Profiling the Immune Response to Periprosthetic Joint Infection and Non-Infectious Arthroplasty Failure

Abstract

Arthroplasty failure is a major complication of joint replacement surgery. It can be caused by periprosthetic joint infection (PJI) or non-infectious etiologies, and often requires surgical intervention and (in select scenarios) resection and reimplantation of implanted devices. Fast and accurate diagnosis of PJI and non-infectious arthroplasty failure (NIAF) is critical to direct medical and surgical treatment; differentiation of PJI from NIAF may, however, be unclear in some cases. Traditional culture, nucleic acid amplification tests, metagenomic, and metatranscriptomic techniques for microbial detection have had success in differentiating the two entities, although microbiologically negative apparent PJI remains a challenge. Single host biomarkers or, alternatively, more advanced immune response profiling-based approaches may be applied to differentiate PJI from NIAF, overcoming limitations of microbial-based detection methods and possibly, especially with newer approaches, augmenting them. In this review, current approaches to arthroplasty failure diagnosis are briefly overviewed, followed by a review of host-based approaches for differentiation of PJI from NIAF, including exciting futuristic combinational multi-omics methodologies that may both detect pathogens and assess biological responses, illuminating causes of arthroplasty failure.

Keywords: PJI; arthroplasty; immune profiling; multi-omics; periprosthetic joint infection.

Figure 1

Causes of periprosthetic joint infection after total hip and total knee arthroplasty based on data from Tai, D.B.G. et al. Clin Microbiol Infect 2022, 28, 255–259 [50]. Graph created in GraphPad Prism v9.4.0 (San Diego, CA, USA).

Figure 2

Common causes of non-infectious arthroplasty involving (A) total knee arthroplasty (TKA) and (B) total hip arthroplasty (THA). TKA data are from Abdel, M.P. et al. Bone Joint J 2017, 99-B, 647–652 [64]. THA data from Ledford, C.K. et al. J Am Acad Orthop Surg 2019, 27 [12]. Graph created in GraphPad Prism v9.4.0 (San Diego, CA, USA).

Figure 3

Periprosthetic joint infection (PJI)-related publication counts between 1969 and 2022. (A) All PJI-related publications were calculated based on a PubMed query with keywords “PJI”, “prosthetic joint infection”, or “periprosthetic joint infection”. (B) PJI diagnosis-related publications were calculated based on a PubMed query with keywords “PJI diagnosis”, “prosthetic joint infection diagnosis”, or “periprosthetic joint infection diagnosis”. Query conducted on 16 January 2023. Graph created in GraphPad Prism v9.4.0 (San Diego, CA, USA).

Figure 4

Immune response to arthroplasty failure due to periprosthetic joint infection (PJI) or non-infectious arthroplasty failure (NIAF) detailing cell-types recruited/activated and host markers. Bolded, starred (*) entries represent those currently used for the diagnosis of PJI. Abbreviations used: 4E-BP1, eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1; BCAT1, branched-chain-amino-acid aminotransferase; BPI, bactericidal/permeability-increasing protein; CCL, chemokine (C-C motif) ligand; CDCP1, complement C1r/C1s, Uegf, Bmp1 domain containing protein 1; COL1A2, collagen α-2(I) chain; CRTAC1, cartilage acidic protein 1; CRP, C-reactive protein; CSF-1, macrophage-colony stimulating factor; CXCL, chemokine (C-X-C motif) ligand; DLST, dihydrolipoamide S-succinyltransferase; EEA1, early endosome antigen 1; ELA-2, neutrophil elastase; EN-RAGE, extracellular newly identified receptor for advanced glycation end products binding protein; ERN1, endoplasmic reticulum to nucleus signaling 1; FABP3, fatty acid-binding protein–heart; FABP5, fatty acid-binding protein–epidermal; FBP1, fructose-1,6-bisphosphatase 1; FCRL4, Fc receptor-like 4; G-CSF, granulocyte colony-stimulating factor, HEXB, β-hexosaminidase subunit β; HGF, hepatocyte growth factor; HSPB1, heat shock protein β-1; IFI30, IFI30 lysosomal thiol reductase; IL, interleukin; LE, leukocyte esterase; LIF, leukemia inhibitory factor; LRG1, leucine-rich α-2-glycoprotein; MBL, mannose-binding lectin; MCAM, melanoma cell adhesion molecule; MCP, monocyte chemoattractant protein; MDSC, myeloid derived suppressor cell; MMP, matrix metallopeptidase; PYGL, glycogen phosphorylase–liver; RNASE1, pancreatic ribonuclease; RNASE3, eosinophil cationic protein; SCF complex, Skp, Cullin, F-box containing complex; TLR-2, toll-like receptor 2; TNF, tumor necrosis factor; TNFRSF9, TNF receptor superfamily member 9; TRANCE, TNF-related activation-induced cytokine; TWEAK, TNF-like weak inducer of apoptosis; ST1A1, sulfotransferase family 1A member 1; STAMBP, signal transducing adaptor molecule binding protein. Created with Biorender.com.

Figure 5

Potential multi-omics diagnostic scheme using simultaneous microorganism detection and assessment of host response to determine whether infection is present, and if so, to define the causative pathogen(s) and inform treatment. Created with Biorender.com.