Syphilis

This statement summarizes the U.S. Preventive Services Task Force (USPSTF) recommendations on screening for syphilis and the supporting scientific evidence, and updates the 1996 recommendations contained in the Guide to Clinical Preventive Services, second edition. (1) In 1996, the USPSTF recommended routine screening for syphilis infection for all pregnant women and for persons at increased risk for infection. Since then, the USPSTF criteria to rate the strength of the evidence have changed. (2) Therefore, this recommendation statement has been updated and revised based on the current USPSTF methodology and rating of the strength of the evidence. Explanations of the current task force ratings and of the strength of overall evidence are given in Tables 1 and 2, respectively. The complete information on which this statement is based, including evidence tables and references, is available in the brief update (3) on this topic on the USPSTF Web site (http://www.preventiveservices.ahrq.gov). The recommendation statement and brief update are also available in print from the Agency for Healthcare Research and Quality Publications Clearinghouse (1-800-358-9295; e-mail: ahrqpubs@ahrq.gov). The recommendation is also posted on the Web site of the National Guideline Clearinghouse (http://www.guideline.gov).

This recommendation statement was first published in Annals of Family Medicine (Ann Fam Med 2004;2:362-5).

Summary of Recommendations

* The USPSTF strongly recommends that physicians screen persons at increased risk for syphilis infection. A recommendation.

Although the USPSTF found no new direct evidence that screening for syphilis infection leads to improved health outcomes in persons at increased risk (see Clinical Considerations), there is adequate evidence that screening tests can accurately detect syphilis infection and that antibiotics can cure syphilis. Screening may result in potential harms (such as clinical evaluation of false-positive results, unnecessary anxiety to the patient, and harms of antibiotic use). The USPSTF concludes that the benefits of screening persons at increased risk for syphilis infection substantially outweigh the potential harms.

* The USPSTF strongly recommends that physicians screen all pregnant women for syphilis infection. A recommendation.

The USPSTF found observational evidence that the universal screening of pregnant women decreases the proportion of infants with clinical manifestations of syphilis infection and those with positive serologies. The USPSTF concludes that the benefits of screening all pregnant women for syphilis infection substantially outweigh potential harms.

* The USPSTF recommends against routine screening of asymptomatic persons who are not at increased risk for syphilis infection. D recommendation.

Given the low incidence of syphilis infection in the general population and the consequent low yield of such screening, the USPSTF concludes that potential harms of screening (i.e., opportunity cost, false-positive test results, and labeling) in a low-incident population outweigh the benefits.

Clinical Considerations

* Populations at increased risk for syphilis infection (as determined by incidence rates) include men who have sex with men and engage in high-risk sexual behavior, commercial sex workers, persons who exchange sex for drugs, and those in adult correctional facilities. There is no evidence to support an optimal screening frequency in these populations. Physicians should consider the characteristics of the communities they serve in determining appropriate screening strategies. Prevalence of syphilis infection varies widely among communities and patient populations. For example, the prevalence of syphilis infection differs by region (the prevalence of infection is higher in the southern United States and in some metropolitan areas than it is in the country as a whole) and by ethnicity (the prevalence of syphilis infection is higher in Hispanic and African-American populations than it is in the white population).

* Persons diagnosed with other sexually transmitted diseases (STDs) (i.e., chlamydia, gonorrhea, genital herpes simplex, human papillomavirus, and human immu-nodeficiency virus [HIV]) may be more likely than others to engage in high-risk behavior, placing them at increased risk for syphilis; however, there is no evidence that supports the routine screening of persons diagnosed with other STDs for syphilis infection. Physicians should use clinical judgment to individualize screening for syphilis infection based on local prevalence and other risk factors (see above).

* Nontreponemal tests commonly used for initial screening are the venereal disease research laboratory (VDRL) and rapid plasma reagin (RPR), followed by a confirmatory fluorescent treponemal antibody absorbed (FTA-ABS) or Treponema pallidum particle agglutination (TP-PA). The optimal screening interval in average-and high-risk persons has not been determined.

* All pregnant women should be tested for syphilis infection at their first prenatal visit. For women in high-risk groups, repeat serologic testing may be necessary in the third trimester and at delivery. Follow-up serologic tests should be obtained to document decline initially after treatment. These follow-up tests should be performed using the same nontreponemal test initially used to document infections (e.g., VDRL or RPR) to ensure comparability.

Discussion

In 2002, the reported nationwide incidence rate of primary and secondary cases of syphilis infection was 2.4 per 100,000 persons (state incidence rates ranged from zero to 5.4 per 100,000 persons), and the rate of congenital syphilis infection nationwide was 11.1 per 100,000 live births (state incidence rates ranged from zero to 31.1 per 100,000 live births). (4) Rates of primary and secondary syphilis infection had been decreasing steadily during the 1990s; however, in 2001, the rate increased for the first time in a decade. This increase was evident only in men and was associated with outbreaks in several urban areas among men who have sex with men, high reported rates of HIV co-infection, and high-risk sexual behavior. The prevalence of syphilis infection differs by region (3.1 and 1.7 per 100,000 persons in the south and northeast United States, respectively) and by ethnicity (9.8, 2.7, and 1.2 per 100,000 persons for African Americans, Hispanics, and whites, respectively).4 The median seropositivity has been reported as 2.1 to 12.2 percent in incarcerated women and 0.9 to 5.2 percent in incarcerated men. (4) Commercial sex workers and persons who exchange sex for drugs have a higher incidence of syphilis infection. (5,6) Late-stage syphilis infection includes gummatous, cardiovascular, and neurologic complications that can lead to significant disability and premature death. Congenital syphilis infection results in fetal or perinatal death in 40 percent of affected pregnancies, (1) as well as disease complications in surviving newborns, including central nervous system abnormalities; deafness; multiple skin, bone, and joint deformities; and hematologic disorders. (7)

The USPSTF examined the evidence from 1994 to 2003 to determine the efficacy of syphilis screening in decreasing syphilis-related morbidity and mortality in the general population, as well as in high-risk populations and in pregnant women. (3) The USPSTF found no direct evidence that screening for syphilis infection in the general population or in high-risk populations reduces morbidity or mortality. The USPSTF did find observational evidence that screening for syphilis infection in pregnant women and/or neonates reduces the prevalence of congenital syphilis infection in neonates. (8,9)

Traditionally, screening for syphilis infection is a two-step process that involves an initial nontreponemal test (VDRL or RPR) followed by a confirmatory treponemal test (FTA-ABS or TP-PA). Sensitivity of the RPR and VDRL tests are estimated to be 78 to 86 percent for detecting primary syphilis infection, 100 percent for detecting secondary syphilis infection, and 95 to 98 percent for detecting latent syphilis infection. Specificity ranges from 85 to 99 percent and may be reduced in persons who have preexisting conditions (i.e., collagen vascular disease, pregnancy, intravenous drug use, advanced malignancy, tuberculosis, malaria, and viral and rickettsial diseases) that produce false-positive results. The FTA-ABS test has a sensitivity of 84 percent for detecting primary syphilis infection and almost 100 percent sensitivity for detecting syphilis infection in other stages, and a specificity of 96 percent. (10) Several new screening tests are currently being studied, including immunochromatographic strip, line immunoassay, enzyme-linked immunosorbent assay, RPR card, and rapid syphilis test. (3) New screening tests currently being studied for use in pregnant women and infants include: IgM immunoblotting and polymerase chain reaction assay of serum and cerebrospinal fluid for central nervous system infection in infants, placenta histopathology, and umbilical cord blood testing. (3)

The yield of screening using a two-step process (RPR followed by confirmatory FTA-ABS) 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 five cases per 100,000 persons, an RPR sensitivity of 91 percent and specificity of 95 percent, and FTA-ABS sensitivity of 92 percent and specificity of 96 percent), one would have to screen more than 24,000 patients to detect a single case of syphilis infection (number needed to screen [NNS], 24,000); 200 per 100,000 persons screened would have false-positive test results. On the other hand, in a high-risk population of incarcerated women (assuming a prevalence of 12 percent, an RPR sensitivity of 91 percent and specificity of 95 percent, and FTA-ABS sensitivity of 92 percent and specificity of 96 percent), 10 persons would have to be screened to detect one case of syphilis infection (NNS, 10); almost 2,000 per 100,000 people screened would have false-negative test results.

Antibiotic therapy is highly effective in eliminating T. pallidum and preventing congenital infection when administered early to pregnant women. (11) Penicillin G long has been an effective regimen for all stages of syphilis, (12) and new trials focus on antibiotics that are easier to administer or that are alternatives for patients who are allergic to penicillin. A number of small, poor-quality cohort and randomized controlled trials on the use of oral azithromycin have been published and report comparable outcomes to penicillin treatment. (13-16) Little evidence is available to guide therapy in pregnant women.

No studies have focused directly on harms of screening or treatment. Potential harms of screening may include opportunity costs to the physician and patient (e.g., time, resources) and false-positive results, which may lead to stress, labeling, and further workup. Harms of treatment include adverse drug-related effects including anaphylaxis from penicillin allergy and the Jarisch-Herxheimer reaction (i.e., febrile reaction with headache, myalgia, and other symptoms) that may occur within the first 24 hours after any therapy for syphilis.

Seven cost studies done in different countries support continued universal testing during pregnancy. (7) A British study found that universal prenatal screening of pregnant women was about as cost-effective as targeted screening programs. (17)

Recommendations of Others

Guidelines from the Centers for Disease Control and Prevention can be accessed at http://www.cdc.gov/mmwr/preview/mmwrhtml /00050909.htm.

Guidelines from the American Academy of Family Physicians can be accessed at http://www.aafp.org/x24973.xml.

Guidelines from the American Academy of Pediatrics and American College of Obstetricians and Gynecologists can be found in Guidelines for Perinatal Care. (18)

Address correspondence to Ned Calonge, M.D., M.P.H., Chair, U.S. Preventive Services Task Force, c/o Program Director, USPSTF, Agency for Healthcare Research and Quality, 540 Gaither Rd., Rockville, MD 20850 (e-mail: uspstf@ahrq.gov).

The U.S. Preventive Services Task Force recommendations are independent of the U.S. government. They do not represent the views of the Agency for Healthcare Research and Quality, the U.S. Department of Health and Human Services, or the U.S. Public Health Service.

REFERENCES

(1.) U.S. Preventive Services Task Force. Guide to clinical preventive services. 2d ed. Washington, D.C.: Office of Disease Prevention and Health Promotion, 1996.

(2.) Harris RP, Helfand M, Woolf SH, et al; Methods Work Group, Third U.S. Preventive Services Task Force. Current methods of the U.S. Preventive Services Task Force: a review of the process. Am J Prev Med 2001;20(3S):21-35.

(3.) Nelson HD, Glass N, Huffman L, Villemyer K, Hamilton A. Screening for syphilis: a brief update for the U.S. Preventive Services Task Force. Rockville, Md.: Agency for Healthcare Research and Quality, 2004. Accessed online September 22, 2004, at: http://www.preventiveservices.ahrq.gov.

(4.) Centers for Disease Control and Prevention, Sexually Transmitted Disease Surveillance, 2002 supplement, Syphilis Surveillance Report. Atlanta, Georgia: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, 2004.

(5.) Marx R, Aral SO, Rolfs RT, Sterk CE, Kahn JG. Crack, sex, and STD. Sex Transm Dis 1991;18:92-101.

(6.) Centers for Disease Control and Prevention. Relationship of syphilis to drug use and prostitution--Connecticut and Philadelphia, Pennsylvania. MMWR Morbid Mortal Wkly Rep 1988;37:755-8, 64.

(7.) Walker DG, Walker GJ. Forgotten but not gone: the continuing scourge of congenital syphilis. Lancet Infect Dis 2002;2:432-6.

(8.) Coles FB, Muse AG, Hipp SS. Impact of a mandatory syphilis delivery test on reported cases of congenital syphilis in Upstate New York. J Pub Health Manag Pract 1998;4:50-6.

(9.) Marx R, Aral SG, Rolfs RT, Sterk CE, Kahn JG. Current trends congenital syphilis--United States, 1983-1985. MMWR Morbid Mortal Wkly Rep 1986;35:625-8.

(10.) Golden MR, Marra CM, Holmes KK. Update on syphilis: resurgence of an old problem. JAMA 2003;290:1510-4.

(11.) Workowski KA, Levine WC. Selected topics from the Centers for Disease Control and Prevention Sexually Transmitted Diseases Treatment Guidelines 2002;3:421-33.

(12.) Augenbraun MH. Treatment of syphilis 2001: nonpregnant adults. Clin Infect Dis 2002;35(Suppl 2):S187-90.

(13.) Gruber F, Kastelan M, Cabrijan L, Simonic E, Brajac I. Treatment of early syphilis with azithromycin. J Chemother 2000;12:240-3.

(14.) Hook EW 3d, Martin DH, Stephens J, Smith BS, Smith K. A randomized, comparative pilot study of azithromycin versus benzathine penicillin G for treatment of early syphilis. Sex Transm Dis 2002;29:486-90.

(15.) Hook EW 3d, Stephens J, Ennis DM. Azithromycin compared with penicillin G benzathine for treatment of incubating syphilis. Ann Intern Med 1999;131:434-7.

(16.) Mashkilleyson AL, Gomberg MA, Mashkilleyson N, Kutin SA. Treatment of syphilis with azithromycin. Int J STD AIDS 1996;7:13-5.

(17.) Connor N, Roberts J, Nicoll A. Strategic options for antenatal screening for syphilis in the United Kingdom: a cost effectiveness analysis. J Med Screen 2000;7:7-13.

(18.) American Academy of Pediatrics. Guidelines for perinatal care. 5th ed. Elk Grove Village, Ill.: American College of Obstetricians and Gynecologists, 2002.

This clinical content conforms to AAFP criteria for evidence-based continuing medical education (EB CME). EB CME is clinical content presented with practice recommendations supported by evidence that has been systematically reviewed by an AAFP-approved source. The practice recommendations in this activity are available online at http://www.ahrq.gov/clinic/ uspstf/uspssyph.htm.

This is one in a series excerpted from the Recommendation Statements released by the U.S. Preventive Services Task Force (USPSTF). These statements address preventive health services for use in primary care clinical settings, including screening tests, counseling, and chemoprevention. The complete statement is available in HTML and PDF formats through the AFP Web site at http://www.aafp.org/afp/20041115/us.html. This statement is part of AFP's CME. See "Clinical Quiz" on page 1853.

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