Until recently, syphilis was an anachronism for medical professionals.
The sexually transmitted disease (STD) was so common in the 19th century that it earned its own specialty: syphilology. But the advent of penicillin in the 20th century meant that the disease was easily treatable, and by the 1990s, syphilis had been virtually eradicated in the US.
However, in the last decade it has made a dramatic comeback. Cases have increased by 80% in the last five years and the US now has the highest syphilis rates since 1950. More than 200,000 Americans were diagnosed with the disease in 2022. Since 2012, the U.S. Centers for Disease Control and Prevention (CDC) has had a 10-fold increase in the number of babies born with the disease.
Last week, the National Institutes of Health (NIH) took a major step toward addressing one of the biggest problems: the difficulty of testing for syphilis. It said that the $2.4 million to improve syphilis testingwhich has not changed much since the 1950s, until the 21st century.
David Harvey, executive director of the National Coalition of STD Directors, called the new funding “a testament to the federal syphilis task force,” a group that has convened to address the surge in new cases.
But “combating an STI like syphilis is not just about improving diagnostics,” he noted, referring to testing. “We need more diagnostic tools in other areas, and we need more investment in therapeutic research and vaccines.”
The bacteria that cause the disease, Treponema pallidumis one of the most invasive diseases known to medicine. T-pallidum can cross the blood-brain barrier and placenta in pregnant women and enter any organ system, attacking organs such as the heart and bones.
Common symptoms include painless sores around the vagina, penis, anus, or in the throat; a rash on the hands and feet; flu-like symptoms; and patchy hair loss. But these early symptoms are often mild and come and go.
More advanced stages of the disease can bring dreaded complications, such as neurosyphilis, with dementia-like effects, or ocular syphilis, which can cause blindness. Congenital syphilis, when the disease is passed from mother to child, is a special horror: the disease can cause death and neurological devastation in babies.
The disease has such a wide variety of manifestations that one of the founders of modern medicine noticed: “Whoever knows syphilis knows medicine.” But both testing and treatment remain stuck in the mid-20th century. Treatment is still very effective and involves, bluntly, a large dose of penicillin in the back. But testing is difficult.
“Diagnosing syphilis is surprisingly challenging and difficult,” said Caroline Cameron, a professor of biochemistry and microbiology at the University of Victoria in Canada, who received a two-year NIH grant to improve tests for directly detecting the bacteria.
The technology still relies on serology, or a test for an immune response. It takes days to weeks to confirm a diagnosis of syphilis, and tests cannot determine whether an infection is active or gone. Testing in infants, who do not have fully formed immune systems, is particularly difficult.
Cameron’s research focuses on detecting syphilis proteins using mass spectrometry, a laboratory tool that measures the ratio of mass to electrical charge for molecules. If successful, the research could solve one of the biggest frustrations of syphilis testing: determining whether an active infection exists.
“What the field needs is something that can directly detect the presence of the pathogen, not the host response to the pathogen, and do it in this very easy format,” Cameron said. Her lab “takes patient samples like urine and blood and then analyzes them for these proteins that are only found in this pathogen — they’re not found in other infectious diseases, they’re not found in human proteins.”
Serology is “a reasonable approach,” said Dr. Stephen Salipante, a professor in the department of laboratory medicine and pathology at the University of Washington and another NIH grantee. “It’s well-researched and used by many clinical labs.”
However, with potentially weeks between diagnosis and treatment, “it can happen that patients are diagnosed with syphilis but are lost to follow-up,” Salipante said. “So you’ve diagnosed the patient, but you’ve lost the patient and can’t treat them.”
This has been particularly problematic because of who is at risk for syphilis – usually marginalized people who are not well served by medicine. Mothers who give birth to children infected with syphilis are a particularly powerful example: 40% had no prenatal carebut such women make up only about 5% of all pregnant women. Men who have sex with men and people with substance abuse disorders are also more likely to get syphilis than the general population.
Salipante’s research is investigating whether researchers can create a test using DNA molecules called aptomers – single-stranded nucleic acid molecules that target specific diseases, such as syphilis. The goal is for such a test to be administered in a doctor’s office while the patient waits, perhaps in a format as simple as a dipstick.
“The most important aspect of this is that theoretically it’s something that can be done very quickly in a point-of-care setting,” Salipante said. “Rather than sending this off to a lab remotely … our ultimate goal and hope is that this can be done very quickly, in 30 minutes or an hour, by non-specialists in a doctor’s office or emergency room, and it can be done while the patient is still there.” Aptomer tests have already been developed for some other infectious diseases, such as Covid-19, though they are still experimental.
Dr. Joshua Lieberman, assistant director of the Division of Molecular Diagnostics and Microbiology, also at the University of Washington, hopes that molecule-specific tests could also help with recurring shortages of antibiotics used to treat syphilis. Lieberman is a co-investigator with Salipante.
The penicillin product used to treat syphilis is Bicillin LA, an antibiotic that has been tested recurring shortages partly driven by the explosive growth of syphilis cases. The antibiotic is notoriously difficult to produce and is still derived from fungi.
“What I’d like to do is combine that test — yes or no, that organism or its DNA is there — with ‘Is there a marker for resistance to a specific antibiotic in that organism?'” Lieberman said. “This is similar to what we do with many of our tests for mycobacteria in tuberculosis,” he said. This could help identify antibiotic resistance and susceptibility to new antibiotics.
Harvey noted that even if diagnostic research is successful — and achieves the trilogy of good, cheap and fast that researchers are aiming for — the US will still need to invest in sexually transmitted disease (STD) clinics to implement the technology.
“You need to have more research coupled with a robust public health infrastructure,” Harvey said. “That includes public education campaigns and outbreak response.”