Rising Syphilis in the United States: Epidemiological Trends, Disparities, and Behavioral Risk Factors

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Despite growing awareness among healthcare providers and public health agencies, comprehensive epidemiological analyses of the populations most affected remain limited. This retrospective descriptive study analyzed national syphilis surveillance data from the Centers for Disease Control and Prevention (CDC) between 2018 and 2022. Trends in syphilis incidence were evaluated across key demographic and behavioral variables, including race and ethnicity, geographic region, sex of sexual partner, and substance use behaviors. Findings reveal persistent and widening disparities, with disproportionate increases in syphilis rates among racial and ethnic minority populations, individuals reporting substance use, and across diverse geographic regions. These results underscore the urgent need for targeted, equity-focused public health interventions and evidence-based policy responses to mitigate the ongoing syphilis epidemic in the United States. Syphilis United States Epidemiological Trends Health Disparities Behavioral Risk Factors Substance Use CDC Surveillance Data Social Determinants of Health Public Health Policy Sexually Transmitted Infections (STIs) Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Introduction Syphilis, one of the most historically significant and devastating sexually transmitted infections (STIs), reached its peak prevalence in the United States in 1947. This burden sharply declined following the widespread availability of penicillin, a breakthrough that transformed the landscape of infectious disease control [ 19 ]. For decades thereafter, syphilis rates steadily declined and eventually plateaued at relatively low levels by the early 2000s, stabilizing around 11 to 12 cases per 100,000 population [ 3 ]. However, in recent years, a troubling reversal has emerged. Since 2018, the United States has experienced a dramatic resurgence in syphilis cases, including a striking 80 percent increase in newly reported infections [ 4 ]. Despite the availability of effective diagnostic tools, the mechanisms driving this sharp increase remain insufficiently understood and underexplored in the current literature. Syphilis is caused by the gram-negative spirochete Treponema pallidum , a bacterium transmitted primarily through sexual contact involving the vaginal, anal, or oral mucosa. Following exposure, the bacterium penetrates mucous membranes or microscopic skin abrasions, with symptom onset typically occurring within 10 to 90 days [ 9 ]. Vertical transmission from mother to fetus can also occur during pregnancy or delivery, resulting in congenital syphilis, which carries an elevated risk of adverse perinatal outcomes, including stillbirth [ 8 ]. Often referred to as “the great imitator,” syphilis progresses through distinct clinical stages that can mimic other conditions, contributing to delayed or missed diagnoses. The primary stage is characterized by the appearance of a single, painless chancre at the site of infection, often accompanied by regional lymphadenopathy. Without treatment, syphilis advances to the secondary stage in approximately one-quarter of cases, manifesting systemically with fever, malaise, generalized lymphadenopathy, and a characteristic maculopapular rash involving the palms and soles. If untreated, the infection may enter a latent phase and eventually progress to tertiary syphilis, which can involve the cardiovascular system, central nervous system, and multiple organ systems, often resulting in irreversible damage [ 19 ]. Given the severe consequences of untreated syphilis and its reemergence as a significant public health concern, this study investigates the epidemiological trends of syphilis in the United States between 2018 and 2022 using national surveillance data. Specifically, we aim to characterize patterns of syphilis prevalence across racial and ethnic groups, sexual behaviors, geographic regions, and substance use patterns. We hypothesize that social determinants of health including limited access to healthcare, socioeconomic disadvantage, and high-risk behavioral factors have contributed to the disproportionate burden of syphilis among vulnerable populations. A deeper understanding of these associations is critical to inform targeted public health interventions, address existing disparities, and curb the ongoing rise of syphilis in the United States. We hypothesize that social determinants of health, including limited access to care, socioeconomic disadvantage, and behavioral risk factors, have contributed to the disproportionate burden of syphilis among specific populations. Understanding these associations is essential to inform public health interventions and reduce the ongoing spread of syphilis in the United States. Methods Data Source and Surveillance System This study utilized publicly available data from the Centers for Disease Control and Prevention (CDC) national surveillance system on sexually transmitted infections (STIs), which provides comprehensive epidemiological data on infectious disease trends in the United States from 1941 to 2022. The CDC dataset is compiled through the National Notifiable Disease Surveillance System (NNDSS), a standardized reporting system for tracking and monitoring infectious diseases nationwide. This database includes case counts and rates for chlamydia, gonorrhea, syphilis, and congenital syphilis, reported annually by state and local health departments. Data Extraction and Variable Selection For the purpose of this study, we extracted data specifically related to syphilis, including primary and secondary syphilis, as well as congenital syphilis. Syphilis data were further stratified and analyzed across seven key variables: STI Trends : Percent changes in cases of chlamydia, gonorrhea, and syphilis over one-year (2021–2022) and five-year (2018–2022) periods. Race/Ethnicity : Syphilis rates per 100,000 population were evaluated for the following racial and ethnic groups: American Indian/Alaska Native (AI/AN), Asian, Black/African American (AA), Hispanic/Latino, Multiracial, Native Hawaiian/Pacific Islander (NH/PI), and White. Sexual Behavior : Analysis of reported behaviors, including exchanging sex for drugs or money, engaging in sex while intoxicated and/or high on drugs, sex with anonymous partners, and sex with a person who injects drugs. Sex of Partner : Cases of syphilis were stratified based on reported sex of sexual partner, categorized as: men who have sex with men (MSM), men who have sex with women only (MSW), men with unknown sex of partners (MSU), and women. Substance Use : Patterns of substance use were analyzed, including cocaine, crack, heroin, injection drug use, and methamphetamine use. Sex and Gender : Syphilis cases were assessed based on biological sex (male and female) from 2018 to 2022. Age Groups : Rates of syphilis were evaluated for males and females across age groups (15–19, 20–24, 25–29, 30–34, and 35–44 years), with rates averaged over the five-year study period. Geographic Distribution : States with the highest reported rates of primary and secondary syphilis in 2022 were identified and visualized. Statistical Analysis Descriptive analysis was conducted to examine trends in primary and secondary syphilis across demographic, behavioral, and geographic variables. Syphilis rates were compared with rates of other common STIs (chlamydia and gonorrhea) to contextualize observed trends. Chi-square tests were performed to assess associations between syphilis occurrence and categorical variables, including race/ethnicity, sex, substance use, and sexual behavior. Odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were calculated for variables with available denominators. Statistical significance was set at a p-value < 0.05. Due to limitations of the CDC dataset, confounders such as socioeconomic status, education, or healthcare access could not be directly assessed. Data Visualization All visualizations were generated using the ggplot2 package in R software. Bar charts with standard deviation error bars were created using geom_bar(stat="identity") for categorical variables, and geom_errorbar() to depict variability. Geographic distribution maps were constructed using CDC-provided county-level data to illustrate state-specific syphilis prevalence, with darker shading representing higher case rates. Results Trends in Common Sexually Transmitted Infections in the United States, 2018–2022 Recent epidemiological trends highlight a shifting and increasingly concerning burden of sexually transmitted infections (STIs) across the United States. Chlamydia and gonorrhea continue to be among the most commonly reported communicable diseases nationwide. While chlamydia demonstrated an overall decline of 6.20% over the past five years, it remained relatively stable with a marginal increase of 0.30% in the most recent year ( Fig. 1 ). Gonorrhea, in contrast, exhibited a five-year increase of 11.10%, despite an 8.70% decrease from 2021 to 2022 ( Fig. 1 ). Syphilis displayed the most dramatic change, with a 78.90% increase over five years and a 17.00% rise in just the last year alone ( Figs. 1 and Supplementary Fig. 1) . These trends reflect a growing public health challenge, particularly in light of the resurgence of syphilis, and emphasize the need for enhanced surveillance, outreach, and intervention strategies. Geographic Distribution of Syphilis Cases Across the United States Geographic analysis revealed that the highest rates of syphilis including both primary and secondary syphilis as well as congenital syphilis, were concentrated in the Midwest and Southern regions of the United States (Fig. 2 ). Among these, South Dakota was disproportionately affected, reporting the highest rate of primary and secondary syphilis during the study period. The identification of geographic hotspots for syphilis suggests potential disparities in healthcare access, public health infrastructure, and preventive services, particularly in rural and underserved areas. These findings underscore the need for targeted interventions that account for regional variations in resource availability, healthcare delivery, and social determinants of health. Sex- and Age-Related Patterns of Syphilis Incidence Between 2018 and 2022, syphilis cases were consistently higher among males compared to females, reflecting a greater reported burden of infection among males during this period ( Fig. 3 A ). While both sexes experienced an upward trend in case counts over the five-year span, males consistently accounted for a disproportionately greater number of cases. Notably, the number of syphilis cases among females nearly doubled, reflecting a concerning rise in incidence within this group as well. To further evaluate these trends, syphilis rates were averaged across the five-year period and stratified by age group for each sex. Among both males and females, the 25–29-year-old age group exhibited the highest rates of syphilis during the study period ( Figs. 3 B and 3 C ). In females, greater variability in case rates was observed beginning at age 20, as indicated by wider standard deviations, suggesting potential fluctuations in exposure or testing practices over time. Racial and Ethnic Disparities in Syphilis Rates While all racial and ethnic groups experienced increases in syphilis cases between 2018 and 2022, certain populations bore a disproportionately higher burden of infection. Individuals identifying as Black/African American and American Indian/Alaska Native (AI/AN) exhibited comparable five-year average rates of syphilis. However, in 2022, AI/AN individuals had the highest reported infection rate, which significantly influenced the overall average for this group ( Fig. 4 ). Odds ratio analysis in 2022 demonstrated that AI/AN individuals had the highest likelihood of syphilis infection compared to White Americans (OR: 17.87; 95% CI: 14.01–22.80; p < 0.001), followed by Black/African Americans (OR: 7.03; 95% CI: 5.53–8.94; p < 0.001) (Table 1 ). All racial and ethnic groups showed significantly elevated odds of infection relative to White Americans, except those identifying as Asian, who had a significantly lower odds of infection (OR: 0.45; 95% CI: 0.32–0.65; p < 0.001).These findings suggest that, although syphilis prevalence is rising broadly, the magnitude and pace of that increase are not evenly distributed across demographic groups, reflecting underlying structural inequities and barriers to care (Supplementary Table 1). Table 1 Odds Ratios (OR) for Syphilis Infection by Race and Ethnicity, United States, 2022. Race/Ethnicity Odds Ratio (OR) 95% Confidence Interval p-value American Indian/Alaska Native (AI/AN) 17.87 14.01–22.80 < 0.001 Black/African American (Black/AA) 7.03 5.53–8.94 < 0.001 Native Hawaiian/Pacific Islander (NH/PI) 3.81 2.98–4.87 < 0.001 Multiracial 2.93 2.29–3.77 < 0.001 Hispanic/Latino 2.01 1.55–2.61 < 0.001 White (Reference Group) 1.00 — — Asian 0.45 0.32–0.65 < 0.001 This table presents the odds ratio of syphilis for racial and ethnic demographics in 2022. White Americans were used as the reference group. All racial groups showed a higher likelihood of syphilis infection when compared to White Americans apart from Asian race. Syphilis Prevalence by Sexual Behavior Characteristics Between 2018 and 2022, individuals reporting sexual activity with anonymous partners consistently exhibited the highest rates of syphilis, with this behavior associated with the greatest risk of infection in 2022 (OR: 13.1; 95% CI: 9.70–17.72; p < 0.001) ( Fig. 5 , Table 2 ) . Engaging in sexual activity while intoxicated was also strongly associated with increased risk (OR: 9.49; 95% CI: 6.99–12.83; p < 0.001). In comparison, having sex with a person who injects drugs was associated with a more modest increase in risk (OR: 1.68; 95% CI: 1.17–2.37; p < 0.001). When evaluated against the reference category of transactional sex (defined as exchanging sex for drugs or money), all other behaviors, including anonymous sex, sex while intoxicated or high on drugs, and sex with a person who injects drugs, were associated with significantly higher odds of syphilis infection. Moreover, all four behavior categories demonstrated a general upward trend in reported syphilis cases over the five-year period, with certain behaviors, particularly anonymous sexual activity and intoxicated sex, showing more pronounced increases ( Fig. 5 ). Table 2 Odds Ratios (OR) for Syphilis Infection by Reported Sexual Behaviors, United States, 2022. Sexual Behavior Odds Ratio (OR) 95% Confidence Interval p-value Exchanging sex for drugs or money (Reference Group) 1.00 — — Sex with an anonymous partner 13.10 9.70–17.72 < 0.001 Sex while intoxicated or high on drugs 9.49 6.99–12.83 < 0.001 Sex with a person who injects drugs 1.68 1.17–2.37 < 0.001 Odds ratios (OR) for syphilis infection in 2022 by reported sexual behavior, using exchanging sex for drugs or money as the reference group. All other behaviors were associated with significantly higher odds of syphilis infection. Engaging in sex with an anonymous partner showed the highest risk, with over 13 times greater odds of infection compared to the reference group. Association Between Substance Use and Syphilis Infection All substance use behaviors depict an increasing trend over the five-year span from 2018 to 2022, further suggesting an increasing prevalence of syphilis ( Fig. 6 ). Individuals who use crack have 38% lower odds of syphilis infection compared to cocaine users (OR: 0.38, 95% CI: 0.35–0.42, P < 0.001) (Table 3 ). Similarly, heroin use is associated with 43% lower odds of syphilis infection (OR: 0.57, 95% CI: 0.52–0.62, P < 0.001). In contrast, injection drug use is linked to an 89% increase in the odds of syphilis infection (OR: 1.89, 95% CI: 1.77–2.02, P < 0.001). Methamphetamine use shows the strongest association, with users experiencing over three times higher odds of syphilis infection compared to cocaine users (OR: 3.34, 95% CI: 3.13–3.55, P < 0.001). These findings underscore the varying risks of syphilis infection among different substance users, with injection drug use and methamphetamine use being particularly associated with elevated risk. Table 3 Syphilis OR for Substance Use in 2022 Substance Use Behavior Odds Ratio (OR) 95% Confidence Interval p-value Cocaine use (Reference Group) 1.00 — — Crack use 0.38 0.35–0.42 < 0.001 Heroin use 0.57 0.52–0.62 < 0.001 Injection drug use 1.89 1.77–2.02 < 0.001 Methamphetamine use 3.34 3.13–3.55 < 0.001 Odds ratios (OR) for syphilis infection in 2022 by reported substance use behavior, using cocaine use as the reference group (OR = 1.00). Methamphetamine use was associated with the highest odds of syphilis infection, followed by injection drug use. In contrast, crack and heroin use were associated with significantly lower odds of infection compared to cocaine use. Syphilis Incidence by Sex of Sexual Partner When stratified by reported sex of sexual partners, men who have sex with men (MSM) consistently accounted for the highest number of syphilis cases from 2018 to 2022 ( Fig. 7 ). While syphilis cases among MSM remained relatively stable over this period, greater year-to-year fluctuations were observed among men who have sex with women only (MSW), men with unknown sex of partners (MSU), and women. Notably, syphilis cases among women showed the greatest variability across the five-year period. The consistently high burden of syphilis among MSM underscores a persistent disparity in this population, which remains a critical focus for targeted public health interventions. Discussion The resurgence of syphilis in the United States represents a growing public health crisis, driven by a complex interplay of social, structural, and behavioral determinants. Despite existing prevention efforts, including condom distribution and sex education programs [ 5 ]. syphilis rates have risen sharply over the past five years, underscoring the limitations of current strategies in addressing this evolving epidemic. Geographic and racial disparities were prominent, with the highest rates of syphilis reported in the Midwest and Southern regions, particularly in rural states like South Dakota, New Mexico, and Oklahoma. These areas face longstanding barriers to healthcare access, including provider shortages, transportation limitations, and reduced availability of STI screening and treatment services [ 15 , 16 ]. American Indian/Alaska Native (AI/AN) and Black/African American populations were disproportionately affected, reflecting historical and systemic inequities shaped by poverty, limited healthcare access, and systemic racism within healthcare delivery [ 1 , 6 , 10 , 14 ]. Strengthening partnerships with Indigenous-led healthcare organizations, expanding mobile clinics, and leveraging telemedicine services may help mitigate these barriers and improve access to STI prevention and care in high-burden communities. Previous community-engaged interventions, particularly in HIV prevention, have demonstrated the effectiveness of culturally tailored public health campaigns in improving testing uptake and reducing transmission in underserved populations [ 18 , 20 ]. Such community-centered approaches should be applied to syphilis prevention efforts to ensure cultural relevance and trust-building within affected populations. The widening disparities by sex and age highlight the need to expand prevention efforts beyond traditionally targeted populations. While males continue to bear a higher burden of syphilis, the near doubling of cases among females over the study period is concerning and may reflect under-testing, healthcare access barriers, and evolving behavioral risk patterns [ 21 ]. Integrating syphilis screening into routine reproductive health services, including prenatal care, and expanding outreach to women in high-burden areas should be prioritized. Behavioral and substance use factors remain central drivers of syphilis transmission. High-risk sexual behaviors, including anonymous sex and sex while intoxicated or high on drugs, were significantly associated with increased odds of infection. Additionally, methamphetamine use demonstrated the strongest association with syphilis, aligning with prior research linking stimulant use to increased sexual risk behaviors, particularly among men who have sex with men (MSM) [ 7 ]. Integrating STI prevention into harm reduction programs, including syringe service programs and substance use treatment services, is critical. Such approaches have been effective in reducing HIV and HCV transmission and should be adapted to address syphilis as well [ 18 ]. The recent shortage of benzathine penicillin G (BPG), the first-line treatment for syphilis, poses an additional barrier to disease control efforts [ 11 ]. Ensuring a stable and equitable supply of essential STI medications must be a public health priority, as treatment delays may lead to ongoing transmission and adverse health outcomes [ 17 ]. National policies aimed at strengthening the STI medication supply chain and creating reserve stockpiles could mitigate the impact of future shortages. Finally, improvements in STI surveillance infrastructure are urgently needed. Standardizing and improving the collection of race and ethnicity data, particularly in private healthcare settings, will enable more accurate monitoring of disparities and better allocation of resources [ 12 , 13 ]. Targeted public health campaigns, such as the CDC's successful "Get Yourself Tested" (GYT) initiative, have demonstrated the potential for increasing STI testing rates among youth and marginalized populations [ 2 ]. Leveraging similar culturally tailored, community-informed campaigns could enhance syphilis prevention efforts nationally. Conclusion This study underscores that the resurgence of syphilis in the United States is neither random nor inevitable; it is a reflection of persistent health inequities shaped by geography, race, socioeconomic disadvantage, and behavioral health risks. The disproportionate burden of syphilis among American Indian/Alaska Native and Black/African American populations, individuals in rural areas, and those with substance use vulnerabilities signals critical gaps in current prevention and healthcare strategies. Moving forward, a comprehensive public health response must go beyond clinical care alone. Integrating STI prevention with behavioral health services, expanding community-based screening and treatment, and investing in culturally tailored outreach are essential to reducing the burden of disease and narrowing health disparities. Strengthening these efforts will not only mitigate the growing impact of syphilis but also foster a more resilient, equitable, and responsive public health system. Declarations Ethics approval and consent to participate Not applicable. Clinical Trial Not applicable. Consent for publication Not applicable. Availability of data and material The data supporting these findings are available for public access at the Centers for Disease Control and Prevention repository, https://www.cdc.gov/sti-statistics/ Competing interests The authors declare that they have no competing interests. Funding The authors received no specific funding for this work. Authors' contributions E.R. and A.F. conceptualized the study and developed the initial project framework. E.R. led the drafting of the original manuscript. A.F. contributed to manuscript writing and supported data analysis. L.M. conducted data analysis and assisted with interpretation of findings. G.W. contributed to data analysis, data visualization, and figure preparation. J.C. provided intellectual leadership for the project, offering critical guidance on study design, interpretation of results, and framing of key arguments, as well as extensive editorial revisions to ensure scientific rigor, clarity, and cohesion of the final manuscript. 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BMC Public Health, 2023; 23(1):1748. https://bmcpublichealth.biomedcentral.com/articles/10.1186/s12889-023-16658-9 Yumori, C., Zucker, J., Theodore, D., Chang, M., Carnevale, C., Slowikowski, J., LaSota, E., Olender, S., Gordon, P., Cohall, A., Sobieszczyk, M. E. Women Are Less Likely to Be Tested for HIV or Offered Preexposure Prophylaxis at the Time of Sexually Transmitted Infection Diagnosis. Sex transm dis, 2021;48(1):32–6. https://doi.org/10.1097/OLQ.0000000000001265 Additional Declarations No competing interests reported. Supplementary Files SyphilisData.xlsx SupplementaryFigures.docx Cite Share Download PDF Status: Published Journal Publication published 12 Sep, 2025 Read the published version in BMC Infectious Diseases → Version 1 posted Editorial decision: Revision requested 20 May, 2025 Reviews received at journal 19 May, 2025 Reviews received at journal 16 May, 2025 Reviews received at journal 14 May, 2025 Reviewers agreed at journal 03 May, 2025 Reviewers agreed at journal 01 May, 2025 Reviewers agreed at journal 30 Apr, 2025 Reviewers agreed at journal 30 Apr, 2025 Reviewers agreed at journal 30 Apr, 2025 Reviewers agreed at journal 30 Apr, 2025 Reviewers invited by journal 30 Apr, 2025 Editor invited by journal 30 Apr, 2025 Editor assigned by journal 15 Apr, 2025 Submission checks completed at journal 15 Apr, 2025 First submitted to journal 13 Apr, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6441272","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":451544582,"identity":"04c44d5e-e1e0-4708-8966-aa567e409dde","order_by":0,"name":"Erica Rankin","email":"","orcid":"","institution":"Nova Southeastern University","correspondingAuthor":false,"prefix":"","firstName":"Erica","middleName":"","lastName":"Rankin","suffix":""},{"id":451544583,"identity":"bc674c1c-ba42-4da4-94e4-b8387725f69d","order_by":1,"name":"Ashley Forrest","email":"","orcid":"","institution":"Nova Southeastern University","correspondingAuthor":false,"prefix":"","firstName":"Ashley","middleName":"","lastName":"Forrest","suffix":""},{"id":451544584,"identity":"496b14dc-67eb-4522-a203-08404dc0bfb4","order_by":2,"name":"Lahana Maharjan","email":"","orcid":"","institution":"International Health Initiatives","correspondingAuthor":false,"prefix":"","firstName":"Lahana","middleName":"","lastName":"Maharjan","suffix":""},{"id":451544585,"identity":"3ac8c782-8fec-4587-8d1f-54cb59943283","order_by":3,"name":"Griffin Wei","email":"","orcid":"","institution":"Washington University in St Louis","correspondingAuthor":false,"prefix":"","firstName":"Griffin","middleName":"","lastName":"Wei","suffix":""},{"id":451544586,"identity":"3196d74d-5b57-43d5-ae89-7445b6a8b5d2","order_by":4,"name":"Cyril Blavo","email":"","orcid":"","institution":"Nova Southeastern University","correspondingAuthor":false,"prefix":"","firstName":"Cyril","middleName":"","lastName":"Blavo","suffix":""},{"id":451544587,"identity":"92bc27f7-331c-43c8-95b6-f099cabcdc8e","order_by":5,"name":"Jyotsna Chawla","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAwElEQVRIiWNgGAWjYBACxgYeIFnAIAflMxOrxYDBmHgtDAwQLYkNRGthbj978DOPgV36dvYeww8MFdYwvXgc1pOXLM1jkJy7s+eMsQTDmXQitMzgMZDOMWDO3XAjLUGCse0wUVqMf+cY1Kcb3EhL/sH4jzgtZkBbDicY3Eg+JsHYQIyWnhwz6z8Gxw03nDl8zCLhWLoxQS2G7WeMb86oqJY3ON7YfONDjbUsYS0oKhIIKQcBeWIUjYJRMApGwQgHAMYkPA/q5ZWaAAAAAElFTkSuQmCC","orcid":"","institution":"Nova Southeastern University","correspondingAuthor":true,"prefix":"","firstName":"Jyotsna","middleName":"","lastName":"Chawla","suffix":""}],"badges":[],"createdAt":"2025-04-13 22:38:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6441272/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6441272/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12879-025-11332-4","type":"published","date":"2025-09-12T15:57:12+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":82298947,"identity":"fb1d2a19-b365-4a6b-a240-6c5163db5ba9","added_by":"auto","created_at":"2025-05-08 20:30:18","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":56783,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePercent Change in Reported Cases of Common Sexually Transmitted Infections (STIs) in the United States, 2018–2022 and 2021–2022.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOne-year (2021–2022) and five-year (2018–2022) percent changes in reported cases of chlamydia, gonorrhea, and syphilis based on CDC surveillance data. Percent change was calculated relative to case counts in 2018 and 2021, respectively. Syphilis demonstrated the most substantial increase over both time periods. Statistical significance of changes in syphilis rates was confirmed using a z-test for difference in proportions (p \u0026lt; 0.001 for both comparisons).\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6441272/v1/548ba7bb2fc20874661b0220.jpg"},{"id":82298949,"identity":"a0cfa222-a9ef-4ade-8b21-628b456f3653","added_by":"auto","created_at":"2025-05-08 20:30:18","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":69162,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eGeographic Distribution of Syphilis Rates by State, United States, 2022.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eChoropleth map illustrating primary and secondary syphilis rates by state in 2022 based on CDC surveillance data. Darker shading indicates higher rates of syphilis per 100,000 population.\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6441272/v1/dc35d7af9d70c921a8429db1.jpg"},{"id":82298952,"identity":"0464d0ac-2eed-47aa-9bfb-eb9f623320ed","added_by":"auto","created_at":"2025-05-08 20:30:18","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":45537,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFigure 3A. Annual Reported Syphilis Cases by Sex, United States, 2018–2022.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTrends in reported syphilis case counts from 2018 to 2022, stratified by sex. While males consistently accounted for a higher number of cases each year, the rate of increase among females was more pronounced over the five-year period, with reported cases nearly doubling from 2018 to 2022. \u003cem\u003e\"Count\"\u003c/em\u003eon the Y-axis = \u003cem\u003eNumber of reported P\u0026amp;S syphilis cases\u003c/em\u003e\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6441272/v1/03ffeaf065087da43011f998.jpg"},{"id":82298954,"identity":"c7968fa9-7777-4dce-ac6b-4549c268cd67","added_by":"auto","created_at":"2025-05-08 20:30:18","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":45041,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFigure 3B. Average Syphilis Rates Among Males by Age Group, United States, 2018–2022.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAverage syphilis rates per 100,000 population among males, stratified by age group, from 2018 to 2022. Error bars represent the standard deviation across annual rates during the five-year period.\u003c/p\u003e","description":"","filename":"3b.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6441272/v1/b46124d51409c6190d70f7f3.jpg"},{"id":82299861,"identity":"f7b7fd7d-4020-4cd1-aafb-e436acf09240","added_by":"auto","created_at":"2025-05-08 20:38:18","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":46620,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFigure 3C. Average Syphilis Rates Among Females by Age Group, United States, 2018–2022.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAverage syphilis rates per 100,000 population among females, stratified by age group, from 2018 to 2022. Error bars represent the standard deviation across annual rates during the five-year period.\u003c/p\u003e","description":"","filename":"3c.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6441272/v1/650a6559640fe5be66feb592.jpg"},{"id":82299864,"identity":"1208b0f1-838f-4801-9273-9b2a78797f01","added_by":"auto","created_at":"2025-05-08 20:38:18","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":60260,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFigure 4. Syphilis Rates by Race and Ethnicity, United States, 2018–2022.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRates of primary and secondary syphilis per 100,000 population among racial and ethnic groups. Bars represent the 2018–2022 average and 2022 rates separately. AI/AN = American Indian/Alaska Native; Black/AA = Black/African American; NH/PI = Native Hawaiian/Pacific Islander.\u003c/p\u003e","description":"","filename":"4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6441272/v1/138ab2883bbf2184a392753c.jpg"},{"id":82298964,"identity":"b51d5261-51a9-49ff-9102-9756c8f6cb40","added_by":"auto","created_at":"2025-05-08 20:30:18","extension":"jpg","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":59212,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFigure 5. Syphilis Cases by Reported Sexual Behaviors, United States, 2018–2022.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTotal number of reported syphilis cases from 2018 to 2022, stratified by sexual behavior. Sexual behavior categories, as defined by the CDC, include exchanging sex for drugs or money, sex while intoxicated or high on drugs, sex with a person who injects drugs, and sex with an anonymous partner. \u003cem\u003e\"Count\"\u003c/em\u003e on the Y-axis = \u003cem\u003eNumber of reported P\u0026amp;S syphilis cases\u003c/em\u003e\u003c/p\u003e","description":"","filename":"5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6441272/v1/a1182b312c7053c572606c2a.jpg"},{"id":82299869,"identity":"46fa37a4-8de0-4f30-8d85-6d34d37e36b0","added_by":"auto","created_at":"2025-05-08 20:38:18","extension":"jpg","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":65858,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFigure 6. Syphilis Rates by Reported Substance Use, United States, 2018–2022.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAverage syphilis rates per 100,000 population from 2018 to 2022, stratified by reported substance use behavior. Substance use categories, as defined by the CDC, include cocaine, crack, heroin, injection drug use, and methamphetamine use. \u003cem\u003e\"Count\"\u003c/em\u003e on the Y-axis = \u003cem\u003eNumber of reported P\u0026amp;S syphilis cases\u003c/em\u003e\u003c/p\u003e","description":"","filename":"6.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6441272/v1/ab9a067222af4c39cd2db103.jpg"},{"id":82300341,"identity":"b4e97021-8e20-48ff-8498-bd68de599331","added_by":"auto","created_at":"2025-05-08 20:46:18","extension":"jpg","order_by":9,"title":"Figure 9","display":"","copyAsset":false,"role":"figure","size":42763,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFigure 7. Total Reported Syphilis Cases by Sex of Sexual Partner, United States, 2018–2022.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTotal number of reported syphilis cases from 2018 to 2022, stratified by sex of sexual partner. Categories, as defined by the CDC, include men who have sex with men (MSM), men who have sex with women only (MSW), men with unknown sex of partners (MSU), and women. Unknown or missing data were excluded. Error bars represent the standard deviation across annual case counts during the five-year period. \u003cem\u003e\"Count\"\u003c/em\u003eon the Y-axis = \u003cem\u003eNumber of reported syphilis cases\u003c/em\u003e\u003c/p\u003e","description":"","filename":"7.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6441272/v1/8493e2d6caf89b7c5a64a202.jpg"},{"id":91359065,"identity":"b227eabb-3f85-42db-9efc-1f75a4f7c4df","added_by":"auto","created_at":"2025-09-15 16:04:46","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1601370,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6441272/v1/d2a95309-baa3-466c-9b35-dc2ac8b073bd.pdf"},{"id":82298946,"identity":"9e5e587d-fa46-47d3-a8e3-13b0f14acf80","added_by":"auto","created_at":"2025-05-08 20:30:18","extension":"xlsx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":23804,"visible":true,"origin":"","legend":"","description":"","filename":"SyphilisData.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-6441272/v1/370ab757f16ab27adf1f40d4.xlsx"},{"id":82299856,"identity":"788b776c-4fe6-406f-a0cc-2e43f0135c79","added_by":"auto","created_at":"2025-05-08 20:38:18","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":35962,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFigures.docx","url":"https://assets-eu.researchsquare.com/files/rs-6441272/v1/0de26ea1d8255ee1b292bb3c.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Rising Syphilis in the United States: Epidemiological Trends, Disparities, and Behavioral Risk Factors","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSyphilis, one of the most historically significant and devastating sexually transmitted infections (STIs), reached its peak prevalence in the United States in 1947. This burden sharply declined following the widespread availability of penicillin, a breakthrough that transformed the landscape of infectious disease control [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. For decades thereafter, syphilis rates steadily declined and eventually plateaued at relatively low levels by the early 2000s, stabilizing around 11 to 12 cases per 100,000 population [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. However, in recent years, a troubling reversal has emerged. Since 2018, the United States has experienced a dramatic resurgence in syphilis cases, including a striking 80 percent increase in newly reported infections [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Despite the availability of effective diagnostic tools, the mechanisms driving this sharp increase remain insufficiently understood and underexplored in the current literature.\u003c/p\u003e \u003cp\u003eSyphilis is caused by the gram-negative spirochete \u003cem\u003eTreponema pallidum\u003c/em\u003e, a bacterium transmitted primarily through sexual contact involving the vaginal, anal, or oral mucosa. Following exposure, the bacterium penetrates mucous membranes or microscopic skin abrasions, with symptom onset typically occurring within 10 to 90 days [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Vertical transmission from mother to fetus can also occur during pregnancy or delivery, resulting in congenital syphilis, which carries an elevated risk of adverse perinatal outcomes, including stillbirth [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOften referred to as \u0026ldquo;the great imitator,\u0026rdquo; syphilis progresses through distinct clinical stages that can mimic other conditions, contributing to delayed or missed diagnoses. The primary stage is characterized by the appearance of a single, painless chancre at the site of infection, often accompanied by regional lymphadenopathy. Without treatment, syphilis advances to the secondary stage in approximately one-quarter of cases, manifesting systemically with fever, malaise, generalized lymphadenopathy, and a characteristic maculopapular rash involving the palms and soles. If untreated, the infection may enter a latent phase and eventually progress to tertiary syphilis, which can involve the cardiovascular system, central nervous system, and multiple organ systems, often resulting in irreversible damage [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eGiven the severe consequences of untreated syphilis and its reemergence as a significant public health concern, this study investigates the epidemiological trends of syphilis in the United States between 2018 and 2022 using national surveillance data. Specifically, we aim to characterize patterns of syphilis prevalence across racial and ethnic groups, sexual behaviors, geographic regions, and substance use patterns. We hypothesize that social determinants of health including limited access to healthcare, socioeconomic disadvantage, and high-risk behavioral factors have contributed to the disproportionate burden of syphilis among vulnerable populations. A deeper understanding of these associations is critical to inform targeted public health interventions, address existing disparities, and curb the ongoing rise of syphilis in the United States. We hypothesize that social determinants of health, including limited access to care, socioeconomic disadvantage, and behavioral risk factors, have contributed to the disproportionate burden of syphilis among specific populations. Understanding these associations is essential to inform public health interventions and reduce the ongoing spread of syphilis in the United States.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eData Source and Surveillance System\u003c/h2\u003e \u003cp\u003eThis study utilized publicly available data from the Centers for Disease Control and Prevention (CDC) national surveillance system on sexually transmitted infections (STIs), which provides comprehensive epidemiological data on infectious disease trends in the United States from 1941 to 2022. The CDC dataset is compiled through the National Notifiable Disease Surveillance System (NNDSS), a standardized reporting system for tracking and monitoring infectious diseases nationwide. This database includes case counts and rates for chlamydia, gonorrhea, syphilis, and congenital syphilis, reported annually by state and local health departments. \u003cb\u003eData Extraction and Variable Selection\u003c/b\u003e\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eFor the purpose of this study, we extracted data specifically related to syphilis, including primary and secondary syphilis, as well as congenital syphilis. Syphilis data were further stratified and analyzed across seven key variables: \u003cb\u003eSTI Trends\u003c/b\u003e: Percent changes in cases of chlamydia, gonorrhea, and syphilis over one-year (2021\u0026ndash;2022) and five-year (2018\u0026ndash;2022) periods.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eRace/Ethnicity\u003c/b\u003e: Syphilis rates per 100,000 population were evaluated for the following racial and ethnic groups: American Indian/Alaska Native (AI/AN), Asian, Black/African American (AA), Hispanic/Latino, Multiracial, Native Hawaiian/Pacific Islander (NH/PI), and White.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eSexual Behavior\u003c/b\u003e: Analysis of reported behaviors, including exchanging sex for drugs or money, engaging in sex while intoxicated and/or high on drugs, sex with anonymous partners, and sex with a person who injects drugs.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eSex of Partner\u003c/b\u003e: Cases of syphilis were stratified based on reported sex of sexual partner, categorized as: men who have sex with men (MSM), men who have sex with women only (MSW), men with unknown sex of partners (MSU), and women.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eSubstance Use\u003c/b\u003e: Patterns of substance use were analyzed, including cocaine, crack, heroin, injection drug use, and methamphetamine use.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eSex and Gender\u003c/b\u003e: Syphilis cases were assessed based on biological sex (male and female) from 2018 to 2022.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eAge Groups\u003c/b\u003e: Rates of syphilis were evaluated for males and females across age groups (15\u0026ndash;19, 20\u0026ndash;24, 25\u0026ndash;29, 30\u0026ndash;34, and 35\u0026ndash;44 years), with rates averaged over the five-year study period.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eGeographic Distribution\u003c/b\u003e: States with the highest reported rates of primary and secondary syphilis in 2022 were identified and visualized.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eDescriptive analysis was conducted to examine trends in primary and secondary syphilis across demographic, behavioral, and geographic variables. Syphilis rates were compared with rates of other common STIs (chlamydia and gonorrhea) to contextualize observed trends.\u003c/p\u003e \u003cp\u003eChi-square tests were performed to assess associations between syphilis occurrence and categorical variables, including race/ethnicity, sex, substance use, and sexual behavior. Odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were calculated for variables with available denominators. Statistical significance was set at a p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05. Due to limitations of the CDC dataset, confounders such as socioeconomic status, education, or healthcare access could not be directly assessed.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eData Visualization\u003c/h3\u003e\n\u003cp\u003eAll visualizations were generated using the \u003cem\u003eggplot2\u003c/em\u003e package in R software. Bar charts with standard deviation error bars were created using geom_bar(stat=\"identity\") for categorical variables, and geom_errorbar() to depict variability. Geographic distribution maps were constructed using CDC-provided county-level data to illustrate state-specific syphilis prevalence, with darker shading representing higher case rates.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n \u003ch2\u003eTrends in Common Sexually Transmitted Infections in the United States, 2018\u0026ndash;2022\u003c/h2\u003e\n \u003cp\u003eRecent epidemiological trends highlight a shifting and increasingly concerning burden of sexually transmitted infections (STIs) across the United States. Chlamydia and gonorrhea continue to be among the most commonly reported communicable diseases nationwide. While chlamydia demonstrated an overall decline of 6.20% over the past five years, it remained relatively stable with a marginal increase of 0.30% in the most recent year \u003cem\u003e(\u003c/em\u003eFig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e\u003cem\u003e).\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003eGonorrhea, in contrast, exhibited a five-year increase of 11.10%, despite an 8.70% decrease from 2021 to 2022 \u003cem\u003e(\u003c/em\u003eFig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e\u003cem\u003e).\u003c/em\u003e Syphilis displayed the most dramatic change, with a 78.90% increase over five years and a 17.00% rise in just the last year alone \u003cem\u003e(\u003c/em\u003eFigs. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e \u003cem\u003eand Supplementary Fig.\u0026nbsp;1)\u003c/em\u003e. These trends reflect a growing public health challenge, particularly in light of the resurgence of syphilis, and emphasize the need for enhanced surveillance, outreach, and intervention strategies.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n \u003ch2\u003eGeographic Distribution of Syphilis Cases Across the United States\u003c/h2\u003e\n \u003cp\u003eGeographic analysis revealed that the highest rates of syphilis including both primary and secondary syphilis as well as congenital syphilis, were concentrated in the Midwest and Southern regions of the United States (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). Among these, South Dakota was disproportionately affected, reporting the highest rate of primary and secondary syphilis during the study period.\u003c/p\u003e\n \u003cp\u003eThe identification of geographic hotspots for syphilis suggests potential disparities in healthcare access, public health infrastructure, and preventive services, particularly in rural and underserved areas. These findings underscore the need for targeted interventions that account for regional variations in resource availability, healthcare delivery, and social determinants of health.\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eSex- and Age-Related Patterns of Syphilis Incidence\u003c/h3\u003e\n\u003cp\u003eBetween 2018 and 2022, syphilis cases were consistently higher among males compared to females, reflecting a greater reported burden of infection among males during this period \u003cem\u003e(\u003c/em\u003eFig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eA\u003cem\u003e).\u003c/em\u003e While both sexes experienced an upward trend in case counts over the five-year span, males consistently accounted for a disproportionately greater number of cases. Notably, the number of syphilis cases among females nearly doubled, reflecting a concerning rise in incidence within this group as well.\u003c/p\u003e\n\u003cp\u003eTo further evaluate these trends, syphilis rates were averaged across the five-year period and stratified by age group for each sex. Among both males and females, the 25\u0026ndash;29-year-old age group exhibited the highest rates of syphilis during the study period \u003cem\u003e(\u003c/em\u003eFigs. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eB and \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eC\u003cem\u003e).\u003c/em\u003e In females, greater variability in case rates was observed beginning at age 20, as indicated by wider standard deviations, suggesting potential fluctuations in exposure or testing practices over time.\u003c/p\u003e\n\u003ch3\u003eRacial and Ethnic Disparities in Syphilis Rates\u003c/h3\u003e\n\u003cp\u003eWhile all racial and ethnic groups experienced increases in syphilis cases between 2018 and 2022, certain populations bore a disproportionately higher burden of infection. Individuals identifying as Black/African American and American Indian/Alaska Native (AI/AN) exhibited comparable five-year average rates of syphilis. However, in 2022, AI/AN individuals had the highest reported infection rate, which significantly influenced the overall average for this group \u003cem\u003e(\u003c/em\u003eFig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e\u003cem\u003e).\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eOdds ratio analysis in 2022 demonstrated that AI/AN individuals had the highest likelihood of syphilis infection compared to White Americans (OR: 17.87; 95% CI: 14.01\u0026ndash;22.80; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), followed by Black/African Americans (OR: 7.03; 95% CI: 5.53\u0026ndash;8.94; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). All racial and ethnic groups showed significantly elevated odds of infection relative to White Americans, except those identifying as Asian, who had a significantly lower odds of infection (OR: 0.45; 95% CI: 0.32\u0026ndash;0.65; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001).These findings suggest that, although syphilis prevalence is rising broadly, the magnitude and pace of that increase are not evenly distributed across demographic groups, reflecting underlying structural inequities and barriers to care (Supplementary Table 1).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eOdds Ratios (OR) for Syphilis Infection by Race and Ethnicity, United States, 2022.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"4\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eRace/Ethnicity\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eOdds Ratio (OR)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e95% Confidence Interval\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ep-value\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAmerican Indian/Alaska Native (AI/AN)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e17.87\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14.01\u0026ndash;22.80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBlack/African American (Black/AA)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.53\u0026ndash;8.94\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNative Hawaiian/Pacific Islander (NH/PI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.81\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.98\u0026ndash;4.87\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMultiracial\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.93\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.29\u0026ndash;3.77\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHispanic/Latino\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.55\u0026ndash;2.61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWhite (Reference Group)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026mdash;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026mdash;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAsian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.32\u0026ndash;0.65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eThis table presents the odds ratio of syphilis for racial and ethnic demographics in 2022. White Americans were used as the reference group. All racial groups showed a higher likelihood of syphilis infection when compared to White Americans apart from Asian race.\u003c/p\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n \u003ch2\u003eSyphilis Prevalence by Sexual Behavior Characteristics\u003c/h2\u003e\n \u003cp\u003eBetween 2018 and 2022, individuals reporting sexual activity with anonymous partners consistently exhibited the highest rates of syphilis, with this behavior associated with the greatest risk of infection in 2022 (OR: 13.1; 95% CI: 9.70\u0026ndash;17.72; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) \u003cem\u003e(\u003c/em\u003eFig. \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e, Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e\u003cem\u003e)\u003c/em\u003e. Engaging in sexual activity while intoxicated was also strongly associated with increased risk (OR: 9.49; 95% CI: 6.99\u0026ndash;12.83; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). In comparison, having sex with a person who injects drugs was associated with a more modest increase in risk (OR: 1.68; 95% CI: 1.17\u0026ndash;2.37; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e\n \u003cp\u003eWhen evaluated against the reference category of transactional sex (defined as exchanging sex for drugs or money), all other behaviors, including anonymous sex, sex while intoxicated or high on drugs, and sex with a person who injects drugs, were associated with significantly higher odds of syphilis infection.\u003c/p\u003e\n \u003cp\u003eMoreover, all four behavior categories demonstrated a general upward trend in reported syphilis cases over the five-year period, with certain behaviors, particularly anonymous sexual activity and intoxicated sex, showing more pronounced increases \u003cem\u003e(\u003c/em\u003eFig. \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e\u003cem\u003e).\u003c/em\u003e\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eOdds Ratios (OR) for Syphilis Infection by Reported Sexual Behaviors, United States, 2022.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"4\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSexual Behavior\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eOdds Ratio (OR)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e95% Confidence Interval\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ep-value\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eExchanging sex for drugs or money (Reference Group)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026mdash;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026mdash;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSex with an anonymous partner\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e13.10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9.70\u0026ndash;17.72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSex while intoxicated or high on drugs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e9.49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6.99\u0026ndash;12.83\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSex with a person who injects drugs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.17\u0026ndash;2.37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003eOdds ratios (OR) for syphilis infection in 2022 by reported sexual behavior, using exchanging sex for drugs or money as the reference group. All other behaviors were associated with significantly higher odds of syphilis infection. Engaging in sex with an anonymous partner showed the highest risk, with over 13 times greater odds of infection compared to the reference group.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n \u003ch2\u003eAssociation Between Substance Use and Syphilis Infection\u003c/h2\u003e\n \u003cp\u003eAll substance use behaviors depict an increasing trend over the five-year span from 2018 to 2022, further suggesting an increasing prevalence of syphilis \u003cem\u003e(\u003c/em\u003eFig. \u003cspan class=\"InternalRef\"\u003e6\u003c/span\u003e\u003cem\u003e).\u003c/em\u003e Individuals who use crack have 38% lower odds of syphilis infection compared to cocaine users (OR: 0.38, 95% CI: 0.35\u0026ndash;0.42, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). Similarly, heroin use is associated with 43% lower odds of syphilis infection (OR: 0.57, 95% CI: 0.52\u0026ndash;0.62, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). In contrast, injection drug use is linked to an 89% increase in the odds of syphilis infection (OR: 1.89, 95% CI: 1.77\u0026ndash;2.02, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Methamphetamine use shows the strongest association, with users experiencing over three times higher odds of syphilis infection compared to cocaine users (OR: 3.34, 95% CI: 3.13\u0026ndash;3.55,\u0026nbsp;\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). These findings underscore the varying risks of syphilis infection among different substance users, with injection drug use and methamphetamine use being particularly associated with elevated risk.\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eSyphilis OR for Substance Use in 2022\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"4\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSubstance Use Behavior\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eOdds Ratio (OR)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e95% Confidence Interval\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ep-value\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCocaine use (Reference Group)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026mdash;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026mdash;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCrack use\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.35\u0026ndash;0.42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHeroin use\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.52\u0026ndash;0.62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eInjection drug use\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.89\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.77\u0026ndash;2.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMethamphetamine use\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.13\u0026ndash;3.55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003eOdds ratios (OR) for syphilis infection in 2022 by reported substance use behavior, using cocaine use as the reference group (OR\u0026thinsp;=\u0026thinsp;1.00). Methamphetamine use was associated with the highest odds of syphilis infection, followed by injection drug use. In contrast, crack and heroin use were associated with significantly lower odds of infection compared to cocaine use.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\n \u003ch2\u003eSyphilis Incidence by Sex of Sexual Partner\u003c/h2\u003e\n \u003cp\u003eWhen stratified by reported sex of sexual partners, men who have sex with men (MSM) consistently accounted for the highest number of syphilis cases from 2018 to 2022 \u003cem\u003e(\u003c/em\u003eFig. \u003cspan class=\"InternalRef\"\u003e7\u003c/span\u003e\u003cem\u003e).\u003c/em\u003e While syphilis cases among MSM remained relatively stable over this period, greater year-to-year fluctuations were observed among men who have sex with women only (MSW), men with unknown sex of partners (MSU), and women. Notably, syphilis cases among women showed the greatest variability across the five-year period. The consistently high burden of syphilis among MSM underscores a persistent disparity in this population, which remains a critical focus for targeted public health interventions.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe resurgence of syphilis in the United States represents a growing public health crisis, driven by a complex interplay of social, structural, and behavioral determinants. Despite existing prevention efforts, including condom distribution and sex education programs [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. syphilis rates have risen sharply over the past five years, underscoring the limitations of current strategies in addressing this evolving epidemic. Geographic and racial disparities were prominent, with the highest rates of syphilis reported in the Midwest and Southern regions, particularly in rural states like South Dakota, New Mexico, and Oklahoma. These areas face longstanding barriers to healthcare access, including provider shortages, transportation limitations, and reduced availability of STI screening and treatment services [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. American Indian/Alaska Native (AI/AN) and Black/African American populations were disproportionately affected, reflecting historical and systemic inequities shaped by poverty, limited healthcare access, and systemic racism within healthcare delivery [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Strengthening partnerships with Indigenous-led healthcare organizations, expanding mobile clinics, and leveraging telemedicine services may help mitigate these barriers and improve access to STI prevention and care in high-burden communities. Previous community-engaged interventions, particularly in HIV prevention, have demonstrated the effectiveness of culturally tailored public health campaigns in improving testing uptake and reducing transmission in underserved populations [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Such community-centered approaches should be applied to syphilis prevention efforts to ensure cultural relevance and trust-building within affected populations. The widening disparities by sex and age highlight the need to expand prevention efforts beyond traditionally targeted populations. While males continue to bear a higher burden of syphilis, the near doubling of cases among females over the study period is concerning and may reflect under-testing, healthcare access barriers, and evolving behavioral risk patterns [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Integrating syphilis screening into routine reproductive health services, including prenatal care, and expanding outreach to women in high-burden areas should be prioritized. Behavioral and substance use factors remain central drivers of syphilis transmission. High-risk sexual behaviors, including anonymous sex and sex while intoxicated or high on drugs, were significantly associated with increased odds of infection. Additionally, methamphetamine use demonstrated the strongest association with syphilis, aligning with prior research linking stimulant use to increased sexual risk behaviors, particularly among men who have sex with men (MSM) [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Integrating STI prevention into harm reduction programs, including syringe service programs and substance use treatment services, is critical. Such approaches have been effective in reducing HIV and HCV transmission and should be adapted to address syphilis as well [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. The recent shortage of benzathine penicillin G (BPG), the first-line treatment for syphilis, poses an additional barrier to disease control efforts [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Ensuring a stable and equitable supply of essential STI medications must be a public health priority, as treatment delays may lead to ongoing transmission and adverse health outcomes [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. National policies aimed at strengthening the STI medication supply chain and creating reserve stockpiles could mitigate the impact of future shortages. Finally, improvements in STI surveillance infrastructure are urgently needed. Standardizing and improving the collection of race and ethnicity data, particularly in private healthcare settings, will enable more accurate monitoring of disparities and better allocation of resources [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Targeted public health campaigns, such as the CDC's successful \"Get Yourself Tested\" (GYT) initiative, have demonstrated the potential for increasing STI testing rates among youth and marginalized populations [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Leveraging similar culturally tailored, community-informed campaigns could enhance syphilis prevention efforts nationally.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study underscores that the resurgence of syphilis in the United States is neither random nor inevitable; it is a reflection of persistent health inequities shaped by geography, race, socioeconomic disadvantage, and behavioral health risks. The disproportionate burden of syphilis among American Indian/Alaska Native and Black/African American populations, individuals in rural areas, and those with substance use vulnerabilities signals critical gaps in current prevention and healthcare strategies.\u003c/p\u003e \u003cp\u003eMoving forward, a comprehensive public health response must go beyond clinical care alone. Integrating STI prevention with behavioral health services, expanding community-based screening and treatment, and investing in culturally tailored outreach are essential to reducing the burden of disease and narrowing health disparities. Strengthening these efforts will not only mitigate the growing impact of syphilis but also foster a more resilient, equitable, and responsive public health system.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cem\u003eEthics approval and consent to participate\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eClinical Trial\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eConsent for publication\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAvailability of data and material\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe data supporting these findings are available for public access at the Centers for Disease Control and Prevention repository, https://www.cdc.gov/sti-statistics/\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCompeting interests\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eFunding\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe authors received no specific funding for this work.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAuthors\u0026apos; contributions\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eE.R. and A.F. conceptualized the study and developed the initial project framework. E.R. led the drafting of the original manuscript. A.F. contributed to manuscript writing and supported data analysis. L.M. conducted data analysis and assisted with interpretation of findings. G.W. contributed to data analysis, data visualization, and figure preparation. J.C. provided intellectual leadership for the project, offering critical guidance on study design, interpretation of results, and framing of key arguments, as well as extensive editorial revisions to ensure scientific rigor, clarity, and cohesion of the final manuscript. C.B. provided project oversight and contributed to the final review of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAcknowledgements\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBoutrin, M. C., Williams, D. R. What Racism Has to Do with It: Understanding and Reducing Sexually Transmitted Diseases in Youth of Color. Healthcare (Basel, Switzerland), 2021; 9(6):673. https://doi.org/10.3390/healthcare9060673\u003c/li\u003e\n\u003cli\u003eCenters for Disease Control and Prevention (CDC). Get Yourself Tested (GYT) Campaign Overview. 2017. https://www.cdc.gov/sti/?CDC_AAref_Val=https://www.cdc.gov/std/prevention/gyt.htm. Accessed 2025. \u003c/li\u003e\n\u003cli\u003eCenters for Disease Control and Prevention. Sexually transmitted infections surveillance. 2022. https://www.cdc.gov/sti-statistics. Accessed 30 January 2025. \u003c/li\u003e\n\u003cli\u003eCenters for Disease Control and Prevention. Syphilis during pregnancy - STI treatment guidelines. 2021. https://www.cdc.gov/std/treatment-guidelines/syphilis-pregnancy.htm. Accessed 10 April 2025. \u003c/li\u003e\n\u003cli\u003eChen, T., Wan, B., Wang, M., Lin S., Wu Y., Huang J. 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Ann NY Acad Sci, 2008;1136(1):126\u0026ndash;136. https://doi.org/10.1196/annals.1425.017 \u003c/li\u003e\n\u003cli\u003eSchmidt, R., Carson, P. J., Jansen, R. J. Resurgence of Syphilis in the United States: An Assessment of Contributing Factors. Infectious diseases, 2019;12. https://doi.org/10.1177/1178633719883282\u003c/li\u003e\n\u003cli\u003eSkewes, M. C., Blume, A. W. Understanding the link between racial trauma and substance use among American Indians. Am Psychol, 2019;74(1):88\u0026ndash;100. https://doi.org/10.1037/amp0000331\u003c/li\u003e\n\u003cli\u003eSnider, W., Depew, I., Cook, S., Roth, D. Benzathine Penicillin G Shortage and Secondary Syphilis. Cureus, 2024;16(8):e66787. https://doi.org/10.7759/cureus.66787\u003c/li\u003e\n\u003cli\u003eSyringe Service Programs for Persons Who Inject Drugs in Urban, Suburban, and Rural Areas \u0026mdash; United States, 2013 [Internet]. The Centers for Disease Control and Prevention; 2015 [cited 13 APR 2025]. Available from https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6448a3.htm\u003c/li\u003e\n\u003cli\u003eTudor, M. E. (2024, April 21). Syphilis. StatPearls [Internet]. https://www.ncbi.nlm.nih.gov/books/NBK534780/\u003c/li\u003e\n\u003cli\u003eVitsupakorn S, Pierce N, Ritchwood TD. Cultural interventions addressing disparities in the HIV prevention and treatment cascade among Black/African Americans: a scoping review. BMC Public Health, 2023; 23(1):1748. https://bmcpublichealth.biomedcentral.com/articles/10.1186/s12889-023-16658-9\u003c/li\u003e\n\u003cli\u003eYumori, C., Zucker, J., Theodore, D., Chang, M., Carnevale, C., Slowikowski, J., LaSota, E., Olender, S., Gordon, P., Cohall, A., Sobieszczyk, M. E. Women Are Less Likely to Be Tested for HIV or Offered Preexposure Prophylaxis at the Time of Sexually Transmitted Infection Diagnosis. Sex transm dis, 2021;48(1):32\u0026ndash;6. https://doi.org/10.1097/OLQ.0000000000001265\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-infectious-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"infd","sideBox":"Learn more about [BMC Infectious Diseases](http://bmcinfectdis.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/infd","title":"BMC Infectious Diseases","twitterHandle":"#bmcinfectdis","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Syphilis, United States, Epidemiological Trends, Health Disparities, Behavioral Risk Factors, Substance Use, CDC Surveillance Data, Social Determinants of Health, Public Health Policy, Sexually Transmitted Infections (STIs)","lastPublishedDoi":"10.21203/rs.3.rs-6441272/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6441272/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eSyphilis has re-emerged as a significant public health concern in the United States, with reported cases rising steadily since 2018 and reaching levels not observed since the pre-antibiotic era. Despite growing awareness among healthcare providers and public health agencies, comprehensive epidemiological analyses of the populations most affected remain limited.\u003c/p\u003e \u003cp\u003eThis retrospective descriptive study analyzed national syphilis surveillance data from the Centers for Disease Control and Prevention (CDC) between 2018 and 2022. Trends in syphilis incidence were evaluated across key demographic and behavioral variables, including race and ethnicity, geographic region, sex of sexual partner, and substance use behaviors. Findings reveal persistent and widening disparities, with disproportionate increases in syphilis rates among racial and ethnic minority populations, individuals reporting substance use, and across diverse geographic regions. These results underscore the urgent need for targeted, equity-focused public health interventions and evidence-based policy responses to mitigate the ongoing syphilis epidemic in the United States.\u003c/p\u003e","manuscriptTitle":"Rising Syphilis in the United States: Epidemiological Trends, Disparities, and Behavioral Risk Factors","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-08 20:30:13","doi":"10.21203/rs.3.rs-6441272/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-05-20T09:07:55+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-05-19T16:31:28+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-05-16T23:16:38+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-05-14T04:40:37+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"280800282964220495890312290148370573434","date":"2025-05-03T22:38:04+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"316045680121616563031965308690032925038","date":"2025-05-01T06:59:56+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"286310594493324324898009802250851375681","date":"2025-04-30T17:18:05+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"11150282965038498368445407890420074539","date":"2025-04-30T16:45:54+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"300910347201900337135991458289987793835","date":"2025-04-30T16:45:24+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"188268752535724972462935679661987344124","date":"2025-04-30T11:55:50+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-04-30T11:47:10+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-04-30T08:47:55+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-04-16T01:43:04+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-04-16T01:42:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Infectious Diseases","date":"2025-04-13T22:29:23+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-infectious-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"infd","sideBox":"Learn more about [BMC Infectious Diseases](http://bmcinfectdis.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/infd","title":"BMC Infectious Diseases","twitterHandle":"#bmcinfectdis","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"054e3721-992f-4b52-90e4-38dad640c547","owner":[],"postedDate":"May 8th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-09-15T16:01:24+00:00","versionOfRecord":{"articleIdentity":"rs-6441272","link":"https://doi.org/10.1186/s12879-025-11332-4","journal":{"identity":"bmc-infectious-diseases","isVorOnly":false,"title":"BMC Infectious Diseases"},"publishedOn":"2025-09-12 15:57:12","publishedOnDateReadable":"September 12th, 2025"},"versionCreatedAt":"2025-05-08 20:30:13","video":"","vorDoi":"10.1186/s12879-025-11332-4","vorDoiUrl":"https://doi.org/10.1186/s12879-025-11332-4","workflowStages":[]},"version":"v1","identity":"rs-6441272","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6441272","identity":"rs-6441272","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}