A Hospital for Special Surgery (HSS)-led team of investigators is the first to demonstrate that bacterial DNA from prosthetic joint infections can be detected in circulating blood and sequenced to identify the bacteria causing the infection. The innovative approach has the potential to help doctors treat patients who develop prosthetic joint infections with targeted antibiotics faster than is currently possible with standard lab cultures and monitor infection clearance before conducting revision surgeries. The study was published July 22 online first in the Journal of Bone & Joint Surgery.
More than one million Americans undergo knee, hip, elbow and shoulder replacements annually. About one in 75 patients, less than two percent, develop bacterial infections around the joint implants, called prosthetic joint infections. Though the numbers of affected patients are small, the consequences of prosthetic joint infection can be severe.
HSS performs more joint replacement surgeries than any other hospital in the world—a total of 11,000 annually. “Our infection rate is significantly below the national average, but prosthetic joint infections are devastating for affected patients,” says Mathias P. Bostrom, MD, chief of the Adult Reconstruction and Joint Replacement Service at HSS. “Many do not return to the full potential of their original joint replacement.”
It is essential to identify the bacteria causing an infection so that a patient receives the right antibiotic. Since current blood tests only report levels of inflammatory markers, such as C-reactive protein and erythrocyte sedimentation rate, surgeons typically collect a fluid sample from the joint via needle aspiration. However, standard lab test results take at least three days and fail to identify the infectious pathogen in 15 to 20 percent of cases due to the challenges of growing bacteria in culture.
When bacterial identification is unknown, surgeons withhold antibiotics until they obtain tissue samples during the implant removal surgery. The removal procedure involves taking out the contaminated implant hardware and infected soft tissue. Surgeons insert a temporary spacer containing high-dose antibiotics, and they may also place antibiotic beads into the joint. Patients are also treated with high-dose intravenous antibiotics. It takes about six weeks to three months for an infection to clear before patients can undergo another operation to remove the spacer and receive a new permanent joint implant.
The idea for finding a new way to improve the diagnostic approach for patients with prosthetic joint infections began with principal investigator Laura Donlin, PhD, co-director of the Derfner Foundation Precision Medicine Laboratory and a member of the arthritis and tissue degeneration program of the HSS Research Institute. She attended a talk by a professor of bioengineering at Stanford University who had analyzed DNA shed from transplanted organs circulating in blood, called cell-free DNA, as an early detection system for transplant rejection. But through genomic sequencing of circulating cell-free DNA, he had also found increased levels of viral cell-free DNA in some patients’ blood indicating they had developed viral infections while taking immunosuppressant medications.
Dr. Donlin wondered if it would be possible to use the same approach to identify bacteria in patients with prosthetic joint infections. “It was unknown whether bacterial DNA from localized tissue infections around joint implants would be detectable in blood,” says Dr. Donlin. “It’s a challenging environment with many other bits of circulating microbial DNA from skin flora, the gut microbiome and other infections.”
For their proof-of-concept study, Dr. Donlin together with orthopedic surgeons including Michael P. Cross, MD and Dr. Bostrom and colleagues at HSS and Weill Cornell Medicine collected blood samples from 53 patients with known hip or knee prosthetic joint infections beginning in 2018. Karius, a genomic insights company based in Redwood City, California, sequenced blood samples collected from patients before treatment for infection and at the time of reimplantation surgery. They compared microbial cell-free DNA in the blood samples to their proprietary database of more than 1,300 known microbial genomes. The HSS investigators compared sequencing findings with results from standard tissue cultures.
Among surgical tissue samples from these 53 patients, traditional lab cultures identified the bacterial species in 35 cases and the bacterial genus in 11 cases, an overall detection rate of 87 percent. Microbial cell-free DNA sequencing identified the bacterial species in 23 cases in agreement with standard culture results. The new approach also identified the bacterial species in eight cases where cultures identified the bacterial genus only and four cases where cultures failed to determine the presence of bacteria.
On its own, microbial cell-free DNA sequencing pinpointed the bacterial species in 66 percent of samples. However, as an addition to standard culture results, it increased pathogen detection from 87 to 94 percent of samples. Microbial cell-free DNA sequencing was three days faster reporting the bacterial species for cases where culture results had only identified the bacterial family.
Analyses of follow-up blood samples after joint removal surgery and treatment with antibiotics showed undetectable or reduced bacteria levels. “For most patients, we saw microbial cell-free DNA levels drop below detection, indicating the infections had most likely cleared,” says Dr. Donlin. “But there were some cases with lower yet detectable levels after six weeks of antibiotic treatment. Considering that cell-free DNA lives in the bloodstream for only a few minutes, that meant these patients still had an ongoing infection and might require modification to their antibiotic treatment plan.”
“An indication that there is an infection, at least to the genus level for samples that fail to show results in standard cultures, will be beneficial for diagnosing and treating patients earlier for improved outcomes,” says Dr. Bostrom. “As a monitoring tool, microbial cell-free DNA sequencing has the potential to provide important information on the right time to change or stop antibiotics and for reimplantation surgery.”
Dr. Donlin and colleagues are improving the sensitivity and specificity of the new diagnostic method in collaboration with Karius and planning a multicenter study to test it on a larger scale. “In the future, we hope microbial cell-free DNA sequencing will prove to be a useful tool for detecting joint infections more quickly than is currently possible,” Dr. Donlin says. “We’re very excited that our innovation may one day translate to improved outcomes for patients.”
The study was supported by funding provided by the Price Family Foundation, the Stavros Niarchos Foundation Complex Joint Reconstruction Center at HSS, the Feldstein Medical Foundation, the Carson Family Charitable Trust, the Ambrose Monell Foundation, the HSS Research Institute’s David Z. Rosensweig Center for Genomics Research, the National Institutes of Health, the Bill and Melinda Gates Foundation, the Leukemia & Lymphoma Society and the National Science Foundation.
HSS is the world’s leading academic medical center focused on musculoskeletal health. At its core is Hospital for Special Surgery, nationally ranked No. 1 in orthopedics (for the 11th consecutive year), No. 4 in rheumatology by U.S. News & World Report (2020-2021), and the best pediatric orthopedic hospital in NY, NJ and CT by U.S. News & World Report “Best Children’s Hospitals” list (2021-2022). HSS is ranked world #1 in orthopedics by Newsweek (2020-2021). Founded in 1863, the Hospital has the lowest complication and readmission rates in the nation for orthopedics, and among the lowest infection rates. HSS was the first in New York State to receive Magnet Recognition for Excellence in Nursing Service from the American Nurses Credentialing Center five consecutive times. The global standard total knee replacement was developed at HSS in 1969. An affiliate of Weill Cornell Medical College, HSS has a main campus in New York City and facilities in New Jersey, Connecticut and in the Long Island and Westchester County regions of New York State, as well as in Florida. In addition to patient care, HSS leads the field in research, innovation and education. The HSS Research Institute comprises 20 laboratories and 300 staff members focused on leading the advancement of musculoskeletal health through prevention of degeneration, tissue repair and tissue regeneration. The HSS Global Innovation Institute was formed in 2016 to realize the potential of new drugs, therapeutics and devices. The HSS Education Institute is a trusted leader in advancing musculoskeletal knowledge and research for physicians, nurses, allied health professionals, academic trainees, and consumers in more than 130 countries. The institution is collaborating with medical centers and other organizations to advance the quality and value of musculoskeletal care and to make world-class HSS care more widely accessible nationally and internationally. www.hss.edu.