Draft Recommendation Statement
Syphilis Infection in Nonpregnant Adults and Adolescents: Screening
This opportunity for public comment expired on January 18, 2016 at 8:00 PM EST
Note: This is a Draft Recommendation Statement. This draft is distributed solely for the purpose of receiving public input. It has not been disseminated otherwise by the USPSTF. The final Recommendation Statement will be developed after careful consideration of the feedback received and will include both the Research Plan and Evidence Review as a basis.
Recommendations made by the USPSTF are independent of the U.S. government. They should not be construed as an official position of the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.
Draft: Recommendation Summary
The number of cases of primary and secondary syphilis have increased since 2000. In 2013, 17,375 cases (5.5 cases per 100,000 persons) of primary and secondary syphilis were reported in the United States.1 Left untreated, syphilis can progress to late-stage disease in approximately 15% of persons who are infected.2 Consequences of late-stage syphilis include development of inflammatory lesions throughout the body (e.g., aortitis, gummatous lesions, and osteitis), which can lead to cardiovascular or organ dysfunction. Syphilis infection of the central nervous system (neurosyphilis) can occur at any stage of disease and can result in blindness, paresis, tabes dorsalis, and dementia. Syphilis infection also increases the risk for acquiring or transmitting HIV infection.
For the USPSTF recommendation on screening for syphilis in pregnant women, go to the USPSTF Web site (www.uspreventiveservicestaskforce.org).
There are numerous screening tests for syphilis. Most commonly, a combination of nontreponemal and treponemal antibody tests is used. The USPSTF found convincing evidence that screening algorithms with high sensitivity and specificity are available to accurately detect syphilis.
Benefits of Early Detection and Treatment
The USPSTF found convincing evidence that treatment with antibiotics can lead to substantial health benefits in nonpregnant persons who are at increased risk for syphilis infection by curing syphilis infection, preventing manifestations of late-stage disease, and preventing sexual transmission to others.
Harms of Early Detection and Treatment
The USPSTF found no direct evidence on the harms of screening for syphilis in nonpregnant persons who are at increased risk for infection. Potential harms of screening include false-positive results that require clinical evaluation, unnecessary anxiety to the patient, and the potential for stigma. The harms of antibiotic treatment are well established, and the magnitude of these harms is no greater than small.
The USPSTF concludes with high certainty that the net benefit of screening for syphilis infection in nonpregnant persons who are at increased risk for infection is substantial.
Draft: Clinical Considerations
This recommendation applies to asymptomatic, nonpregnant adolescents and adults who are at increased risk for syphilis infection. Screening for syphilis in nonpregnant populations is an important public health approach to preventing the sexual transmission of syphilis and subsequent vertical transmission of congenital syphilis. Screening for syphilis in pregnant women is discussed in a separate recommendation statement (available on the USPSTF Web site at www.uspreventiveservicestaskforce.org).
Assessment of Risk
The USPSTF recommends screening for syphilis in men who have sex with men (MSM) and in persons living with HIV. Based on 2013 surveillance data,1 these two groups have the highest risk for syphilis infection; 75% of cases of primary and secondary syphilis occurred among MSM, and almost half of MSM diagnosed with syphilis were also coinfected with HIV. One study found that rates of syphilis coinfection were 5 times higher in HIV-positive MSM compared with HIV-positive men who do not have sex with men.3 Based on older study data from northern California, the adjusted relative risk for syphilis infection in persons living with HIV (vs. those without HIV) was 86.0 (95% confidence interval, 78.6 to 94.1); 97% of those living with HIV and with incident syphilis were male.4
When deciding who to screen for syphilis infection, clinicians should also consider other sociodemographic factors that are associated with increased prevalence rates, including male sex combined with age younger than 29 years, race/ethnicity, geography, incarceration, and sex work. Males accounted for 91% of all cases of primary and secondary syphilis in 2013. Men ages 20 to 29 years had the highest prevalence rate, nearly 3 times higher than in the average U.S. male population.1 Syphilis prevalence rates are also higher in certain racial/ethnic groups; in 2013, prevalence rates of primary and secondary syphilis were 16.8 cases per 100,000 blacks, 8.6 cases per 100,000 Native Hawaiians/Pacific Islanders, 6.3 cases per 100,000 Hispanics, 4.6 cases per 100,000 American Indians/Alaska Natives, 3.0 cases per 100,000 whites, and 2.5 cases per 100,000 Asians.1 The southern United States comprises the largest proportion of syphilis cases (40%); however, the case rate is currently highest in the western United States (6.8 cases per 100,000 persons). Metropolitan areas also have increased prevalence rates of syphilis.1 Clinicians should be aware of the prevalence rates of syphilis in the communities they serve. Risk factors for syphilis often do not present independently and may frequently overlap.
Although direct evidence is lacking on screening in nonpregnant persons who are not at increased risk for syphilis infection, based on the established test performance characteristics of screening tests and the low prevalence rate of syphilis in this population, the yield of screening in persons who are not at increased risk for syphilis is likely low. Screening in this population will result in high false-positive rates and overtreatment.
Current screening tests for syphilis rely on detection of antibodies rather than direct assay of the organism. Screening for syphilis infection is a two-step process that involves an initial nontreponemal test (Venereal Disease Research Laboratory [VDRL] or rapid plasma reagin [RPR] test) followed by a confirmatory treponemal antibody detection test (fluorescent treponemal antibody absorption [FTA-ABS] or Treponema pallidum particle agglutination [TP-PA] test). More recently, a reverse sequence screening algorithm has been developed in which an automated treponemal test (such as enzyme-linked immunoassay, chemiluminescent immunoassay, or a multiplex flow immunoassay) is performed first, followed by a nontreponemal test. If the test results are discordant in the reverse sequence algorithm, a second treponemal test (preferably using a different treponemal antibody) is performed. There is limited evidence on the accuracy of screening using the reverse sequence algorithm. Findings from two studies suggest that using a reverse sequence algorithm may detect additional cases of syphilis missed by the usual algorithm.5 However, more studies are needed before definitive conclusions can be made.
The optimal screening frequency for persons who are at increased risk for syphilis infection is not well-established. MSM or persons living with HIV may benefit from more frequent screening. Initial studies suggest that detection of syphilis infection in MSM or persons living with HIV improves when screening is performed every 3 months compared with annually.5
In its 2015 guidelines on the treatment of sexually transmitted diseases, the Centers for Disease Control and Prevention (CDC) recommends parenteral penicillin G benzathine for the treatment of syphilis. Dosage and route may vary depending on the stage of disease and patient characteristics. To obtain the most up-to-date information, clinicians are encouraged to access the CDC Web site (www.cdc.gov/std/tg2015/syphilis.htm).
Additional Approaches to Prevention
Public health agencies and local health departments play an important role in the prevention and treatment of syphilis. Local health departments are often responsible for investigating incident cases of syphilis and identifying potential contacts who may need further testing or treatment. Primary care clinicians should be aware of applicable local public health laws and reporting requirements for syphilis cases.
The USPSTF has made a separate recommendation on screening for syphilis in pregnant women, as well as screening for gonorrhea and chlamydia in sexually active adolescents and adults (available at www.uspreventiveservicestaskforce.org).
Draft: Other Considerations
Although testing for syphilis in persons living with HIV may be part of HIV management care provided in a specialty setting, screening for syphilis is often conducted in primary care settings, and primary care providers are encouraged to routinely screen their patients who are living with HIV.
Research Needs and Gaps
Studies that directly evaluate the effectiveness of screening for syphilis on related morbidity and mortality in other high-risk populations, in addition to MSM and persons living with HIV, are needed, as well as studies that help identify effective intervals of screening. Studies in adolescent populations are particularly needed. Additionally, studies that evaluate the effectiveness of formal risk assessment instruments or other methods to identify persons who are at increased risk for infection who could benefit from screening are needed. Further studies on the diagnostic accuracy of reverse sequence screening algorithms in well-defined patient populations are needed, as well as studies on the interpretation and management of discrepant serology test results (such as a positive automated treponemal test, negative nontreponemal test, and positive second treponemal test).
Burden of Disease
Syphilis is a chronic, systemic infectious disease caused by the bacterium T. pallidum. Left untreated, syphilis infection can progress through the following stages: primary, secondary, latent (early and late), and tertiary disease. Syphilis infection of the nervous system (neurosyphilis) can occur at an any stage. Although not always present or noticed by patients, manifestations of primary syphilis include ulcers or a single chancre at the infection site. Manifestations of secondary syphilis include skin rash, mucocutaneous lesions, and lymphadenopathy. Manifestations of tertiary syphilis include inflammatory lesions of the cardiovascular system (e.g., aortitis or coronary vessel disease), skin (e.g., gummatous lesions), bone (e.g., osteitis), or other tissue. Rarely, other structures may be involved. Manifestations of early neurosyphilis include cranial nerve dysfunction, meningitis stroke, acute altered mental status, and auditory or ophthalmic abnormalities; late neurologic manifestations include tabes dorsalis and general paresis and can occur 10 to 30 years after initial infection.6 Syphilis can be sexually transmitted during the early stages of infection (primary, secondary, and early latent syphilis); reported transmission rates range from 15.9% to 30.3%.7, 8 Syphilis can be vertically transmitted during any stage. Syphilis infection increases the risk for acquiring or transmitting HIV if exposed; in persons living with HIV, syphilis infection is associated with a subsequent increase in HIV viral load and decrease in CD4 cell counts.1, 9-11
In 2013, the total number of syphilis cases reported for all stages (including 348 cases of congenital syphilis) and all ages in the United States was 56,471, which is a 13.1% increase from the previous year. The case count (17,375 cases) and case rate (5.5 cases per 100,000 persons) of primary and secondary syphilis were the highest reported since 1995. All but 28 cases occurred in persons age 15 years and older. There were 21,819 cases (7.0 cases per 100,000 persons) of late and late-latent syphilis.1
Scope of Review
The USPSTF commissioned a systematic review,5 of studies published since it previously reviewed the literature on this topic in 2004.12 The USPSTF also considered evidence from its previous evidence review. Included studies had to be applicable to the United States, as determined by the similarity of study participants and availability of health care services and screening tests in the study setting. The review focused on screening for syphilis infection in asymptomatic, nonpregnant adults and adolescents, including patients coinfected with other sexually transmitted infections (such as HIV).
Accuracy of Screening Tests
Screening for syphilis is usually a two-step process. A nontreponemal test (RPR or VDRL test) is performed first, followed by a treponemal test (TP-PA or FTA-ABS test) if the first nontreponemal test is positive. Positive results on both tests indicate past or present syphilis infection. Sensitivity of the RPR and VDRL tests are estimated to be 78% to 86% for detecting primary syphilis infection, 100% for detecting secondary syphilis infection, and 96% to 98% for detecting latent syphilis infection. Specificity is about 98% and may be reduced in persons who have preexisting conditions (i.e., collagen vascular disease, pregnancy, intravenous drug use, advanced malignancy, tuberculosis, malaria, or viral and rickettsial diseases) that produce false-positive results. The TP-PA and FTA-ABS tests have a sensitivity of 84% to 88% for detecting primary syphilis infection and almost 100% for detecting syphilis infection in other stages, and a specificity of 96% to 97%.
The yield of screening using a two-step process (RPR test followed by confirmatory FTA-ABS test) can be estimated using test characteristics and the incidence of syphilis infection in a given population. For example, in the general population (assuming a prevalence of 5 cases per 100,000 persons, RPR sensitivity of 91% and specificity of 95%, and FTA-ABS sensitivity of 92% and specificity of 96%), one would have to screen more than 24,000 patients to detect a single case of syphilis infection (number needed to screen, 24,000); further, 200 per 100,000 persons screened would have false-positive test results. In a high-risk population (e.g., assuming a prevalence of 12%, RPR sensitivity of 91% and specificity of 95%, and FTA-ABS sensitivity of 92% and specificity of 96%), one would have to screen 10 patients to detect a single case of syphilis infection (number needed to screen, 10); almost 2,000 per 100,000 persons screened would have false-negative test results.5
More recently, automated treponemal tests have been developed, including enzyme-linked immunoassays, chemiluminescence immunoassays, and multiplex flow immunoassays. The reported sensitivity of these assays ranges from 64% to 100% (depending on stage of disease and type of test used), and specificity ranges from 95.4% to 99.9%.5 These automated treponemal tests are often used in a reverse sequence screening algorithm, in which an automated treponemal test is performed first, followed by a nontreponemal test (quantitative) if the initial automated treponemal test is positive. A positive result on both the automated treponemal test and the nontreponemal test indicates past or present syphilis infection. If the result of the automated treponemal test is positive but the nontreponemal test is negative, a second treponemal test (TP-PA, FTA-ABS, or other test) is performed; a positive result on the second treponemal test indicates past or present syphilis infection,13 The USPSTF reviewed two studies that compared a reverse screening algorithm with the traditional two-step approach to screening.14, 15 One study was conducted in a low-prevalence U.S. population,15 and the other in a high-prevalence metropolitan area in Canada.14 Although both studies found that more cases were detected using the reverse-sequence algorithm, use of the reverse-sequence algorithm was associated with a higher false-positive rate. Overall, more studies on the reverse-sequence screening algorithm are needed before definitive conclusions can be made on its effectiveness.
Effectiveness of Early Detection and Treatment
Based on CDC data,1 MSM and persons living with HIV are at highest risk for syphilis infection. In 2013, the majority of cases (75%) of primary and secondary syphilis occurred among MSM, and nearly half of MSM diagnosed with syphilis were also co-infected with HIV. Increased prevalence of syphilis infection was also associated with male sex combined with age younger than 29 years, race/ethnicity (blacks, Native Hawaiians/Pacific Islanders, Hispanics, and American Indians/Alaska Natives had higher prevalence rates than whites, ranging from 4.6 to 16.8 vs. 3.0 cases per 100,000 persons), and geography (southern and western United States and metropolitan areas).
The USPSTF found no recent studies on the direct effectiveness of screening for syphilis to reduce complications or transmission of syphilis infection or acquisition of other sexually transmitted infections in asymptomatic, nonpregnant adults and adolescents. Older clinical trials and observational studies and almost 50 years of clinical experience provide evidence that penicillin is effective in the treatment of syphilis infection.6 Penicillin G has long been an effective and accepted regimen for the treatment of all stages of syphilis infection, and new trials are focusing on antibiotics that are easier to administer or are alternatives for individuals who are allergic to penicillin. There are limited data on these alternative regimens.6 Given the well- documented risk factors associated with increased prevalence of syphilis and the availability of accurate screening tests for and antibiotics to treat syphilis infection, the USPSTF found overall that screening for syphilis infection in persons who are at increased risk for infection to be effective.
Potential Harms of Screening and Treatment
No studies have directly evaluated the harms of screening. Potential harms of screening include opportunity costs to the clinician and patient (e.g., time and resources) and false-positive results that may lead to stress, labeling, and further diagnostic workup. Harms of treatment include rare adverse drug-related effects, including anaphylaxis due to penicillin allergy and the Jarisch-Herxheimer reaction (febrile reaction with headache, myalgia, and other symptoms), which may occur within the first 24 hours after any therapy for syphilis.
Estimate of Magnitude of Net Benefit
Overall, the USPSTF found convincing evidence that screening for syphilis infection in asymptomatic, nonpregnant persons who are at increased risk for infection provides substantial benefit. Accurate screening tests are available to identify syphilis infection in populations at increased risk. Effective treatment with antibiotics can prevent progression to late-stage disease, with small associated harms, providing an overall substantial health benefit.
Draft: Update of Previous USPSTF Recommendation
This recommendation is consistent with and updates the 2004 USPSTF recommendation. The current recommendation statement includes updated information on prevalence and risk factors in the United States and data on newer screening tests and screening approaches. Additionally, screening for syphilis infection in pregnant women is now addressed in a separate recommendation statement (available at www.uspreventiveservicestaskforce.org).
Draft: Recommendations of Others
The CDC recommends at least annual screening in sexually active MSM using syphilis serology and confirmatory testing for those with reactive screening tests. Persons living with HIV should be screened at least annually; more frequent screening may be appropriate based on individual risk behaviors and local epidemiology.6 The American Congress of Obstetricians and Gynecologists recommends that screening be based on local area epidemiology and syphilis prevalence within correctional facilities. The American Academy of Family Physicians is currently updating its recommendations.
1. Centers for Disease Control and Prevention. Sexually Transmitted Disease Surveillance 2013. Atlanta: U.S. Department of Health and Human Services; 2014.
2. Syphilis: CDC Fact Sheet (Detailed). Centers for Disease Control and Prevention. http://www.cdc.gov/std/syphilis/stdfact-syphilis-detailed.htm. Accessed November 20, 2015.
3. Yang B, Hallmark CJ, Huang JS, et al. Characteristics and risk of syphilis diagnosis among HIV-infected male cohort: a population-based study in Houston, Texas. Sex Transm Dis. 2013;40(12):957-63.
4. Horberg MA, Ranatunga DK, Quesenberry CP, et al. Syphilis epidemiology and clinical outcomes in HIV-infected and HIV-uninfected patients in Kaiser Permanente Northern California. Sex Transm Dis. 2010;37(1):53-8.
5. Cantor A, Nelson HD, Daeges M, Pappas M. Screening for Syphilis in Nonpregnant Adolescents and Adults: A Systematic Review to Update the 2004 U.S. Preventive Services Task Force Recommendation. Evidence Synthesis No. 136. AHRQ Publication No. 14-05213-EF-1. Rockville, MD: Agency for Healthcare Research and Quality; 2015.
6. Workowski KA, Bolan GA; Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep.2015;64(RR-03):1-137.
7. Moore MB, Price EV, Knox JM, Elgin LW. Epidemiologic treatment of contacts to infectious syphilis. Public Health Rep. 1963;78:966-70.
8. Schroeter AL, Turner RH, Lucas JB, Brown WJ. Therapy for incubating syphilis. Effectiveness of gonorrhea treatment. JAMA. 1971;218(5):711-3.
9. Buchacz K, Patel P, Taylor M, et al. Syphilis increases HIV viral load and decreases CD4 cell counts in HIV-infected patients wtih new syphilis infections. AIDS. 2004;18(15):2075-9.
10. Kofoed K, Gerstoft J, Mathiesen LR, Benfield T. Syphilis and human immunodeficiency virus (HIV)-1 coinfection: influence on CD4 T-cell count, HIV-1 viral load, and treatment response. Sex Transm Dis. 2006;33(3):143-8.
11. Palacios R, Jiménez-Oñate F, Aguilar M, et al. Impact of syphilis infection on HIV viral load and CD4 cell counts in HIV-infected patients. J Acquir Immune Defic Syndr. 2007;44(3):197-201.
12. Nelson HD, Glass N, Huffman L, et al. Screening for Syphilis: Brief Update for the U.S. Preventive Services Task Force. Rockville, MD: Agency for Healthcare Research and Quality; 2004.
13. Centers for Disease Control and Prevention. Discordant results from reverse sequence syphilis screening--five laboratories, United States, 2006-2010. MMWR Morb Mortal Wkly Rep. 2011;60(5):133-7.
14. Mishra S, Boily MC, Ng V, et al. The laboratory impact of changing syphilis screening from the rapid-plasma reagin to a treponemal enzyme immunoassy: a case-study from the Greater Toronto Area. Sex Transm Dis. 2011;38(3):190-6.
15. Binnicker MJ, Jespersen DJ, Rollins LO. Direct comparison of the traditional and reverse syphilis screening algorithms in a population with a low prevalence of syphilis. J Clin Microbiol. 2012;50(1):148-50.
Internet Citation: Draft Recommendation Statement: Syphilis Infection in Nonpregnant Adults and Adolescents: Screening . U.S. Preventive Services Task Force. May 2016.