In all, 27 original studies reviewing risk factors relating to primary total hip and knee arthroplasty infections were included. The number of risk factors identified ranged from 1 to 18. Four studies (14.8%) reviewed PJI on the hip, 3 (11.21%) on the knee, and 20 (74.1%) reviewed both joints. The statistical methods used to determine significance are also shown in Table 1[4,5,9-33].

The quality of the included studies is demonstrated in Table 2. Nineteen studies (70.4%) were retrospective and 8 (29.6%) prospective. Record bias was identified in the majority of studies (66.7%). The definition of PJI varied amongst the studies but there was a general consensus to define infection by previously validated methods.

This included the presence of 2 or more cultural positive results for the same microorganism (plus other features on infection) in 4 studies (14.8%), the CDC definition in 5 studies (18.5%), the Medicare code for infection in 5 studies (18.5%), and 9 studies (33.3%) based their definition on patients meeting 3 of the following 5 features; (1) abnormal serology (ESR > 30 mm/h; CRP > 1 mg/dL); (2) strong clinical and radiographic suspicion for infection; (3) positive joint aspiration culture for infection; (4) evidence of purulence during the subsequent surgical intervention; and (5) positive intraoperative culture.

One study used the MSIS criteria, which includes: (1) a sinus tract; (2) positive culture results from 2 or more tissue or fluid samples; and (3) 4 of the following 6 criteria are present: (I) elevated CRP/ESR; (II) elevated synovial WCC; (III) high synovial PMN leukocyte percentage; (IV) presence of purulence in the joint; (V) positive culture result from one sample from the affected joint; and (VI) PMN leukocyte count of more than 5 per high-powered field in 5 high-powered fields on histologic analysis at 400 × magnification[34].

Risk factors relating to the host have been shown in Table 3, and are the most abundant group of risk factors identified. The majority of the risk factors are systemic referring to patient co-morbidities that are negatively associated with patient outcome following a primary THR or TKR, such as presence of diabetes mellitus[4,9,17,20,26], immunocompromised[5,15,21], concomitttent systemic infection[5,10,27,31], cardiology[4,16,21] and gastroenterology disorders[22,28], high ASA (American Society of Anesthesiologists) grade[12,15,20] and malnutrition[13,17,21,23,25,26,33].

Patient demographics also have been shown to have an impact upon risk of PJI, including age[16], rural residence[16], race[20], male gender[14,18,20,31], and alcohol[26] or tobacco use[23,29,31,32]. Previous operations to the joint (excluding revisions arthroplasty as this was excluded from analysis) increased the risk of PJI[5,32].

Risk factors relating to the provider are shown in Table 4. Prolonged operative duration of greater than 115 minutes in hip arthroplasty is a strong predictor of infection[5,14,23], as is non-same day surgery[23]. During knee arthroplasty, exposure to the joint requiring quadriceps release significantly increases the risks of infection[20].

Protective measures include the use of antibiotic surgical prophylaxis systemically[5] and locally as irrigation[20], but antibiotic impregnated cement may or may not be protective[18,20]. In addition, bilateral procedures during the same operation have been shown by some studies to increase the risk[12], whilst in others decrease it[20].

Post-operatively patients may present with a superficial infection to the joint with a warm, cellulitic, and sometimes discharging wound, which is a high predictor of an underlying PJI[5,11,9,15]. Table 5 demonstrates other factors that have a high correlation with a PJI, including receiving a blood transfusion[11,12,15] (especially if the blood has been stored for greater than 14 d[24]), post-operative urinary tract infection (UTI)[5,12], and onset of cardiac arrhythmias[12].

Several risk factors were shown to have greater significance than others, and a vast majority of the risk factors were directly related to the patient (host-factors). The most significant risks were the use of preoperative high dose steroids (OR = 21.0, 95%CI: 3.5-127.2, P < 0.001)[21], a BMI above 50 (OR = 18.3, P < 0.001)[13], tobacco use (OR = 12.76, 95%CI: 2.47-66.16, P = 0.017)[23], BMI below 20 (OR = 6.00, 95%CI: 1.2-30.9, P = 0.033)[21], diabetes (OR = 5.47, 95%CI: 1.77-16.97, P = 0.003)[26], and coronary artery disease (OR = 5.10, 95%CI: 1.3-19.8, P = 0.017)[21].

We further categorised the resultant risk factors into whether or not they were modifiable, reflecting the opportunity of the surgeon to optimise their patient pre-operatively and to reduce the risk of developing a PJI (Table 6).

The most frequently quoted risk factor was diabetes mellitus[4,9,17,20,22,26], which had one of the highest odds ratios[26]. Almost all the other highest odds ratio, or hazard ratio, also belonged to medical conditions ultimately impairing a patients immunity, as demonstrated from high dose pre-operative steroids[21], malnutrition (reflective of high alcohol intake[26], BMI below 20[21] and above 50[13]), and tobacco use[23]. Malignancy[4,5], rheumatoid arthritis[4,15,16], and liver cirrhosis[28] can also impair a patient’s immunity.

Immunosuppression has long been known to increase a patient’s risk of systemic infection, and has widely been documented in arthroplasty patients. Ragni et al[36] demonstrated this in human immunodeficiency virus-positive hemophiliacs with CD4 counts of 200 mm³ or less undergoing orthopaedic surgery. Post-operative infection occurred in 10 (15.1%) of 66 patients[36]. Local steroid injection causing focal immunosuppression about the joint has also been shown to increase the risk, compared to those that have not received any joint injections in hip arthroplasty cases[37].

In rheumatoid patients treated with immunosuppressive drugs (including biologic agents) undergoing all orthopeadic procedures, a statistically significant higher risk of infection was seen in this patient cohort compared to a degenerative/post-traumatic group (OR = 2.58, 95%CI: 1.91-3.48, P < 0.001)[38]. Furthermore this risk was significantly increased in patients taking multiple disease-modifying antirheumatic drugs (DMARDs) (P = 0.036) or tumor necrosis factor α (TNFα) inhibitors (P = 0.032), especially if the last dose of TNFα inhibitor was given < 1 administration interval before surgery[38].

While not directed specifically to immunosuppression, other co-morbidities have a role in reducing the patients systemic response to infection. Cardiac dysfunction[4,16,21], renal failure[4,15], anaemia[4,9,16] and coagulopathy[16] have all been shown to increase the risk of infection. This may be directed through specific cellular pathways[39], but may demonstrate the insult the surgical procedures has in causing a secondary inflammatory insults, worsening multiple organ dysfunction[40,41].

Deranges in renal function, with progressively higher poor glomerular filtration rate (GFR) in either the acute or chronic stages, reduces the ability to remove unwanted and hazardous chemicals from the blood, and places the patient at a higher risk. Lieberman et al[42] demonstrated a high rates of infection in patients on chronic renal dialysis (19%), however in a separate patient series no significant increase in infection risk was seen[43].

We believe that if a patient is known to have systemic infection, or a localised infection but distant to the operative joint, the risk of haematological spread of infection to the implant is highly likely. We have demonstrated a statistically significant increased risk of PJI in patients with a pre-operative confirmation of a genitourinary infection[10,27], nasal S. Aureus and MRSA infections[31], or other distant organ infections[6], such as hepatitis B[44].

Conditions that further increase this risk are those that may make the patient more susceptible for the introduction of a new pathogen, such as chronic pulmonary disease[4,31] with known high rates of pneumonia, peripheral vascular disease[4,16] with high risk of skin ulceration and introduction of skin contaminates, and recent oesophagogastroduodenoscopy (EGD) with biopsy[22], risking the introduction of gut flora to the blood system.

Furthermore, perioperative blood transfusion increases the risk of PJI in both hip and knee arthroplasty[11,12,15], and allogeneic blood transfusion has been shown to instigate a detrimental immunomodulation reaction, and decreases T-cell-mediated immunity, and may enhance the acute inflammatory response[45,46]. Stored blood can cause a significant increase in inflammatory cytokine release from the stored neutrophils, and superoxide release results in delaying neutrophil apoptosis and risks cytotoxicity[47,48].

This has been confirmed in a recent systematic meta-analysis of 6 studies demonstrating the association between allogeneic blood transfusion and an increased risk for a SSI after total hip and knee arthroplasty. Data was included from over 20000 patients, and the blood transfusion group had a significantly higher frequency of infection (pooled OR = 1.71, 95%CI: 1.23-2.40, P = 0.002) compared to the non-exposed group[49].

The use of antibiotic-impregnated cement was shown by Dale et al[18] to protect against revisions due to infection, whereas Namba et al[20] identified an increased risk. Such conflicting outcomes are common in the literature regarding the use of antibiotic-impregnated cement in primary procedures. A prospective randomized study with 2948 cemented total knee arthroplasties failed to see an improvement of PJI rates by using bone cement loaded with erythromycin and colistin compared to controls[50], whereas the Norwegian Arthroplasty Register has demonstrated a synergistic effect of systemic and cement antibiotics[51]. However there is a general consensus that antibiotic-impregnated cement has a greater role in revision cases[52], and is recommended as standard practice in these high-risk cases[53].

Systemic antibiotics given at anaesthetic induction are generally the standard of care, and continued post-operatively for a further two doses in the United Kingdom, and for two days in Italy (authors experience). The choice of antibiotic varies in each Institute to reflect the prominent pathogen and patient cohort. Multiple studies have demonstrated the benefits of antibiotics given during the procedure to reduce the risk of post-operative infection[51,54].

Concerning the relative impact of the hospitals yearly volume of procedures, we found only one retrospective review of joint registry data, that suggests that the fewer total knee arthroplasties undertaken per year will result in a lower rate of infection[20]. This particular finding needs, in our opinion, further validation, since it contradicts other reports demonstrating better outcomes from greater volumes of surgery and greater experience of the surgeons, as exemplified by the Hospital for Special Surgery, New York[55], while other studies have shown no difference between the two[56].

Furthermore, the use of a drain post-operatively has been shown by Peel et al[15] to reduce the risk of PJI following knee arthroplasty, however multiple meta-analyses and prospective, randomised, controlled trials have demonstrated no significant difference in post-operative infections between the wounds treated with a drain and those without[57,58].

When the risk factors were further categorised into modifiable or not, the vast majority of factors were non-modifiable. Many risk factors increased a patient’s risk by less than 5 times (OR < 5), and very few increased the risk by more than 10 times.

However, the presence of non-modifiable risk factors still requires attention, and may be more important than modifiable ones. Alternate methods should be adopted to reduce the patient’s burden and may include a combination of implant modifications (such as silver or disposable microbiological coatings)[59,60], antibiotic impregnated cement or bone graft[61,62], or other novel therapies[63] to provide a personalized and more effective prophylaxis.

It is the responsibility of the operating team to act upon these, and modify or optimise the patient prior to surgery. For example, intensive insulin therapy, maintaining tight blood glucose concentrations between 80 and 110 mg/dL, has been shown to decrease infection-related complications and mortality[64]. Normal renal function should be sought, nutrition improved, cardiac investigations and interventions should be offered, local and systemic infections appropriately treated, as should chronic anaemia, and patients should be informed to withhold DMARDs and stop tobacco smoking and alcohol use preoperatively.

Indeed, determining individual patients risks is an important step in personalized informed consent. Surgeons may quote published rates or their own, but the risk is individual and should reflect all the aforementioned factors, which may have consequences in the medico-legal evaluation in case of damage evaluation after PJI.

Previous attempts to combine such measures in a scoring system have been attempted by The Mayo Clinic[65] who based the data on their cohort of patients at baseline and at one month. Bozic et al[35] developed a risk calculator using data from 11 years worth of Medicare claims. A similar tool has been developed in the Chinese population[26].

The main disadvantage of such tools is the calculations relate to a specific set of patients, and may not reflect the general public risks, as they have not been externally validated. In addition the data is unlikely to appreciate advances in perioperative care over the time period, and may not capture patients with late onset PJI if follow-up is short.

A wide variety of studies were included in this systematic review, which gives an overview of risk factors for hip and knee PJI but the quality of each study is generally poor. As previously discussed, only 8 studies (29.6%) were prospective, and one third of studies demonstrated record bias. Reporting bias was also seen amongst the studies, as a variety of diagnostic criteria were used. This is common amongst studies reviewing PJI as there is no gold standard measure to determine presence of infection, nor an agreement to the medical, or surgical management, for these patients[53].

Our search criteria only highlighted studies with “risk factor” in the title, and therefore we did not search for studies looking at individual risk factors. Therefore studies, some of high quality, may not have met our inclusion criteria. Furthermore, we were unable to undertake a meta-analysis due to the heterogeneity of the data.

In conclusion, as demonstrated, current data is conflicting as the influence of the risk factors vary widely, and we believe more emphasis is required regarding the multiplicity effects of risk factors. We need larger studies and novel tools to investigate single and combined risk factors, and to identify key areas of improvement and modification for these patients.

The literature has demonstrated significant variation in the number and type of risk factors that places a patient at higher risk of developing a PJI, which is heavily weighted towards the patient. However the provider has a role in addressing the modifiable risk factors pre-operatively to optimise their patient, and develop new strategies to limit the impact of non-modifiable factors.

Several studies have previously shown the impact of various risk factors on the probability of developing an infection after joint replacement. The heterogeneity of the available data notwithstanding, in this systematic review a detailed analysis of the respective weight of known risk factors, classified as host-, provider- or post-surgical-related, is performed; moreover, a further distinction in modifiable or not-modifiable risk factors is proposed.

A classification and ranking of known risk factors may open new frontiers in prevention and control of peri-prosthetic infections. Furthermore, it can be helpful to improve the information to the patient prior to surgery, to drive personalised prophylaxis and to better evaluate the cost-to-benefit ratio of new technologies, like antibacterial coatings, designed to reduce bacterial adhesion on implanted biomaterials.

This systematic review sheds new lights on the relative impact of various risk factors that increase a patient’s risk of developing lower limb periprosthetic joint infections (PJI). This ultimately reiterates the importance of optimising the patients pre-operatively by addressing modifiable risk factors (such as their immunosuppression, nutrition, diabetes, and smoking), and develops strategies to limit the impact of non-modifiable factors.

The data obtained in this systematic review may form the basis for the development of specific software, like the “PJI Risk App”, an application for smartphones, specifically designed to calculate the risk of developing a peri-prosthetic infection in a given patient. This in turn may be useful for surgeons and their patients to understand the specific risk of undergoing joint replacement and eventually to better tailor antibiotic prophylaxis.

In this manuscript authors reviewed provider risk factors of chronic PJI. This study is interesting and the objective very clear.