Our findings suggest that easily accessible globulin and A/G ratio were associated with PJI and could be used as the reasonable biomarkers to diagnose PJI. Although several biomarkers related to the infection or inflammation are recommended critical in the diagnosis of PJI by MSIS guidelines, there is currently no convincible consensus available regarding the most appropriate and reliable diagnostic biomarkers. Globulin and A/G ratio represent the systemic inflammatory conditions and immune status [11–15]. However, no scientific evidence supporting their role as diagnostic markers in PJI is present.
Globulin, as a major serum protein component, is synthesized and secreted mostly by the liver and plasma cells in response to inflammatory and infective reactions. Antibodies and inflammatory cytokines are the two major components of globulin [10]. Another serum protein, albumin, has been reported to be negatively regulated by the acute phase reactant and is considered as a biomarker of inflammation and nutritional status [17, 18]. Collectively, the inverse relationship between globulin and albumin in response to inflammation and infection functions to dramatically decrease the A/G ratio, suggesting that the A/G ratio is strongly representing the inflammatory status and infection of our body [16]. Therefore, we newly introduced globulin and A/G ratio, reflected the patient’s inflammatory and infection status, as biomarkers of PJI.
No research has been studied regarding the relationship between globulin, A/G ratio, and PJI. However, various clinical studies have validated the potential role of globulin and A/G ratio in pathogenesis of inflammatory and infectious diseases [12, 13, 19, 20]. A previous study demonstrated a strong association between high levels of serum globulin and extent of hepatic fibrosis in patients with chronic hepatitis B infection [19]. Similarly, Schmilovitz-Weiss et al. reported that high serum globulin levels could serve as a marker to predict the extent of hepatic fibrosis in patients with post-transplant recurrent hepatitis C infection [13]. Moreover, low A/G ratio is a useful marker to predict poor prognosis in cancer patients [16, 21]. In cervical cancer, high globulin levels and low A/G ratio were linked with inflammation and poor prognosis [16]. In accordance with these results, we also observed that high globulin levels and low A/G ratio were independently associated with the risk of PJI and the associations remained significant even after accounting for demographic variables. Further, ROC curve analysis revealed that globulin and A/G ratio showed acceptable predictive value for the diagnosis of PJI. Nonetheless, both biomarkers have a lower diagnostic performance than ESR and CRP which have been reported repeatedly to have better diagnostic power (in terms of AUC, sensitivity, specificity) in the diagnosis of PJI [5, 8, 22]. However, the AUC of globulin and A/G ratio was larger than 0.7, indicating an acceptable diagnostic performance. In contrast, the diagnostic value of total protein and albumin was limited. Interestingly, albumin did not show significant difference between septic and aseptic groups in our study, which was inconsistent with the results of some previous studies [23, 24]. The discrepancy could be due to heterogeneity of study populations, sample sizes, and patient selection [24, 25].
Another reason for investigating the association between globulin, A/G ratio, and PJI was due to the observation that patients who underwent TJA were more likely to be elderly and exhibited comorbidities such as diabetes mellitus and renal insufficiency, all of which may be associated with poor immunity and higher complications, including PJI [24]. As the preoperative globulin and A/G ratio are crucial parameters to evaluate the general and immune status of the patients, any abnormal changes in these two biomarkers should be further investigated. Although not proven by the present study, we hypothesize that evaluation of patients with higher globulin or low A/G ratio and correction of these parameters might prevent postoperative complications. Besides, all the patients who plan to have surgery are required to screen the basic metabolic panel which contains globulin and A/G ratio. Hence, globulin and the A/G ratio are cost-effective and easily accessible parameters, in which patients do not need to get more tests checked preoperatively.
To the best of our knowledge, this is the first instance to illustrate the association of globulin and A/G ratio with PJI. However, the current study is not without limitations. First, the study was not able to include all the confounding variables, for example, invisible inflammatory conditions or infections, which might impact the globulin levels. Nevertheless, we did exclude some of the common inflammatory and infective diseases (e.g. tuberculosis). And multivariate logistic regression analysis was performed to avoid the unwanted impact of confounding factors. Second, the current study was a retrospective review and we were unable to determine the causality and direction of the relationship between globulin, A/G ratio, and PJI. Despite that, our study did reveal that there was a strong association between globulin, A/G ratio, and PJI. Third, globulin includes four categories of proteins. In our study, we did not separate globulin into specific molecules by electrophoresis because of the retrospective design of the study. However, we hope that future research could pay attention to the association between the four categories of globulin and PJI. Fourth, this was a single-centre study and a relatively small number of patients were recruited, particularly in the septic group. Large multicentre studies are required to validate the present findings. Nevertheless, data from one centre with controlled laboratory protocols strengthen our study’s methodology as this could be more generalized and decrease the heterogeneity between groups. Finally, our study cohort included patients requiring revision arthroplasty, which could miss patients with asymptomatic infections or mild clinical manifestations.