OREF grant recipient investigates serum infection markers and reimplantation timing after PJI
Overall, the more than 600,000 total knee and 300,000 total hip replacements performed in the United States each year lead to positive patient outcomes; however, rare complications such as periprosthetic joint infections (PJIs) can arise. PJIs, which occur in approximately 1 percent to 3 percent of total joint arthroplasty (TJA) patients, have a huge impact on society and patients—an impact that is only expected to increase as patients live longer and as the number of TJA procedures performed each year increases. In fact, by 2030, the rate of PJI is expected to be 6.4 percent among total hip procedures and 6.8 percent among total knee procedures.

"PJI places an immense psychological burden on the patient and the family," said Javad Parvizi, MD, 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 patients hasn't been perfect—some have to have their leg amputated, while others are left completely disabled. Moreover, the 5-year mortality rate for PJI approaches 30 percent, worse than for some cancers."

After witnessing the death of a patient who had undergone numerous surgeries to treat a PJI, Dr. Parvizi decided 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 U.S. 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 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
PJIs 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 to 8 weeks later, the surgeon removes the spacer and implants new joint replacement components. Before the second stage, however, the surgeon must be certain the patient is infection-free—or risk reinfection, which occurs in about 10 percent to 20 percent of PJI patients.

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 they show false negatives, which increase the chance of a second implant failure.

"In one study, 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.

Infection indicators
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 multicenter 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. Parvizi and his research team compared these concentrations in patients in whom treatment ultimately failed 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 healthcare system. Dr. Parvizi and his research team found one such marker.

"This marker is called the D-dimer," he said. "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 and his team also used an animal model of infection to learn if any blood markers could be used to determine the presence of 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," explained Dr. Parvizi. "The research done with this OREF grant has brought us one step closer to a potential, definitive method for treating patients with PJI."

Funding translational research
Dr. Parvizi said that the funding he has received from OREF has been critical in helping him become a clinician scientist. It has also given him the opportunity to generate preliminary data necessary to apply for further funding and evaluation of periprosthetic infection PJI treatment methods.

"Our research has real translational elements that have the potential to impact clinical practice," he said.

Amy Kile is the publications manager for OREF. She can be reached at kile@oref.org

© Orthopaedic Research and Education Foundation (OREF)

References:

1. CDC National Hospital Discharge Survey: Procedures by selected patient characteristics: Number by procedure category and age: 2010. Available at http://www.cdc.gov/nchs/nhds/nhds_tables.htm. Accessed October 11, 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;89:780–785.
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;467(7):1699–1705.