Until recently, syphilis was an anachronism for medical professionals.
The sexually transmitted infection (STI) 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 could be easily treated, and by the 1990s syphilis was almost eliminated from the US.
Over the past decade, however, it has made a dramatic comeback. Cases have risen 80% in the past five years, and the US now has the highest syphilis rates since 1950. More than 200,000 Americans was diagnosed with the disease in 2022. Since 2012, the US Centers for Disease Control and Prevention (CDC) has a 10-fold increase in the number of babies born with the disease.
Last week, the National Institutes of Health (NIH) took an important step to fight back against one of the key problems – the fact that testing for syphilis is so difficult. It said it would spend $2.4 million to promote syphilis testingwhich has not changed much since the 1950s, in 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 convened to address the spate of new cases.
But “fighting 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 greater investment in therapeutic research and vaccines.”
The bacteria that cause the disease, Treponema pallidumis one of the most invasive known to medicine. T. pallidum can cross the blood-brain barrier, the placenta in pregnant mothers and enter any organ system and attack organs such as the heart or bones.
Common symptoms include painless ulcers around the vagina, penis, anus or in the throat; 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 that can cause blindness. Congenital syphiliswhen the disease is transmitted from mother to child is a special terror: the disease can cause death and neurological devastation in babies.
The incidence of the disease is so diverse that one of the fathers of modern medicine noticed: “He who knows syphilis knows medicine.” But both testing and treatment remain stuck in the mid-20th century. Treatment is still highly effective and involves, bluntly, a big shot of penicillin in the back. But testing is hard.
“Diagnosing syphilis is surprisingly challenging and difficult,” said Caroline Cameron, a professor of biochemistry and microbiology at the University of Victoria in Canada, who was awarded a two-year NIH grant to advance tests to directly identify the bacteria to detect, said.
The technology still relies on serology, or a test for an immune response. It takes days to weeks for a syphilis diagnosis to be confirmed, and tests cannot determine whether an infection is active or has cleared. Testing in infants, who do not have a fully formed immune system, is particularly difficult.
Cameron’s research looks at detecting syphilis proteins using mass spectrometry, a laboratory instrument 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 is present.
“What the field needs is something that can directly detect the presence of the pathogen, not the host’s response to the pathogen, and it needs to be in that very easy format,” Cameron said. Her lab “takes patient samples like urine like blood and then analyzes them for these proteins that are only found in this pathogen – they are not found in any other infectious disease, they are not found in any human protein”.
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-regarded, it’s used by many clinical laboratories.”
With possible weeks between diagnosis and treatment, “the patients can often be diagnosed with syphilis but 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 – mostly marginalized people who are underserved by medicine. Mothers who give birth to children infected with syphilis provide a particularly powerful example: 40% did not have prenatal carebut such women are only responsible for approx 5% of all pregnant women. Men who have sex with men and people with substance use disorders are also more likely to have syphilis than the general population.
Salipante’s research examines 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 given at the doctor’s office while the patient waits, perhaps in as simple a format as a dipstick.
“The most important aspect of this is that, theoretically, this is something that can be done very quickly in a point-of-care setting,” Salipante said. “Instead of sending it remotely to a lab … our ultimate goal and hope is that it can be performed very quickly, within 30 minutes or an hour, by non-specialists in a doctor’s office or emergency room and can be managed while the patient is still there.” Aptomer tests have already been developed for some other infectious diseases, such as Covid-19, although they remain experimental.
Dr. Joshua Lieberman, assistant director of the division of molecular diagnosis and microbiology also at the University of Washington, hopes that molecule-specific testing can also help with recurring antibiotic shortages in syphilis treatment. Lieberman is Salipante’s co-investigator.
The penicillin product used to treat syphilis is Bicillin LA, an antibiotic that recurring deficits driven in part by the explosive growth of syphilis cases. The antibiotic is known to be difficult to manufacture, and is still obtained from mold.
“What I would like to be able to do is to combine that test – yes or no that organism or its DNA is present – with: ‘Is there a marker for resistance to a specific antibiotic in that organism?'” Lieberman said. said. “It’s like what we do with many of our tests for mycobacteria in tuberculosis,” he said. This can help identify both antibiotic resistance and susceptibility to new antibiotics.
Harvey noted that even if diagnostic research is successful — and hits the trifecta of good, cheap and fast that researchers are looking for — the U.S. will still need to invest in STI clinics to deploy the technology.
“You have to have more research along with a robust public health infrastructure,” Harvey said. “This includes public education campaigns and outbreak response.”
