Genetic Study Suggests Global Resurgence of Syphilis

— Muhammad Morshed, PhD, SCCM; Clinical Professor

From The BCCDC Public Health Laboratory

The BCCDC Public Health Laboratory has had a long standing interest in syphilis diagnosis, public health response and in understanding the characteristics of the Treponema pallidum which causes syphilis disease. Recently we participated in a study with the Welcome Sanger Institute, Genome England group, the UK Health Security Agency, the London School of Hygiene and Tropical Medicine, and collaborators from 22 other countries. In this collaboration, we completed an extensive genomic study to understand the recent resurgence of syphilis around the world. This study has been published recently in Nature Microbiology, and showed that the global syphilis population is made up of two lineages, SS14 and Nichols. Detailed analysis of these lineages provides important insights into the genetic diversity of syphilis, with implications for vaccine design and anti-microbial resistance.

Syphilis is a century old sexually transmitted disease (STD) and the spirochete Treponema pallidum enters through the skin, mouth, or anus and causes infection. Infection typically causes a painless skin ulcer (chancre) at the infection site. To date, syphilis remains sensitive to penicillin treatment. However, despite this being a treatable infection and despite using multiple public health interventions, control has been difficult and syphilis continues to re-emerge throughout the world, causing over 6 million infections every year. BCCDC HIV/Sexually Transmitted Infection (STI) Epidemiologists have been keeping track of syphilis infections in BC for many decades. Prior to the mid-1970, syphilis cases in BC were highest in the heterosexual population. Case numbers declined in the 1990’s during the HIV/AIDS crisis, possibly due to preventive measures such as contact tracing, public education, and promotion of condom use. In the late 90’s this disease re-emerged as an outbreak among heterosexual people. A mass treatment initiative with azithromycin was undertaken to attempt to control the outbreak in Vancouver downtown eastside. Although case numbers fell significantly for six months after mass treatment, they returned to pre-intervention levels by 2001. Currently, case numbers started increasing especially amongst the men who have sex with men (MSM). Interestingly, case numbers in downtown eastside cohort remained negative until recently and now, cases among heterosexual males and females have also begun to increase again. Similar trends have been reported in all continents. Fortunately, the number of congenital syphilis cases remain very low due to routine screening in pregnancy. But every case is a prevention opportunity lost.

Healthy individuals can contract syphilis if they come in contact with a chancre from an infected person; this happens most often during sex. Over 90% of people get syphilis infection through vaginal, anal or oral sex. A pregnant person with syphilis can also pass the infection to their unborn child, called congenital syphilis. Babies born with syphilis may suffer permanent damage to their liver, brain, eyes, teeth, bones, glands and lungs. People can also get syphilis through tainted blood transfusion that is why blood donors are screening for syphilis. This is a complex disease with serous health issues that affects people in different stages if left untreated.

Stage 1 - also known as primary syphilis, happens within weeks to months after exposure to an infected person. One or more painless ulcers will form at the original site of infection within 9 to 90 days. This may be an issue for MSM population since ulcers may not be visible for some individuals which may enhance transmission. Left untreated, the ulcer heals and the infection progresses silently to stage 2.

Stage 2 - Secondary syphilis occurs 4weeks to 10 weeks after appearance of chancre. This stage usually begins within 6 weeks. During this time, the bacteria will travel through the body causing a widespread rash. The rash can look very different from person to person. It is often found on the palms of the hands and the soles of the feet. People may get a fever, a sore throat, and swollen glands. They may also feel generally weak and tired. Like primary syphilis, the signs and symptoms of secondary syphilis go away on their own without treatment in 2 to 6 weeks and if left untreated properly at this stage, the disease progresses to stage 3.

Stage 3 - Latent syphilis means secondary syphilis disappears and the infection becomes hidden (latent). Without treatment, syphilis can be present asymptomatically for 1- 20 years or more. People with latent syphilis may sometimes have symptoms (flare-ups) like a skin rash, fever, sore throat, swollen glands or feeling weak and tired. This is most common during the first year of Stage 3. Severe health outcomes begin in Stage 4 (Tertiary or Late syphilis).

Stage 4 - At this stage, approximately one in four people who don't receive any treatment may go onto experience organ and bone damage, inflammation of the aorta, blindness, permanent mental illness, paralysis and sometimes death. So early diagnosis is crucial.

Given the challenge in controlling syphilis, learning more about these spirochetes at the genomic level is extremely important. However, studying T. pallidum is also extremely challenging because it cannot be grown in an artificial culture media which is one of the barriers to widely performing genomic work. Dr. Mathew Bealy’s team in the Welcome Sanger Institute developed a methodology that allowed genome analysis of T. pallidum using clinical genital ulcerated swab (GUD) samples. In our study, a total of 726 syphilis samples from 23 countries (Africa, Australia, Central Asia, Europe, and North America) were utilized, and phylogenetic and cluster analyses were conducted to map the global syphilis population.

We were able to establish the ancestral relationships between different sequences using the knowledge that DNA changes occur at a known and predictable rate over time. We also found that all the global samples evolved from two deeply branching lineages, Nichols and SS14. Both lineages are currently circulating in 12 of the 23 countries sampled, and almost identical samples were present in 14 of these countries which included British Columbia, Canada. Our study also showed that the dominant syphilis lineages infecting patients prior to 1983 were not the same as those infecting patients today. Our analysis shows a transmission bottleneck occurred in the late 1990s that indicates a large decline of T. pallidum , most likely as a result of the HIV/AIDS crisis. The concern from a public health perspective is that the presence of almost identical samples in numerous countries suggests the disease is being transmitted internationally on a regular basis.

The BCCDC PHL is providing an up to date version of syphilis antibody testing which is the mainstay test for syphilis diagnosis, and is continuously monitoring literature for further diagnostic advances. We also provide molecular PCR testing to determine early acute cases using fluid collected from the ulcers. In addition to the diagnostic services, BCCDC PHL and BCCDC HIV/STI are also working on other areas such as studying macrolide resistance, performing genotyping, epidemiology and contact tracing. BCCDC will continue to work on improving diagnostic methods and enrich research activates on this disease as well as on this stealth pathogen. The key message is Syphilis is back and touches people around the globe.

Beale MA, Marks M, Cole MJ, Lee MK, Pitt R, Ruis C, Balla E, Crucitti T, Ewens M, Fernández-Naval C, Grankvist A, Guiver M, Kenyon CR, Khairullin R, Kularatne R, Arando M, Molini BJ, Obukhov A, Page EE, Petrovay F, Rietmeijer C, Rowley D, Shokoples S, Smit E, Sweeney EL, Taiaroa G, Vera JH, Wennerås C, Whiley DM, Williamson DA, Hughes G, Naidu P, Unemo M, Krajden M, Lukehart SA, Morshed MG, Fifer H, Thomson NR. Global phylogeny of Treponema pallidum lineages reveals recent expansion and spread of contemporary syphilis. Nat Microbiol. 2021 Dec;6(12):1549-1560. doi: 10.1038/s41564-021-01000-z. Epub 2021 Nov 24. PMID: 34819643; PMCID: PMC8612932.