PCR swabs: a useful diagnostic tool for identifying syphilis

Previous article: Managing syphilis during pregnancy — practice tip by Drs. Rohit Vijh and Jason Wong, May 17, 2023.

Author

Rohit Vijh, MD MPH CCFP (biography and disclosures)

Disclosures: No relevant financial disclosures for this work. UBC PGME Clinical Instructor, Department of Family Practice, Faculty of Medicine, UBC (receive payments for teaching UGME/PGME students). Mitigating potential bias: Recommendations are consistent with current practice patterns.

Acknowledgements: I would like to thank Dr. Troy Grennan (Medical Lead, BCCDC STI/HIV Services) and Dr. Jason Wong (Medical Director, BCCDC Clinical Prevention Services) for their thoughts and inputs on this practice piece. I would also like to thank the BCCDC STI physicians and nursing team for the invaluable time and teaching they provided me during my residency rotation and as my work as an STI physician.

What I did before

Background

Infectious syphilis rates have continued to rise over the past 10 years. 2021 and 2022 have marked the largest historical rate of syphilis cases in the past decade.¹ A recent shift in the epidemiology of syphilis cases has occurred. Previously, the majority of infectious syphilis cases were among gay, bisexual, and other men who have sex with men (gbMSM). However, in 2022 over 50% of syphilis cases occurred among men who have sex with women only (MSW) and women who have sex with men only (WSW).¹ Syphilis cases among pregnant persons, as well as congenital infections, have also reached historical highs over the past two years.¹ Given the increase in infectious syphilis incidence and changes in populations affected, community providers are more likely to encounter the many different presentations of syphilis in the community.

Infectious syphilis is categorized into three stages: primary, secondary, and early latent, followed by a non-infectious stage (i.e., late latent stage).² Primary syphilis usually presents as a painless ulcer (chancre) that occurs anywhere from 10 to 90 days after sexual contact, and will typically resolve spontaneously.³ Secondary syphilis occurs after systemic dissemination of the bacterium that causes syphilis (Treponema pallidum), typically with a widespread non-itchy maculopapular rash (typically on the chest, abdomen, genitals, palms, and soles) and other nonspecific systemic symptoms (i.e., headache, fever, swollen lymph nodes), and resolves spontaneously within 3–12 weeks.⁴ Secondary syphilis, however, can also present with other specific symptoms (e.g., condyloma lata, proctitis, mucous patches, alopecia areata).

Following the symptomatic stages of infectious syphilis, the infection — if untreated — enters an asymptomatic latent stage. Latent syphilis has two stages: early latent syphilis (infection occurred within the last year) and late latent syphilis (infection after one year). Untreated late latent syphilis can lead to tertiary complications in 15–20% cases over their lifetime, which can affect multiple organ systems (e.g., blood vessels, heart, bones). Neurosyphilis, syphilis infection of the central nervous system, may occur at any stage of the disease, including during the infectious syphilis stages.^2,3

Primary and secondary syphilis can present in a variety of manners which makes diagnosing syphilis challenging (see Table 1).

Table 1. Syphilis Symptoms and the Role of PCR Testing

Furthermore, as a genital lesion has a wide differential, a syphilitic lesion could be misdiagnosed for another pathology (e.g., herpes). Online resources of clinical images surrounding various presentations of syphilis are also available at Syphilis images | DermNet (dermnetnz.org).

The BCCDC website includes resources that provide detailed resources for clinicians considering a diagnosis of syphilis.² Staging of infections is based on laboratory results together with a thorough history and clinical assessment, and is done provincially by a specialized group of STI physicians for all reactive syphilis tests in BC. This process also determines if the reactive serology indicates active infection that requires treatment or a previous infection that requires no treatment.

Pre-existing practice

My pre-existing practice for syphilis diagnostics included sending the patient for syphilis serology. BCCDC Public Health Laboratory, which performs >99% of syphilis testing in BC, uses a reverse screening algorithm that consists of an initial screen by enzyme immunoassay (EIA). Samples that are positive or equivocal by EIA are then reflex tested by a T. pallidum passive particle agglutination assay (TPPA) and rapid plasma reagin (RPR). EIA and TPPA are treponemal tests, which specifically detect syphilis antibodies and remain reactive for life, whereas RPR is a non-treponemal test. Details about interpretation of syphilis serology are well described in the 2020 This Changed My Practice article: Interpretation of Syphilis Serology.⁵

What changed my practice

During the end of my family medicine residency, I spent time working at the provincial STI clinic at BCCDC with a specialized group of infectious disease and family physicians as well as STI certified nurses who care for people with syphilis. During this experience, I was introduced to another diagnostic tool for syphilis presentation: syphilis nucleic acid amplification by PCR (NAAT-PCR).

Given that the screening EIA, the RPR, and the confirmatory TPPA tests usually become positive about 2 to 4 weeks after infection (but may take up to 90 days), there is a chance of false-negative serology during early infection. Therefore, direct detection tests such as a syphilis PCR swab that collects fluid from ulcerative lesions, or other infected tissues (e.g., rectal swab for proctitis symptoms) can enable earlier detection.

A recent study was published by the BCCDC Public Health Laboratory assessing the diagnostic performance of PCR-based T. pallidum DNA detection from 2015–2020.⁶ The study found that this PCR-based syphilis testing exhibited excellent sensitivity (99.5% (95% Confidence Intervals: 96.7%, 100%)) and specificity (100% (95% Confidence Intervals: 99.2%, 100%)).⁶

What I do now

Given the increasing rates of syphilis and changing epidemiology of syphilis with increasing incidence in heterosexual populations, my clinical suspicion for syphilis testing has increased. Due to the broad clinical manifestations of syphilis, I consider syphilis more consistently among sexually active individuals with new or casual partners presenting with generalized presentations such as a maculopapular rash as well as those presenting with oral and genital lesions.

If a patient presents with primary or secondary lesions that are amenable to PCR swabbing (Table 1), I will now collect a PCR swab specimen, in addition to sending the patient for serology. Reasons I would consider a syphilis PCR test include:

1. Swabbing a lesion consistent with primary syphilis can identify early infection. This can help to mitigate transmission by identifying acute treatable infections quickly.
2. Swabbing an uncommon or atypical clinical presentation (e.g., rectal lesion, proctitis) can help support the diagnosis of secondary syphilis.
3. Swabbing symptomatic individuals with specific clinical presentations (Table 1) who may face barriers to serology testing can potentially have a syphilis diagnosis confirmed through an outpatient office visit.

Typically, I would use a genital Aptima (vaginal, cervical, or urethral) swab (Image 1) often used for chlamydia or gonorrhea screening/testing, or viral swabs for HSV (Image 2) with either “Syphilis NAAT swab” or “Syphilis PCR swab” written manually onto a standard lab requisition in the other test section (Image 3) or by selecting “Treponema pallidum Nucleic Acid Testing” on the BCCDC Public Health Laboratory Requisition (Image 5). If collecting multiple swabs from the same lesion, it would be best to collect first the syphilis NAAT then HSV PCR, and finally any other swabs.

Identifying and treating these active infections earlier could mitigate onward syphilis transmission, especially among unsuccessfully engaged populations. However, the routine use of direct detection tests is challenging due to the difficulty of obtaining optimal samples from early cases. Lesions may not be visible if they occur inside the anal or vaginal cavities, or may have resolved.

Thus, in all cases, serological testing continues to be the preferred diagnostic modality and should always be carried out in addition to PCR testing (Images 4 and 6).

Lastly, if I have any questions about the clinical workup for syphilis, I can always contact during weekday business hours the provincial BCCDC STI Physician line (604-707-5610) or the RACE line.

Image 1. Aptima Multitest Swab (Vaginal, Cervical, or Urethral)

Image 2. Viral Swab for HSV

Image 3. Life Labs Requisition for Syphilis PCR

Image 4. Life Labs Requisition for Syphilis Serology

Image 5. BCCDC Requisition for PCR (download)

Image 6. BCCDC Lab Requisition for Serology (download)

Resources

1. Syphilis | SmartSex Resource
2. Non-certified Syphilis DST (bccdc.ca)
3. This Changed My Practice article: Managing syphilis during pregnancy — practice tip
4. This Changed My Practice article: Interpretation of Syphilis Serology
5. Syphilis guide: Treatment and follow-up – Canada.ca
6. Pathways patient handout/website about syphilis: https://pathwaysbc.ca/ci/2279
7. Syphilis images | DermNet (dermnetnz.org)
8. BCCDC Public Health Laboratory Requisition
9. PHSA – BCCDC eLearning Course: Overview of Syphilis for Healthcare Providers in BC, 2 hr online course for clinicians with foundational knowledge around syphilis to support management of syphilis cases and their contacts
10. UBC CPD eLearning Course: Sexually Transmitted and Blood-borne Infections: Barriers to Screening with PDF handouts:
    1. Syphilis in Canada 2011-2020
    2. Field Guide to Common STBBIs in Canada: Syphilis pg 8

References

1. BC Centre for Disease Control. British Columbia syphilis indicators. BCCDC. Accessed February 14, 2024. (View)
2. BC Centre for Disease Control. BCCDC non-certified decision support tool: syphilis. BCCDC. Accessed February 14, 2024. (View)
3. Tudor ME, Al Aboud AM, Leslie SW. Syphilis. Statpearls. Updated May 30, 2023. Accessed February 14, 2024. (View account creation required)
4. Dylewski J, Duong M. The rash of secondary syphilis. CMAJ. 2007;176:33-35. doi:10.1503/cmaj.060665 (View)
5. Clifford-Rashotte M, Press N. Interpretation of syphilis serology. This Changed My Practice, UBC CPD. June 24, 2020. Accessed February 20, 2024. (View)
6. Morshed M, Lee M, Laley J, et al. British Columbia’s experience after implementation of the Treponema pallidum reverse algorithm and PCR detection, 2015 to 2020. Microbiol Spectr. 2022;10(3):e0068622-e0068622. doi:10.1128/spectrum.00686-22 (View)

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