Reasons for elevated preoperative CRP and ESR levels

CRP was initially discovered in the serum of patients with acute lobar pneumonia in 1930 [12]. It serves as an acute-phase protein, representing a non-specific marker of inflammation and tissue damage. Upon encountering trauma or pathogenic microorganisms, liver cells rapidly synthesize CRP. Consequently, CRP has emerged as a routine laboratory test parameter widely employed in clinical diagnosis of infections.

ESR refers to the rate at which erythrocytes settle under specific conditions, often expressed as the distance erythrocytes sediment over the first hour. While the ESR value of healthy individuals typically remains within a narrow range, various pathological conditions, such as acute and chronic infections, tissue injury and necrosis, and malignant tumors can lead to elevated ESR levels [13,14,15,16]. In contrast to ESR, CRP remains unaffected by factors such as hemoglobin and age, rendering it a dependable indicator of infection severity and treatment efficacy [17].

In comparison to fever and white blood cell count, elevated levels of CRP and ESR more accurately, promptly, and sensitively indicate the extent and severity of inflammation in patients. Notably, persistently elevated or significantly increased CRP and ESR levels are indicative of potential PJI [18].

In this study, while 22 patients exhibited negative bacterial culture results, mNGS findings suggested bacterial infection in 14 patients (63.6%), viral infection in 1 patient (4.6%), and yielded negative results in 7 patients (31.8%). However, among the patients with negative mNGS results, 1 patient underwent surgical intervention for acute suppurative appendicitis six months post-joint replacement surgery (suggesting a possibility of latent onset of infection during joint replacement surgery). Furthermore, 2 patients were diagnosed with rheumatoid arthritis and only 4 patients exhibited unexplained increases in ESR and CRP levels.

Hence, a notable observation emerges whereby the majority of patients exhibiting elevated ESR and CRP levels prior to surgery had identifiable underlying causes. The four patients with unexplained elevations suggest potential involvement of rheumatic diseases or latent infections. Diagnosing rheumatic diseases can be challenging due to their diverse nature, while latent or chronic infections in other parts of the body besides the joint might remain undiagnosed due to delayed or inaccurate diagnosis [19, 20].

The necessity of mNGS

Studies have demonstrated the notably low detection rate of traditional bacterial culture, posing significant challenges in diagnosing PJI at an early stage and in guiding appropriate antibiotic usage, thereby leading to treatment delays [21, 22]. Various factors may contribute to the negative bacterial cultures observed in the periarticular soft tissue and joint fluid of the 22 patients included in this study. These factors include the presence of biofilm on the surface of the prosthesis, which can shield pathogenic bacteria present in periarticular soft tissues and joints; reduced virulence and viability of the pathogenic bacteria; stringent culture conditions required of certain pathogenic bacteria; and prior administration of antibiotics before culture [23, 24].

In this study, mNGS indicated a minimal number of detected sequences in each patient with one notable exception: a patient who underwent hip joint replacement surgery exhibited 181 sequences identified for Parvimonas micra. The low number of sequences may explain the negative results in bacterial culture. These findings underscore the low detection rate associated with traditional bacterial culture methods.

Moreover, the results of this study highlight the efficacy of mNGS technology in diagnosing infections. mNGS has emerged as a valuable tool in infection diagnosis boasting superior detection rates for pathogenic bacteria compared to traditional bacterial cultures (82.9% at the species level and 90.2% at the genus level) [25, 26]. It identifies a wide range of causative bacteria including those that prove challenging to detect via conventional methods. mNGS demonstrates remarkable accuracy and sensitivity in diagnosing PJI, facilitating early diagnosis and treatment [27, 28].

Street et al. reported that mNGS exhibits species-level sensitivity, genus-level sensitivity, and species-level specificity of 88% (95% CI 77–94%), 93% (95% CI 84–98%), and 88% (95% CI 79–93%), respectively [29]. Additionally, mNGS can accurately detect pathogenic microorganisms such as viruses that may evade detection by traditional bacterial culture methods [30]. Notably, one case of human herpesvirus type 6A was also detected by mNGS in this study.

Given the advantages of mNGS technology, its integration into the diagnostic protocol is imperative for patients exhibiting unexplained preoperative elevations in ESR and CRP levels.

Significance of local use of antibiotics

While systemic antibiotics can inhibit biofilm formation to a certain extent, reaching the minimum biofilm eradication concentration (MBEC) within the joint cavity necessitates concentrations 100 to 1000 times higher than those required to eliminate free-floating pathogenic bacteria. Achieving such concentrations safely through intravenous administration alone is problematic [31]. However, by combining local antibiotic administration within the joint cavity with systemic treatment, it becomes feasible to attain or surpass the MBEC while maintaining safety. Moreover this combined approach does not exacerbate joint prosthesis wear and tear [32,33,34]. A study by Edelstein et al. demonstrated the efficacy of this strategy in controlling PJI in a rabbit joint model infected with methicillin-resistant Staphylococcus aureus [35]. A series of studies have shown that local antibiotic irrigation, suction, and drainage have achieved good results in the treatment of PJI [35,36,37,38,39]. For example, Professor Cao Li's team from Xinjiang Medical University conducted a large number of PJI Phase I revision surgeries using this method and achieved remarkable results [40]. After learning this method, our team also carried out some PJI Phase I revision surgeries and achieved encouraging results. Although this method is currently not considered an established procedure for treating PJI, it is still an effective measure.

Riesgo et al. conducted a study involving 74 patients diagnosed with PJI [38]. Among these patients, 36 cases received a combination of intravenous and local antibiotics, constituting the experimental group, while 38 patients were treated solely with intravenous antibiotics, constituting the control group. The study revealed a PJI cure rate of 83.3% in the experimental group and 63% in the control group.

In this study, 22 patients underwent treatment with a combination of intravenous and local antibiotics. The selection of antibiotic type, duration of treatment, and the potential transition to oral antibiotics were determined based on the findings from bacterial culture and mNGS. The outcomes of this personalized approach yielded favorable results.

Feasibility analysis of joint replacement in patients with increased ESR and CRP levels for unknown reasons

With the advancements and application in antibiotic bone cement and the utilization of antimicrobial coatings on prostheses, the success rates of one-stage revision surgeries have seen significant improvements compared to previous periods. Various retrospective studies have indicated no substantial variance in infection cure rates between one-stage and two-stage revision procedures [6, 41].

In this cohort of 22 patients exhibiting unexplained elevations in ESR and CRP levels, mNGS identified bacterial infection in 14 patients (63.6%), viral infection in 1 patient (4.6%), and yielded negative results in 7 patients (31.8%). With the exception of a single patient who underwent hip joint replacement and exhibited a high sequence count (181) for P. micra, the number of sequences detected in the remaining patients was minimal. The number of pathogenic bacteria detected by mNGS was limited and the bacterial culture of the periarticular soft tissue and synovial fluid yielded negative results, indicating a relatively low virulence of the detected pathogens. The efficacy of one-stage revision for accurately diagnosed PJI has been well-established. Consequently, it stands to reason that one-stage revision following thorough debridement would be effective for patients exhibiting fewer bacterial sequences and lower virulence.

Notably, following a 1-year follow-up period, none of the 22 patients enrolled in this study developed PJI. Additionally, all patients demonstrated favorable rehabilitation and exercise outcomes. Functional scores exhibited significant improvements compared to baseline assessments, corroborating efficacy of approach. For patients exhibiting unexplained elevation in ESR and CRP levels, primary artificial joint replacement performed according to the one-stage revision for PJI protocol appears to be a viable option.

Limitations of this study

The relatively small sample size of this study may introduce inherent biases and limit the generalizability of the findings. Furthermore, the follow-up duration may not sufficiently capture long-term outcomes, necessitating extended observation to ascertain the occurrence of PJI over time. Consequently, conducting a multicenter study is advisable to corroborate and extend the findings. Finally, the mNGS is more expensive than traditional methods, but is more accurate on diagnosis of bacteria infection, so it is still worth promoting and applying.