Next Generation Sequencing Predicts Failure in Total Joint Arthroplasty

Disruptive new multicenter research has determined that next generation sequencing (NGS) can reliably predict treatment failure due to periprosthetic joint infection (PJI). MicroGenDX, the high complexity laboratory utilized in the study, is upending outdated approaches to infection detection, instead relying on the most up-to-date technologies to not only determine that an infection is present, but to identify the exact micro-organism(s) involved.

“PJI can be devastating, with numerous recent studies indicating that patients with PJI have a five-year mortality rate that matches and exceeds that of common cancers like breast, prostate and melanoma. We are sorely in need of a technology that can provide concrete, quantifiable improvements in patient care,” stated co-author Javad Parvizi, M.D., an orthopedic surgeon and the Director of Clinical Research at the Rothman Orthopaedic Institute in Philadelphia. “With next generation sequencing, I believe we have found such a method.”

Typically, with an infected joint, surgeons remove the implant and either put in a new one at the same time (a one-stage exchange) or put in a new implant at a later date (a two-stage exchange). At the time of removal, a culture is taken in order to determine what organism caused the failure. In the event of a two-stage exchange, a culture is taken to see if any of the organism remains in the joint area.

The problem, says Dr. Parvizi, is that following two-stage exchanges, 20-30 percent of the implants are re-infected. “We have been calling these ‘re-infections,’ but that is not entirely accurate. For 15 years, I have theorized that it is in fact multiple organisms that cause these infections. Cultures, when positive, usually identify the dominant organism and miss the others. They also often fail to identify unusual or slow-growing infective organisms in up to one out of three cases. In this study, we hypothesized that some of the later treatment failures are perhaps not re-infections, but rather infections due to organisms that have been present from the beginning—but not detected via traditional culture methods.”

The prospective study comprised 15 academic institutions (Rothman Orthopaedic Institute at Thomas Jefferson, Cleveland Clinic, University of Pennsylvania, University of Pittsburgh Medical Center, Boston Medical Center, University of Utah, University of Louisville, University of South Florida Department of Orthopaedic Surgery, Northside Hospital, Anderson Orthopaedic Research Institute, Hospital for Special Surgery, University of Florida, Colorado Joint Replacement, University of California San Francisco, Rush University Medical Center)and took over two and a half years. “A total of 851 total hip and knee revisions were recruited with longitudinal clinical follow up obtained,” stated co-investigator Karan Goswami, M.D.

“We found that around 20 percent of the revisions failed during the multicenter study period and, of those, we looked to see which organisms were involved,” stated Dr. Goswami. “In the majority of cases (80-90 percent) that failed due to a supposedly new organism, NGS demonstrated that these organisms were actually in the joint at the time of the first-stage surgery.”

Thus, says Dr. Parvizi, the appropriate word for such situations isn’t necessarily “re-infection,” but rather “persistence.”

While traditional culture tests only isolate living organisms and depend on the environment in which the samples are placed, NGS reveals the precise DNA signature of all the organisms that are present. And critically, negative NGS results can predict the absence of an infection, giving surgeons and patients confidence that their surgery is less likely to fail due to reinfection.

As for cost, Dr. Parvizi indicates, “DNA sequencing is now very reasonably priced. While the initial sequencing of the human genome cost $3 billion, now these tests are available for less than $300.”

“Cultures are a comparatively primitive approach to isolating organisms,” states Dr. Parvizi. “Next generation sequencing provides us with faster and more accurate information so that we can get patients the correct treatment in a more timely manner. No longer will surgeons have to rely on guessing/deduction when it comes to which organisms they are contending with. Going forward, molecular techniques for the isolation of infected organism will soon become the standard of care in orthopedics.”