Inhibition of Angiotensin Converting Enzyme Impairs Anti-staphylococcal Immune Function in a Preclinical Model of Implant Infection.

Background: Evidence suggests the renin-angiotensin system (RAS) plays key immunomodulatory roles. In particular, angiotensin-converting enzyme (ACE) has been shown to play a role in antimicrobial host defense. ACE inhibitors (ACEi) and angiotensin receptor blockers (ARB) are some of the most commonly prescribed medications, especially in patients undergoing invasive surgery. Thus, the current study assessed the immunomodulatory effect of RAS-modulation in a preclinical model of implant infection. Methods:In vitro antimicrobial effects of ACEi and ARBs were first assessed. C57BL/6J mice subsequently received either an ACEi (lisinopril; 16 mg/kg/day), an ARB (losartan; 30 mg/kg/day), or no treatment. Conditioned mice blood was then utilized to quantify respiratory burst function as well as Staphylococcus aureus Xen36 burden ex vivo in each treatment group. S. aureus infectious burden for each treatment group was then assessed in vivo using a validated mouse model of implant infection. Real-time quantitation of infectious burden via bioluminescent imaging over the course of 28 days post-procedure was assessed. Host response via monocyte and neutrophil infiltration within paraspinal and spleen tissue was quantified by immunohistochemistry for F4/80 and myeloperoxidase, respectively. Results: Blood from mice treated with an ACEi demonstrated a decreased ability to eradicate bacteria when mixed with Xen36 as significantly higher levels of colony forming units (CFU) and biofilm formation was appreciated ex vivo (p < 0.05). Mice treated with an ACEi showed a higher infection burden in vivo at all times (p < 0.05) and significantly higher CFUs of bacteria on both implant and paraspinal tissue at the time of sacrifice (p < 0.05 for each comparison). There was also significantly decreased infiltration and respiratory burst function of immune effector cells in the ACEi group (p < 0.05). Conclusion: ACEi, but not ARB, treatment resulted in increased S. aureus burden and impaired immune response in a preclinical model of implant infection. These results suggest that perioperative ACEi use may represent a previously unappreciated risk factor for surgical site infection. Given the relative interchangeability of ACEi and ARB from a cardiovascular standpoint, this risk factor may be modifiable.

IRAK-M in macrophages around septically and aseptically loosened hip implants.

The most common long-term complication of joint arthroplasty is loosening, which is mediated by chronic inflammatory cytokines produced by macrophages stimulated by implant-derived debris and eventually bacterial components adherent to such debris. In this study, antiinflammatory interleukin-1 receptor-associated kinase-M (IRAK-M) was studied in macrophages in interface membranes in vivo using immunohistochemical staining and in titanium particle-stimulated macrophages in vitro using reverse transcriptase-polymerase chain reaction. Results show that the interface membranes of septically and aseptically loosened prosthesis express more IRAK-M protein than control membranes from osteoarthritic patient and that IRAK-M mRNA-levels increase upon particle stimulation. These findings suggest that, the upregulation of IRAK-M in macrophages is involved in the local immunosuppression around implants, and may contribute to septic and aseptic implant loosening.

Diagnosis of periprosthetic joint infection: the utility of a simple yet unappreciated enzyme.

BACKGROUND: The white blood-cell count and neutrophil differential of the synovial fluid have been reported to have high sensitivity and specificity in the diagnosis of periprosthetic infection following total knee arthroplasty. We hypothesized that neutrophils recruited into an infected joint secrete enzymes that may be used as markers for infection. In this prospective study, we determined the sensitivity and specificity of one of these enzymes, leukocyte esterase, in diagnosing periprosthetic joint infection. METHODS: Between May 2007 and April 2010, synovial fluid was obtained preoperatively from the knees of patients with a possible joint infection and intraoperatively from the knees of patients undergoing revision knee arthroplasty. The aspirate was tested for the presence of leukocyte esterase with use of a simple colorimetric strip test. The color change (graded as negative, trace, +, or ++), which corresponded to the level of the enzyme, was noted after one or two minutes. RESULTS: On the basis of clinical, serological, and operative criteria, thirty of the 108 knees undergoing revision arthroplasty were infected and seventy-eight were uninfected. When only a ++ reading was considered positive, the leukocyte esterase test was 80.6% sensitive (95% confidence interval [CI], 61.9% to 91.9%) and 100% specific (95% CI, 94.5% to 100.0%), with a positive predictive value of 100% (95% CI, 83.4% to 100.0%) and a negative predictive value of 93.3% (95% CI, 85.4% to 97.2%). The leukocyte esterase level correlated strongly with the percentage of polymorphonuclear leukocytes (r = 0.7769) and total white blood-cell count (r = 0.5024) in the aspirate as well as with the erythrocyte sedimentation rate (r = 0.6188) and C-reactive protein level (r = 0.4719) in the serum. CONCLUSIONS: The simple colorimetric strip test that detects the presence of leukocyte esterase in synovial fluid appears to be an extremely valuable addition to the physician's armamentarium for the diagnosis of periprosthetic joint infection. The leukocyte esterase reagent strip has the advantages of providing real-time results, being simple and inexpensive, and having the ability to both rule out and confirm periprosthetic joint infection. However, additional multicenter studies are required to substantiate the results of our preliminary investigation before the reagent strip can be used confidently in the clinic or intraoperative setting.