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The “Great Pretender” (Syphilis) is Still Stumping Healthcare Providers

Katherine Glaser, MD, MPH, and Joy Vongspanich Dray, PharmD, BCACP, AAHIVP | May 26, 2021
View more articles from the same authors.

The Case 

A healthy 53-year-old man presented to a clinic after being informed by the health department that he had sexual intercourse with a male partner who was recently diagnosed with and treated for syphilis. He requested screening for sexually transmitted infections (STIs) and reported his exposure to syphilis (as informed by the health department) about 3 weeks earlier. He reported no personal history of prior syphilis infection and denied any penile lesions, discharge, or rash. He acknowledged having unprotected sex with male partners, but reported a history of multiple negative tests for Human Immunodeficiency Virus (HIV). He had no other complaints but was found to have an elevated blood pressure that day. No physical examination occurred. He was advised to follow up about his elevated blood pressure, given one intramuscular dose of penicillin G (2.4 million units) to treat his recent exposure to syphilis, and advised that no further follow-up was indicated. Rapid plasma reagin (RPR) and Treponema pallidum particle agglutination (TPPA) assays were ordered, but the results were not reviewed and documentation in the medical record stated “no results found.” (Editors Note: PSNet case submissions are anonymous and the submitted materials did not indicate whether a nurse or physician failed to review these results).

Almost two years later, the patient presented to his primary care physician (PCP) with orthostatic headaches and neurologic changes. During the PCP visit, the patient noted that the last time he recalled receiving complete STI screening was over twenty years prior. The PCP suspected neurosyphilis and referred him to an infectious disease specialist. Cerebrospinal fluid from a lumbar puncture had a negative Venereal Disease Research Laboratory (VDRL) test, minimal red blood cells, no white blood cells, and elevated protein. Laboratory results included a non-reactive RPR, reactive TPPA, and Treponema pallidum Immunoglobulin G of 4.7 confirming the diagnosis of neurosyphilis. 

He was treated for neurosyphilis with 14 days of intravenous penicillin G, but had both an inflammatory reaction to the treatment and complications of tertiary syphilis including neurologic changes, cardiovascular sequalae including valvular disease, caries sicca of the skull, and musculoskeletal damage. Chronic pancreatitis was also noted. The patient is now in chronic pain and has difficulty sitting or standing, whereas prior to the development of these neurosyphilis complications he had been physically active.

The Commentary 

By Katherine Glaser, MD, MPH, and Joy Vongspanich Dray, PharmD

Though the origins of syphilis remain disputed, syphilis infections have caused death and disability to both adults and infants, who may be infected with congenital syphilis, since the fifteenth century or earlier.1 Given that the clinical manifestations of syphilis vary over the course of the illness, both affected patients and clinicians can be confused about its diagnosis.2 In this case, the clinician with whom the patient initially interacted appears to have learned of his recent exposure to syphilis and based the assessment and treatment on this brief history. Though the patient revealed that he had unprotected sex with male partners, it is unclear if additional questions about past screening for syphilis and other STIs were asked. This is critical information, as the interval since prior syphilis testing can help to estimate the timeframe of infection. A more thorough physical examination may also have improved the treatment plan. Even without a more in-depth history or physical examination findings, timely review of the laboratory results, which were consistent with late latent syphilis, should have prompted a review of the patient’s history and an altered treatment plan. The clinician neglected this step in caring for the patient, jumping to a seemingly straightforward but incorrect diagnosis while failing to consider more serious alternatives.

In that first clinical visit, a thorough history may have revealed that the patient did not recall a recent complete screening for STIs, even though anonymous testing for HIV had occurred many times. Through the previous decades, there were likely many missed opportunities for providing him education about the need for complete screening for STIs, including serology for syphilis and targeted screening for chlamydia and gonorrhea based on sexual activity. Since 2000, the incidence of syphilis has risen for both men who have sex with men and newborn infants (i.e., congenital syphilis).3,4 The estimated prevalence of syphilis in the US in 2018 was 156,000 cases in men and women of reproductive age, but 71.8% of these infections were in men.5 Of the men infected in 2018 who identified the sex of their partners, 77.6% of infections were among men who have sex with men (MSM).6 For this reason, having honest discussions with MSM about activities that could place them at risk of possible infection remains important. The Centers for Disease Control and Prevention (CDC) recommend annual testing for those who identify as MSM,6 and in this situation, the twenty-year testing interval assisted in creating the devastating outcome noted in the case.

This patient, having lived through the early HIV/AIDS epidemic, may have developed mistrust of the healthcare system. Over the thirty years since the beginning of the HIV/AIDS epidemic, many scientific articles, memoirs, and art and theater pieces have contained criticism of the initial neglect with regard to the epidemic and subsequent moralizing. The stigma surrounding HIV/AIDS and MSM is complex and reflects social, political, and economic processes resulting in both individual and systemic discrimination.7 Understanding the historical context of how members of the lesbian, gay, bisexual, and transgender, queer and/or questioning, intersex and asexual and/or ally (LGBTQIA) community have been treated in the mainstream healthcare system, and the stigma that the patient in this case faced as a member of that community, is helpful in providing compassionate and comprehensive care.8 Understanding reasons behind mistrust of the medical system, including historical factors, ongoing discrimination, past trauma, and conspiracy theories, is equally important.9 As medical professionals continue to work towards providing inclusive care and achieving health equity, it is important to be mindful of our interactions with patients and the lasting impacts these interactions may have. 

The clinical manifestations of syphilis are myriad but occur in a stepwise fashion. Syphilis is caused by Treponema pallidum, a slow-growing bacterium. Without treatment, it becomes a chronic infection, as occurred in this patient’s case.8 In the initial stages, syphilis infection manifests as a painless, solitary ulcer, usually at the site of inoculation approximately 2-3 weeks after exposure. This ulcer is often on the distal penis, but can also occur on the vagina or cervix, the anus, the mouth or any exposed body part.8 This lesion will resolve spontaneously without treatment in 3-6 weeks, but if treated it resolves more quickly.10 Secondary syphilis occurs as a rash, commonly reported as a rash of copper-colored lesions on the palms or soles, but its appearance is highly variable, and if the rash occurs on mucous membranes, it is more likely to be warty and is referred to as condyloma lata.8 Again, if left untreated, the manifestations of secondary syphilis resolve spontaneously over the ensuing weeks or months. The next stage of syphilis is latent syphilis, which is further divided into early or late latent syphilis.8

After years or decades, approximately one third of those infected with syphilis but never treated develop symptoms of neurological, cardiovascular, or gummatous syphilis. The patient in this case had cardiovascular and neurological involvement, with presumed tabes dorsalis as evidenced by his difficulty in sitting and standing due to musculoskeletal pain. The caries sicca of the skull, also experienced by the patient in this case, are a noted destruction of the bones of the calvarium, causing deformity.11 Case reports also link syphilis to cases of pancreatitis,12 also experienced by the patient in this case. In addition to these mental and physical discomforts, this patient is now subject to expenses related to his healthcare.

As opposed to many laboratory results that are reported as positive or negative, or within or outside of a pre-determined range, interpretation of syphilis test results remains more difficult. Since direct detection of the pathogen through microscopy is not readily available, the usual means of diagnosis is by serologic testing. Due to the fact that more than one serologic test result is needed to interpretate positive results, this makes for a more difficult interpretation, as both the non-treponemal and treponemal tests are required. Traditionally, a non-treponemal test, such as the rapid plasma reagin (RPR) or venereal disease research laboratory (VDRL) test, was the first test performed.13 However, in the past decade, most laboratories have shifted to initially performing treponemal tests because of their greater sensitivity in detecting primary syphilis.14 Following this testing strategy, the treponemal antibody test is performed first, and, if positive, the non-treponemal test is then performed and reported in conjunction with a titer. Generally, in primary and secondary syphilis, both tests are expected to be positive and concordant while the patient remains symptomatic. For cases of latent syphilis, an absence of symptoms, patient-reported sexual contacts (possibly), and either concordant treponemal and non-treponemal tests or two reactive treponemal tests are expected. In treating early versus late latent syphilis, careful attention must be paid to the interval since a possible sexual contact. In this particular case, the RPR was non-reactive and the treponemal tests were reactive when these tests were conducted two years after the patient’s initial clinic visit, results that are not consistent with a recent exposure to syphilis and; the long duration of time between screening might suggest that this patient had late latent syphilis.

Penicillin remains the primary treatment for syphilis. For primary, secondary, and early latent syphilis, a single dose of benzathine penicillin G should be sufficient but non-treponemal test titers are used to monitor response to treatment. In cases of late latent syphilis, three intramuscular doses at weekly intervals are usually required. As illustrated in this case, neurosyphilis is treated with a longer duration of intravenous penicillin, 18-20 million units per day administered in divided doses given every four hours for 10-14 days.15 Other treatment options are available for patients allergic to penicillin, but these therapies should be used in conjunction with close clinical and laboratory follow-up to verify appropriate serologic response and cure.

Since the advent of the HIV/AIDS epidemic, syphilis has been associated with HIV. Presumably, the patient in this case was tested for HIV after his syphilis infection was identified and found to be HIV-negative. Untreated syphilis increases the risk of HIV infection while ulcers are present as syphilitic ulcers have many lymphocytes which provide portals for HIV acquisition.10 One study showed that co-infection with HIV and syphilis may be associated with social networks and having co-infected associates, while mono-infection with syphilis is associated with attending more social venues.16 In general, people who are considered at high risk for syphilis infection include those recently diagnosed with an STI, people engaging in high-risk sex, sexually active HIV patients, and sexually active MSM.6 Taking a through sexual history using open-ended and non-judgmental questions can identify patients at risk of syphilis or HIV, as well as those who need screening for urethral, oral, or rectal chlamydia or gonorrhea, hepatitis infection, and conditions associated with human papilloma virus (HPV) such as warts or carcinoma.

Approach to Improving Outcomes

This case represents the confluence of several troublesome issues. The clinician’s failure to investigate beyond the patient’s request to be screened resulted in morbidity and disability for the patient. Certainly, the failure to examine the lab results contributed to the negative outcome. Though the patient reported having had previous interactions with the healthcare system for anonymous HIV testing, messages regarding the importance of screening for other STIs were either not provided or not acted on. This scenario can be summarized as a compounding of cognitive errors, including faulty knowledge in that the clinician appeared unaware of current recommendations for testing and diagnosing syphilis, faulty data gathering as evidenced by the lack of a complete patient history and laboratory follow-up, and faulty synthesis as the clinician apparently overlooked all evidence except the presenting complaint of exposure to syphilis 3 weeks previously.

Additionally, the patient in this case could have had negative perceptions about healthcare in general due to events that occurred during the HIV/AIDS epidemic. Such perceptions may have tainted his relationship with the healthcare system, causing an admitted avoidance of routine healthcare. (And because the hospital emergency department (ED) may be the only access point for healthcare for some, screening for STIs in the ED should be considered if indicated by the reported history.)

As demonstrated by this case, the most obvious errors in need of remedy include:

  • Although attention was paid to the patient’s recent exposure to syphilis, his history of sex with men and the long interval since he had a prior complete STI screening were not taken into account;
  • Failure to either obtain a complete sexual history or to recognize the importance of key details in the sexual history;
  • Failure to follow the CDC recommendation for annual STI screening for MSM and to recognize that the patient’s screening history interval was greater than one year;
  • Failure to review and act upon the results from all laboratory studies, following standard algorithms for the interpretation of syphilis tests; and
  • Insufficient education for clinicians regarding avoidance of stigma and systemic discrimination in interactions with MSM or others in the LGBT community.

Attentive listening, asking prudent questions, and appropriate follow-up of laboratory tests based on understanding of currently recommended practices all could have altered the eventual outcome for the patient in this case. Specifically, administering three intramuscular doses of benzathine penicillin may have successfully treated his late latent syphilis, preventing the potentially avoidable sequalae of neurosyphilis and subsequent complications.

In this case, the clinician ordered the appropriate laboratory studies but apparently never viewed their results. As one goal of patient safety, organizations such as the Joint Commission list steps that may be taken to ensure that laboratory studies receive appropriate follow-up. These steps comprise multiple approaches to improving safety as no single system can ensure that all patients are made aware of their laboratory test results. Implementing a robust system to review and verbally communicate laboratory results to patients, as per the recommendations of the Joint Commission, would help prevent such errors in the future. Electronic health record (EHR) systems can alleviate some of the effort involved by communicating results to clinicians and patients and issuing alerts when results have not been viewed.

Additionally, syphilis remains a nationally notifiable disease but that safeguard also appears to have failed in this case. The patient had been initially notified by the health department of his recent exposure to syphilis; so that notification was effective. However, he was not notified of his own laboratory test results, which were—presumably—abnormal. Generally, nationally notifiable diseases are reported to state and then federal authorities, with local government at the city or county level bearing responsibility for following up on cases and treatment.17 Had this mechanism worked sufficiently in this case, the patient would likely have received earlier, more complete treatment, thus greatly improving his chances for a more positive outcome.  

Take-Home Points 

  • Take the time to collect and perform a full assessment of information available in the clinic, including a complete patient history supplemented with additional questions, pertinent physical exam findings, and timely review of laboratory test results.
  • Understand the historical and cultural context of the stigma that populations like MSMs face.
  • Be aware of the local and national epidemiology of infectious diseases such as syphilis, and understand that high-risk populations include MSM, those with HIV, or pregnant women.
  • Create a system-wide process for reviewing and communicating all test results to patients, a process that includes issuing alerts when test results have not been reviewed and acted upon by the ordering provider.


Katherine Glaser, MD, MPH
Quality, Safety, and Comparative Effectiveness Research Training in Primary Care (QSCERT-PC) Fellow
Department of Obstetrics and Gynecology
UC Davis Health

Joy Vongspanich Dray, PharmD, BCACP, AAHIVP
PGY-1 Residency Program Director, Ambulatory Care-HIV
Department of Pharmacy
UC Davis Health


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This project was funded under contract number 75Q80119C00004 from the Agency for Healthcare Research and Quality (AHRQ), U.S. Department of Health and Human Services. The authors are solely responsible for this report’s contents, findings, and conclusions, which do not necessarily represent the views of AHRQ. Readers should not interpret any statement in this report as an official position of AHRQ or of the U.S. Department of Health and Human Services. None of the authors has any affiliation or financial involvement that conflicts with the material presented in this report. View AHRQ Disclaimers
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