Research Summary Research topic: Investigated blood serum proteins to learn if they could be used as an efficient and accurate method to determine if a patient is infection free after being treated for periprosthetic joint infection
Research results: Determined one marker, the D-Dimer, increases when an infection is present
Patient care application of results: A potentially non-invasive way to determine if a patient is still infected after being treated for periprosthetic joint infection, allowing surgeons to reimplant joint replacement components earlier and with less risk
Simplified patient care application: For patients who have been treated for prosthetic joint infection, second total joint replacements that can be done earlier and with less risk of reinfection
Timing is everything
OREF grant recipient investigates serum infection markers and re-implantation timing after periprosthetic joint infection
For patients with long-term joint pain, a total joint replacement can provide relief and a better quality of life. Yet, although there is a high success rate for the more than 600,000 total knee and 300,000 total hip replacements performed in the United States each year, complications can occur.1
Although periprosthetic joint infections (PJIs) are rare, occurring in around 1-3 percent of total joint replacement patients, their impact on society and patients is immense. The number of PJIs is expected to rise as patients live longer and the number of total joint replacements performed each year increases. By 2030, the rate of infection is expected to increase to 6.4 percent for total hip and 6.8 percent for total knee.2
“PJI places an immense psychological burden on the patient and the family,” said Javad Parvizi, MD, orthopaedic surgeon and professor of orthopaedic surgery at Thomas Jefferson University in Philadelphia. “I have seen many patients endure incredible hardship from both a financial and a psychological standpoint. The outcome for some of them hasn’t been perfect—some have to have their leg amputated, some are left completely disabled, and the 5-year mortality rate for periprosthetic joint infection approaches 30 percent, worse than some cancers.”
In fact, it was witnessing the death of a patient who had undergone numerous surgeries to treat a PJI that led Dr. Parvizi to dedicate his work as a clinician scientist to investigating the problem. In 2004, he received an Orthopaedic Research and Education Foundation (OREF) Clinician Scientist Grant to investigate ways to prevent PJI by changing the surface of total knee and hip implant components to release antibiotics that fight infections as they occur.
The work that began with that grant is on hold as Dr. Parvizi and his research team await Food and Drug Administration approval to begin clinical trials. In the meantime, Dr. Parvizi has shifted his focus to finding better treatment methods for patients who do develop a PJI. In 2013, he received the OREF Prospective Clinical Research Grant to investigate whether serum molecular markers could be used to determine optimal timing for reimplantation following a prior resection arthroplasty for treatment of PJI.
PJI treatment standards
Periprosthetic infections almost always require surgical intervention. In the United States, these infections are typically treated with a two-stage exchange arthroplasty. In the first stage, the surgeon removes the prosthesis and replaces it with an antibiotic cement spacer. In the second stage, typically about 6-8 weeks later, the surgeon removes the spacer and implants new joint replacement components. Before the second stage, however, the surgeon must be certain that the patient is infection free or risk reinfection, which occurs in about 10-20 percent of PJI patients. How does the surgeon know that the infection has been eradicated or controlled? When is the optimal time for the second stage?
The current standard of care is for the surgeon to clinically evaluate the patient and order a blood test. Blood is evaluated for erythrocyte sedimentation rate (ESR) and serum C-reactive protein (CRP). Studies have shown, however, that these methods are unreliable indicators of infection. They often show false positives, leading the surgeon to delay reimplantation, or false negatives, which increase the chance of a second implant failure.
“In one study3, researchers were unable to identify an optimum cutoff value for the ESR, CRP or any combination of the two, which would help distinguish patients with successful eradication of infection from those who remain persistently infected,” Dr. Parvizi explained.
If fluid is present, surgeons can also perform a joint aspiration and analyze synovial fluid for white blood cell count and microbiological cultures, but this, too, has limitations. Joint aspiration can be cumbersome in total hip arthroplasty patients, and a large percentage of aspirations are unsuccessful, dry taps.
With their 2013 OREF funding, Dr. Parvizi and his research team investigated a more efficient and accurate method to determine the presence or absence of infection. The researchers conducted a multi-center study that followed 95 patients who had confirmed PJI.
The researchers analyzed blood drawn at the time of admission to develop a baseline for biomarker serum levels. After surgeons removed failed prostheses from these patients and implanted antibiotic cement spacers, the researchers analyzed blood samples at various intervals.
In addition to standard CRP and ESR analysis, the researchers assayed the blood to determine the concentration of several inflammatory proteins that preliminary studies had shown to be elevated in the presence of persistent infection. Dr. Parvzi and his research team compared these concentrations in patients who ultimately failed treatment and those who remained free from infection. By comparing patient outcome with protein levels at each time point, the researchers were able to determine which inflammatory proteins were indicative of infection and at what concentration.
A protein that shows promise as an indicator of infection would give surgeons a reliable, relatively noninvasive, test that would reduce the rate of reinfection. It would also assure surgeons that the patient was infection free, allowing them to replace prostheses earlier, reducing the financial and psychological burden on patients and the health care system. Dr. Parvizi and his research team found one such marker.
“This marker is called the D-Dimer and it appears that the level of the D-Dimer increases when an infection is present. We may be able to take a small sample of blood and test the D-Dimer level to determine if a patient has an infection,” Dr. Parvizi said.
Dr. Parvizi and his team also used an animal model of infection to learn if any blood markers could be promising for indicating persistent infection. They found that five blood markers, including the D-Dimer, increased with infection but they recommend further testing.
“If we can find a blood marker that decreases as the infection resolves, we would be able to use a simple blood test to determine when the infection is gone or if a patient needs additional treatment,” Dr. Parvizi said. “The research done with this OREF grant has brought us one step closer to a potential, definitive method for treating patients with PJI.”
OREF funds translational research
Dr. Parvizi said that the funding he has received from OREF has been critical in helping him become a clinician scientist.
“The clinician scientist grant was elemental in allowing me to set up research infrastructure from the beginning, which has then allowed me to exploit numerous avenues in clinical practice. Without that grant, all of my dreams and intentions to become a clinician scientist probably would have evaporated.”
Dr. Parvizi also said that his 2013 OREF grant gave him the opportunity to generate preliminary data necessary to apply for further funding and evaluation of periprosthetic infection treatment methods, and that OREF is unique in offering grants that allow researchers to investigate clinically relevant questions.
“Although all research funding bodies have the same important mission, the major difference between them and OREF is that OREF funds research that has real translational elements. You will see the implication of research findings for OREF grants and how they impact clinical practice.”
1. National Hospital Discharge Survey: 2010 table, Procedures by selected patient characteristics - Number by procedure category and age. Accessed Aug. 3, 2016.
2. Kurtz S, Ong K, Lau E et al. Projections of primary and revision hip and knee arthroplasty in the United States from 2005 to 2030. J Bone Joint Surg Am 2007; 89:780-5.
3. Ghanem E, Azzam K, Seeley M, Joshi A, Parvizi J. Staged revision for knee arthroplasty infection: what is the role of serologic tests before reimplantation? Clin Orthop Relat Res. 2009 Jul;467(7):1699-705.