy is measured indirectly using serology. Cure is usually defined as reversion to negative or a fourfold reduction in titre of an NTT. However, as noted earlier, a minority of patients remain seropositive, with a less than four-fold reduction in NTT titre, in spite of almost certainly having been cured and with no evidence of progressive disease — the so-called serofast state 186 . The management of these patients depends on taking a careful sexual history to exclude the possibility of reinfection, which can be challenging as patients may not recognize new infections. The serofast state more commonly occurs in patients with late syphilis and low NTT titres and in HIV-positive patients who are not on anti-retroviral treatment 187 . Because few data are available on long-term clinical outcomes in serofast patients, CDC guidelines recommend continuing clinical follow up and retreatment if follow up cannot be ensured 12 .

Second-line treatments

Patients who are allergic to penicillin should be treated with doxycycline or ceftriaxone (though allergy to cephalosporins is more common in those who are allergic to penicillin) with repeat NTT serology as follow up. Doxycycline is contraindicated in pregnancy. Two treatment trials of early syphilis in Africa showed that a single oral dose of azithromycin was equivalent to benzathine penicillin G 188 , 189 . Unfortunately, strains of T. pallidum with a mutation that confers resistance to azithromycin and other macrolide antibiotics are common in the United States, Europe, China and Australia 190 – 194 . A study in HIV-positive patients with syphilis showed that azithromycin to prevent opportunistic infections led to better serological outcomes 195 . The WHO recommends the use of azithromycin for the treatment of syphilis only in settings where the prevalence of macrolide-resistant T. pallidum is known to be very low.

HIV co-infection

In patients with early syphilis, a raised CSF cell count and protein are found more frequently in the CSF of patients with HIV infection than in HIV-uninfected patients, and there is some evidence that early symptomatic neurosyphilis is more common in HIV-positive patients 196 , 197 . As single-dose benzathine penicillin G does not reliably lead to treponemicidal levels in the CSF, some experts have suggested that HIV co-infected patients with early syphilis should receive enhanced treatment 198 . However, a randomized controlled trial ( n = 541) showed no significant difference in clinical outcomes between patients receiving standard or enhanced treatment 15 . Notably, the 101 HIV-infected patients enrolled in the trial responded less well serologically, but due to loss to follow up the study was underpowered to detect a two-fold difference in standard versus enhanced treatment in HIV co-infected patients. Furthermore, a large ( n =573) prospective observational study in Taiwan found no difference between single-dose benzathine penicillin G and enhanced treatment in a per-protocol analysis 199 . However, using a last-observed-carried-forward analysis to account for missing data, the authors concluded that 67.1% of those who received one dose responded serologically compared with 74.8%who received the enhanced treatment, a statistically significant difference ( P =0.044) 199 . Finally, a retrospective study ( n = 478) showed no difference in serological response at 13 months between those receiving single-dose benzathine penicillin G and enhanced treatment 200 . Given the inconclusive results of these studies, many clinicians continue to offer enhanced therapy to HIV co-infected patients with early syphilis.

Treatment in pregnancy

Adverse pregnancy outcomes are common in women with syphilis 45 , 119 . A study in Tanzania found that, of women with latent syphilis who had RPR titres ≥1:8, 25% delivered a stillborn, and 33% a live but preterm infant 21 . A second study showed that adverse pregnancy outcomes due to syphilis can be prevented with a single dose of benzathine penicillin G given before 28 weeks’ gestation 201 and that, in this setting, in which 5–6% of pregnant women had syphilis, this was one of the most cost-effective interventions available in terms of cost per disability-adjusted life year saved 202 .

Penicillin is the only antibiotic known to be effective in treating syphilis in pregnancy and preventing adverse birth outcomes. Since doxycycline is contraindicated in pregnancy, and macrolides such as azithromycin and erythromycin do not cross the placenta well, there are few alternatives to penicillin for the treatment of pregnant women with syphilis who are allergic to penicillin. The CDC recommends desensitization for those who are allergic to penicillin 12 .

The WHO recommends that infants with suspected congenital syphilis, including infants who are born to syphilis-seropositive mothers who were not treated with penicillin >30 days before delivery, should be treated with aqueous benzyl penicillin or procaine penicillin ( Box 1 ). All syphilis-exposed infants, including infants without signs or symptoms at birth, should be followed closely, ideally with NTT titres. Titres should decline by 3 months of age and be nonreactive by 6 months 12 . TTs are not useful in infants due to persistent maternal antibody.

Neurosyphilis and ocular syphilis

CNS involvement can occur during any stage of syphilis, but there is no evidence supporting a need to deviate from recommended syphilis regimens without presence of clinical neurological findings (such as ophthalmical or auditory symptoms, cranial nerve palsies, cognitive dysfunction, motor or sensory deficits, or signs of meningitis or stroke) 203 . With symptoms and tests indicating neurosyphilis, or any suggestion of ocular syphilis regardless of CSF testing, more-intensive treatment is recommended. For example, the CDC recommends that adults with neurosyphilis or ocular syphilis should be treated with high-dose intravenous aqueous crystalline, or intramuscular procaine penicillin plus probenecid, for 10–14 days 204 .

Quality of life

Historical reports dating from the 15 th century indicate that syphilis was perceived as a dangerous infection, and a source of public alarm via fear of contagion and dread of its manifestations and anxiety around its highly toxic ‘cures’ (heavy metal therapy with mercury, arsenicals or bismuth) 205 – 207 . Case reports through the 19 th century as well as modern re-evaluations of skeletal remains support the fact that the disease could cause severe physical stigmata, with individuals having disfiguring rashes; non-healing ulcerations; painful bony lesions that often involved destruction of the nose and palate; visceral involvement; dementia and other incapacitating neurological complications; and early death 208 . Stigmatization associated with syphilis was also evident, with symptomatic patients quarantined to specialized hospitals, and affected people hiding their symptoms — perhaps fearing societal shunning or the dubiously effective treatment regimens even more than the disease 209 . Reductions in syphilis prevalence were documented after the introduction of penicillin 210 and since that time, the most virulent manifestations of the disease have almost vanished, and today it is rare to find a patient with tertiary disease 211 . Nevertheless, continuing reports emphasize that complications of late syphilis, particularly those involving the eyes, CNS and cardiovascular system, can cause lifelong disability and even death 9 . For example, case numbers of ocular syphilis have increased with rising syphilis incidence rates in many communities 212 , with delayed treatment associated with permanently diminished visual acuity 213 . It is essential, therefore, that caregivers be cognizant of the need to screen at-risk patients for latent infection and administer therapy if previous treatment has not been documented.

Few modern studies have addressed quality of life in men and women with syphilis, whether in social, psychological or economic contexts. One study ( n = 250) showed only a minor effect on patient-reported quality of life at time of treatment, and essentially no effect 1 month after treatment 214 . The currently high case rates of syphilis infection and reinfection among MSM in urban centres throughout the world may lend support to the notion that syphilis in the modern era poses limited impact on quality of life as long as it is detected and treated. However, partner notification studies suggest STI diagnoses can lead to significant social stigma, intense embarrassment, and fear of retaliation, domestic violence or loss of relationship 177 . Public health experts have posited that syphilis is the source of more stigma than other STI diagnoses, although this is difficult to measure with certainty because STI programmes tend to focus contact tracing efforts more strongly on syphilis than other curable STIs owing to its serious consequences 215 . In one study measuring the level of shame associated with several stigmatizing skin diseases, patients assigned greatest shame to syphilis — more than to AIDS, other STIs or several disfiguring skin conditions 216 .

Untreated maternal syphilis results in severe adverse perinatal outcomes, most prominently stillbirth, in at least half of affected pregnancies 45 . While MTCT of syphilis is clearly linked to lack of prenatal care, WHO data indicate that globally, whether in wealthy or poor nations, most adverse pregnancy outcomes caused by maternal syphilis are in women who attended prenatal care but were not adequately tested or treated 24 . This suggests other factors, such as weak health systems, gender inequality, lack of political will to support quality STI and reproductive health services, or other structural influences associated with lack of screening might be at play 217 . An increasing literature supports that, as for infant loss, a stillbirth can lead to poor mental and other health outcomes for both parents and the wider family, even extending to health care providers. For example, experiencing a stillbirth has been linked to ‘unspoken grief’ and a variety of psychosocial consequences such as depression, blame, shame, social isolation, problems in future pregnancies and relationship dissolution 218 – 220 . In Haiti, pregnancy loss associated with syphilis (which had a maternal prevalence of 6%) is so common that a myth about a werewolf sucking the blood out of the unborn fetus has developed to help women with their loss and suffering 221 . Economic research suggests a stillbirth results in substantial direct and indirect costs and can sometimes require more resources than a livebirth 219 .

With syphilis continuing to be the leading cause of preventable stillbirths in the developing world and re-emerging as a public health threat in developed nations, particularly in HIV co-infected MSM, the demand for improved diagnostics, prevention strategies and treatments is growing. Here, we describe the most pressing issues and propose a call to action ( Box 2 ).

Major challenges and a call to action wish list

Eliminate mother-to-child transmission of syphilis.

• Requires political commitment
• Prenatal syphilis screening to be integrated into mother-to-child elimination programmes for HIV or as a component of an essential diagnostic package for prenatal care
• Develop point-of-care tests with data connectivity or data transmission capability to facilitate automated surveillance and to improve the efficiency of health systems

Address HIV and syphilis co-infection in MSM

• Requires research into potential synergies between the two infections
• Implement scientific and community involvement to reach at-risk populations
• Integrate programmes for HIV, syphilis, hepatitis and other STIs

Develop tests for active infection, neurosyphilis and congenital syphilis

• Development of biomarkers for test development
• Development of network of clinical sites for rapid validation of new tests

Develop new oral drugs to prevent transmission to fetus and to sexual partners

• Provide incentives for drug discovery programmes
• Provide incentives to evaluate drug combinations

Develop vaccines

• Requires research to better understand pathogenesis
• Requires research to identify vaccine targets and methods for validation

Elimination of MTCT of syphilis

The WHO campaign to eradicate yaws, which treated >50 million people with penicillin and reduced the number of cases by at ≥95% worldwide between 1952 and 1964, was ultimately unsuccessful. What can we learn from this heroic failure? The yaws eradication campaign was based on clinical examination and serological testing to determine prevalence by community, and mass treatment or selective mass treatment (cases and contacts) of communities with penicillin, depending on prevalence. Unfortunately, as the prevalence of yaws fell, it was no longer perceived as an important public health problem worthy of an expensive vertical programme; resources were diverted to other programmes, yaws was forgotten, and it came re-emerged 222 . To some extent the same is true of syphilis; once penicillin became available, its incidence and prevalence declined in many parts of the world, and it was no longer seen as a public health priority. Although screening of all pregnant women for syphilis has continued to be recommended in most countries, coverage has been low in many regions; for example, WHO estimates that approximately 50% of antenatal clinic attenders in Africa are not currently screened for syphilis 24 . This low coverage has resulted in a high burden of entirely preventable stillbirths and neonatal deaths 23 . Exacerbating this situation, the WHO has received reports of stock outs and shortages of injectable benzathine penicillin G in multiple countries, many with a high burden of maternal and congenital syphilis. In collaboration with international partners, the WHO has spearheaded an initiative to assess global supply, current and projected demand, and production capacity for benzathine penicillin G 223 .

Strong advocacy will be needed to ensure that the control and elimination of syphilis is given a high priority on the global health agenda. Policy makers and funders need to be made aware that syphilis is a leading cause of preventable stillbirths and neonatal death, that these deaths can be prevented with a single dose of penicillin given to the mother before 28 weeks gestation, and that this is one of the most cost-effective health interventions available 51 , 202 . Perhaps with this awareness and political will, syphilis MTCT elimination programmes — which have failed to progress in the past 10 years 224 — will witness the success of the MTCT HIV programmes in Africa. Other developments are occurring that are forging change. For example, the availability of POC tests has led to increased coverage of antenatal screening and treatment for syphilis in many settings 148 , and the WHO campaign for the elimination of MTCT of HIV and syphilis has increased the visibility of syphilis on the global health agenda. In 2014, the WHO target for the elimination of MTCT of syphilis was ≤50 cases of congenital syphilis per 100,000 live births. The process targets are antenatal care coverage (at least one visit) of ≥95% of pregnant women; coverage of syphilis testing ≥95% of pregnant women; and treatment of ≥95% of seropositive pregnant woment 225 . Additionally, the WHO has conducted a systematic review of the performance of dual HIV-syphilis rapid tests and issued an information note on testing algorithms for dual HIV-syphilis tests 226 .

The huge reduction in the number of HIV-positive infants in Africa in recent years, a more difficult undertaking than reducing MTCT of syphilis, is proof of concept that congenital syphilis elimination is achievable. Given that Cuba, Thailand, Belarus, Moldova and Armenia have eliminated MTCT of HIV, syphilis or both, elimination can be achieved with political will and a well-organized health care system. Indeed, inclusion of syphilis and HIV screening with tests for anaemia, diabetes and pre-eclampsia as a package of essential diagnostics for prenatal care should be implemented as a minimum standard to ensure safe and healthy pregnancies worldwide.

POC testing has greatly increased access to screening for pregnant women, and has the potential to increase access to screening for high-risk groups such as MSM and FSWs through outreach programmes. However, the quality of testing must be assured given these tests are conducted outside the laboratory. Strategies to ensure reliability of POC tests include use of electronic readers 227 and microfluidic assays powered by smart phones 228 for real-time monitoring of progress 229 , and routine provision of proficiency testing panels 121 , 122 . For example, one study in the Amazon region of Brazil showed that proficiency panels consisting of dried serum tubes that were assessed by each healthcare worked could be used to monitor the performance of healthcare workers in remote settings 123 .

HIV and syphilis co-infection in MSM

In developed countries, the incidence of syphilis in MSM is several hundred times higher than in the general population. Furthermore, the incidence continues to increase as condom use has fallen with increasing use of pre-exposure prophylactic anti-retroviral medications for HIV 42 , 230 . Indeed, with wider HIV treatment coverage in recent years and HIV no longer considered a ‘death sentence’, there has been a decline in safe sex practices and more risk-taking behaviours 231 . However, the alarming increase in incidence of syphilis, compared to other STIs, in HIV-infected MSM cannot be explained by behavioural factors alone. The frequent co-infection of HIV and syphilis in MSM in many countries have led researchers and policy makers to consider the hypothesis that treatment for HIV may be a double-edged sword that contributed to increased susceptibility to syphilis through impairment of the innate or acquired immunity to T. pallidum 42 , 232 .

Accordingly, research is urgently needed to understand the underlying causes of this twin epidemic. The involvement of the MSM community is critical in the design and implementation of innovative approaches to promote the uptake of testing and linkage to care, particularly as this community is still stigmatized and marginalized from care in many societies. Although self-testing for HIV and hepatitis C virus infection is now possible using highly sensitive and specific oral tests that are commercially available, syphilis does not elicit sufficient antibody for an oral test. Thus, implementation science is needed to integrate and optimize the delivery of a package of HIV, syphilis, hepatitis and other STI screening and treatment strategies and partner notification systems for MSM in different cultural, socioeconomic and political settings.

Better diagnostic tests

Research is needed to identify biomarkers that can more accurately distinguish between past, treated and active syphilis requiring treatment, identify patients who have become reinfected, and provide a test of cure. Using current serological tools, a high proportion of patients remain serofast after treatment in some settings, and the optimal management of these individuals is uncertain. Additionally, more-accurate diagnostic tests are needed to confirm the diagnosis of congenital syphilis, as serological tests based on IgG antibodies cannot distinguish between infected infants and those with passively acquired maternal antibodies. IgM tests can be highly sensitive in symptomatic infants but have suboptimal sensitivity in infants who are infected but not symptomatic at birth 12 .

The diagnosis of neurosyphilis also remains a challenge, particularly in HIV co-infected patients, in whom a raised CSF protein or cell count does not necessarily indicate that the patient has neurosyphilis. Promisingly, a POC rapid test has been adapted for the diagnosis of neurosyphilis using CSF 233 ; performance of this test is better in cell-free specimens, requiring the use of a centrifuge. Another promising assay might be measurement of macrophage migration factor (MIF); CSF levels of MIF alone was shown to have a sensitivity of 74.42% and a specificity of 67.74% for the diagnosis of neurosyphilis in one study ( n =43) 234 . By integrating all CSF parameters (pleocytosis, increased protein and MIF), the sensitivity and specificity would be improved to 100% by parallel testing. Additionally, assay of B cell attractant chemokine CXCL13 in the CSF could be used to distinguish the pleoctysosis caused by HIV from that due to neurosyphilis in HIV-infected patients 235 .

Better use of existing drugs

With penicillin, many countries still struggle with the fear of injections on the part of patients and the management of anaphylactic shock on the part of the health care providers. Oral regimens that are safe in pregnancy and effective in preventing the transmission of syphilis to the fetus are urgently needed. Furthermore, macrolide resistance is correlated with treatment failure in patients with primary syphilis 191 , lending further urgency to the need to find alternative oral therapies. Incentives for a drug discovery programme for syphilis needs to be established and, in the meantime, evaluation of existing drug combinations might be useful as alternative to reduce the threat of development of resistance.

Vaccine development

Human challenge studies have shown that people with late latent syphilis are resistant to symptomatic reinfection with heterologous strains of T. pallidum , and protective immunity has been induced in rabbits by repeated inoculation with γ-irradiated T. pallidum 236 , 237 .Accordingly, it should be possible to develop protective vaccines. However, research on virulence determinants of T. pallidum , and our understanding of protective immunity against it, have been hindered by our inability to culture the bacteria in vitro. To overcome this limitation, genome sequencing of T. pallidum directly from clinical samples is now possible 92 , 238 This advance should enable understanding of strain variation on a global scale, and help to identify outer membrane proteins and other surface antigens as possible vaccine candidates 81 . A recent study showed that immunization of rabbits with the lipoprotein TP071 prevented dissemination of T. pallidum and, hence, has become a promising vaccine candidate 81 . Integration of potential vaccine targets with diagnostic targets in discovery programmes also hold promise in accelerating progress towards improved tools for control, prevention and ultimately the elimination of this disease.

Acknowledgments

The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the US Centers for Disease Control and Prevention.

Author contributions

Competing interests

J.D.R. receives royalties for licensing of syphilis diagnostics reagents. The other authors declare no competing interests.

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