Predictors of Urinary Infections and Urosepsis After Ureteroscopy for Stone Disease: a Systematic Review from EAU Section of Urolithiasis (EULIS)

To present the latest evidence related to the predictors of urinary tract infections (UTIs) and urosepsis after ureteroscopy (URS) for stone disease. Our review suggests that almost half of all post-URS complications are related to infectious complications although reported rates of urosepsis were low. The use of antibiotic prophylaxis, treatment of pre-operative UTI, and low procedural time seem to reduce this risk. However, the risk is higher in patients with higher Charlson comorbidity index, elderly patients, female gender, long duration of pre-procedural indwelling ureteric stents and patients with a neurogenic bladder and with high BMI. Infectious complications following ureteroscopy can be a source of morbidity and potential mortality. Although majority of these are minor, efforts must be taken to minimise them especially in high-risk patients. This includes the use of prophylactic antibiotics, limiting stent dwell and procedural time, prompt identification and treatment of UTI and urosepsis, and careful planning in patients with large stone burden and multiple comorbidities.


Introduction
The prevalence and incidence of kidney stone disease (KSD) have been increasing globally in the last 50 years [1]. In England, national data from 2006/2007 to 2013/2014 shows that there has been an increase in the lifetime prevalence of urolithiasis-based admissions and intervention from the historically reported 10 to 14% [2]. This is due to a rise in metabolic syndrome, lifestyle changes but also partly due to global warming as higher monthly ambient temperatures are positively associated with incidence of kidney stones [3•]. Treatment options include ureteroscopy (URS), shock wave lithotripsy (SWL) and percutaneous nephrolithotomy (PCNL) [4][5][6].
Published data from the last 15-20 years has shown a steep rise in the use of URS and PCNL, while the use of SWL and open surgery have declined [7•, 8]. Moreover, URS has shown to achieve higher stone-free rates than SWL and lower complication rates compared with PCNL [4,5].
Following URS, the overall rate of complications varies between 9 and 25% although the majority of these are minor and does not require intervention [9][10][11]. Infectious complications ranging from fever, systemic inflammatory response This article is part of the Topical Collection on Endourology syndrome to urinary tract infection (both upper and lower) are some of the more common post-ureteroscopy complications, alongside haematuria and post-operative pain [11], with overall complication rates of up to 25% [12, 13•]. As ureteroscopy is being performed in increasing numbers with the rising prevalence of KSD [2], it is to be expected that the rate of infectious post-URS complications is consequently also increasing [13,14]. Similarly, the indications of ureteroscopy have expanded, and it is now being performed for high-risk patients such as solitary kidneys, paediatrics, pregnancy and upper tract tumours [15][16][17].
In the literature, there are many small, medium and highvolume prospective studies that have reported on the infectious complications following URS for renal stone disease [18][19][20][21][22][23][24][25][26][27][28][29]. Some studies have also looked at the risk factors for urinary infections following ureteroscopy and advised on strategies to reduce these risks. However, there is a lack of data on the predictors of post-ureteroscopy infectious complications. We conducted a systematic review of literature looking at the infection-related post-ureteroscopy complications reported from high-volume centres.
A cutoff of 400 patients was set to include studies from high-volume endourological centres with relevant endourological experience. All original studies were included and where more than one article was available, the study with the longest follow-up was included. The review was carried out by two reviewers (SC and BKS) independently, and all discrepancies were resolved with mutual agreement.

Evidence Acquisition
Inclusion criteria: 1. Studies reporting on infectious complications postureteroscopy 2. Studies from high-volume endourological centres reporting on a minimum of 400 patients 3. Studies in English language Exclusion criteria: 1. Reviews, commentaries or studies with less than 400 patients 2. Paediatric population 3. Ureteroscopy performed for non-stone disease

Data Extraction and Analysis
Data was extracted for journal title, author's details, year of publication, country of origin, patient demographics, stone characteristics, overall and infection-related complications. Where the infectious complications were reported separately, it was recorded as such. The severity of complications was also categorised according to the Clavien-Dindo classification system for grading complications [32]. Studies which described risk factors for post-URS infection, prevention and management strategies for post-URS infections were also recorded. All data was recorded using Microsoft Excel 2019 (version 16.28).

Results
A total of 2070 articles were initially identified, and 14 full-text English language articles were included in the final review which fit our inclusion criteria (Fig. 1) [13,15,[18][19][20][21][22][23][24][25][26][27][28]. The total number of ureteroscopies included in these papers was 24,373, and the mean age was 51.2 years (range 42-61 years), male:female ratio of 3:2 and a mean BMI of 26.9 (range 23.7-31.8) ( Table 1). All patients' demographic and procedure details were explored as possible risk factors for post-ureteroscopy infections ( Table 2). These were gender, stone size or total stone burden, stone location, ureteral access sheath use and mean operative time. Other risk factors included patient comorbidities, history of recurrent UTIs or positive urine culture, immunocompromised patients, longer procedural time, pre-operative stent dwell time, previous indwelling catheter or neurogenic bladder Table 3).
For the papers which mentioned the stone size and location, the mean stone size (stone length) was 10.5 mm (range 8-14.3 mm). The stone location was reported in 9 papers of which 54% (n = 13,148) were ureteric stones, 22% (n = 5373) were renal stones, 8.6% (n = 2115) were in multiple locations and in 15.4%, it was not reported. A ureteral access sheath use was used in 25.8% (n = 6288) patients and ranged across studies from 206 to 2263 cases. The mean operating time was 52.7 min (range 40-62.4 min). The stone-free rate across studies was 83% (range 68-84.4%).
The total number of complications were noted in 7.9% (n = 1919), of which 3.9% (n = 972) were infectious complications and 4% (n = 1147) were non-infectious complications. Of all the infectious complications, fever was reported in 66% (n = 642). Urosepsis was reported in 7 papers, and there were 126 patients with urosepsis which was 0.51% of the whole cohort and 6.5% of the total reported complications.

Discussion
Our systematic review for high-volume centres shows a post-URS urosepsis rates of 0.51%. Antibiotic prophylaxis was practiced in most of the included studies and offers to reduce this risk [12]. It seems that there are several pre-disposing factors which increases this risk and includes positive pre-operative UTI or prior history of UTIs, patients with higher Charlson comorbidity index or elderly patients, female gender, presence and duration of indwelling ureteric stents, procedural time and patients with a neurogenic bladder and with high BMI [18][19][20][21][22][23][24][25][26][27][28]. Infectious complications vary from fever, urinary tract infection, pyelonephritis, systemic inflammatory response syndrome and urosepsis. Antibiotics should therefore be tailored to local resistance profiles which tend to reduce rates of infection and urosepsis [33]. Baboudjian et al. propose that limiting operative times and treating pre-operative UTI should lead towards reduced postoperative infection rates [29]. There is a substantial patient and economic cost associated with sepsis, which is > $24 billion per year in the USA alone [34]. Urosepsis leads to morbidity and mortality and hence, prevention, early detection and management are paramount [14]. It is the leading cause of mortality for patients with KSD and is more common in patients with comorbidities, high stone burden, obesity, with spinal cord injury or neurogenic bladders. The CROES study revealed a mortality rate of 0.04% which confirms that although the mortality rate of URS is negligible, but, it is not zero, and all precautions must be taken for it [13]. Prevention strategies included the use of prophylactic antibiotics, aggressive treatment of preoperative UTIs, reducing operating duration, caution in elderly and patients with high stone burden [14].
Previous work by Traxer et al. showed that the use of ureteral access sheath (UAS) helps to reduce post-URS infectious complication [35]. However, the use of UAS was not helpful in reducing infectious complications in another study looking at treatment of large renal stones [36]. The presence of indwelling stents more than 1 month was associated with a higher risk of sepsis [20•]. Hence, any pre-procedural ureteric stent must be kept as short as possible prior to offering a definitive ureteroscopy.
In patients with urosepsis due to obstructed ureteric stone, an immediate drainage via a nephrostomy or ureteric stent is needed, in addition to antibiotics and supportive care [37]. A delayed ureteroscopy and stone treatment in these cases lead to good clinical outcome [37].
Urosepsis-related mortality was found to be 2.5 times higher in patients with urinary obstruction and is largely due to urolithiasis [38]. Urgent decompression in obstructed calculus-related sepsis is warranted; otherwise, the mortality is doubled, and this drainage should be early (within 48 h) to reduce the hospital stay [39,40]. Although there is no consensus on the time duration between emergency drainage and elective ureteroscopy, it is generally agreed that this should be as soon as the patient has recovered from the initial sepsis and is stable to undergo the ureteroscopy [37].

Conclusion
Infectious complications following ureteroscopy can be a source of morbidity and potential mortality. Although majority of these are minor, efforts must be taken to minimize them especially in high-risk patients. This includes use of prophylactic antibiotics, limiting stent dwell and procedural time, prompt identification and treatment of UTI and urosepsis, and careful planning in patients with large stone burden and multiple comorbidities.

Compliance with Ethical Standards
Conflict of Interest The authors declare no potential conflicts of interest.

Human and Animal Rights and Informed Consent
This article is a systematic review of literature and hence, no direct patient involvement was recorded or analysed.
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