Hemodialysis International 2018; 22:110–118
Original Article Infection
A single center, open-label, randomized, parallel group study assessing the relationship between asymptomatic bacteriuria and inflammation in maintenance hemodialysis patients Ilia BEBERASHVILI,1 Evgeni GOLOVKO,2 Liat GOLINSKY,1 Nedal GARRA,1 Inna SINUANI,3 Leonid FELDMAN,1 Oleg GORELIK,2 Shai EFRATI,1 Kobi STAV4 1
Nephrology Division, 2Internal Department F, 3Department of Pathology, 4Urology Department, Assaf Harofeh Medical Center, Zerifin, Israel
Abstract Introduction: The significance of asymptomatic bacteriuria in maintenance hemodialysis (MHD) patients remains controversial. We hypothesized that the presence of asymptomatic bacteriuria as a sole clinical manifestation of urinary tract infection (UTI) in asymptomatic MHD patient may contribute to the chronic inflammatory response. Our aim was to explore the relationship between asymptomatic bacteriuria and elevated levels of inflammatory markers in MHD patients. Methods: A randomized open-label single center study of 114 MHD patients was conducted. Forty-six patients presented negative urine culture and 41 subjects were excluded due to different reasons. The remaining 27 patients (mean age of 71.5 6 12.2 years, 63% men), fulfilling the criteria for having asymptomatic bacteriuria, were randomly assigned to either the treatment group (13 patients) or the observational group (14 subjects). The treatment group received 7 days of antibiotic treatment given according to bacteriogram sensitivity. After 3 months of follow-up all measurements of the study were repeated. The primary end point was change in inflammatory biomarkers from baseline by the end of the study. Findings: There were no statistically significant differences in white blood cell changes (P 5 0.27), ferritin (P 5 0.09), C-reactive protein (P 5 0.90), and interleukin-6 (P 5 0.14) levels between the groups from baseline to the end of study or at the end of the study. Analyzing cross-sectional data, asymptomatic bacteriuria was found to not be a predictor of higher levels of inflammatory parameters at baseline. Discussion: Asymptomatic bacteriuria is not a modifiable risk factor for chronic inflammation in the MHD population. Key words: Bacteriuria, hemodialysis, inflammation, IL-6, CRP
Correspondence to: I. Beberashvili, MD, Nephrology Division, Assaf Harofeh Medical Center, Zerifin, 70300, Israel. E-mail:
[email protected]; iliabeber@yahoo. com Conflict of Interest: The authors declared no conflict of interest. Disclosure of grants or other funding: None.
INTRODUCTION The majority of maintenance hemodialysis (MHD) patients have elevated serum levels of inflammatory markers that are powerful predictors of clinical outcomes in this population.1,2 The possible causes of a generalized C 2017 International Society for Hemodialysis V
DOI:10.1111/hdi.12547
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increase in the inflammatory response in patients with end stage kidney disease (ESKD) are decreased clearance of proinflammatory cytokines, patient-related mechanisms (underlying disease and comorbidities), as well as factors related to dialysis techniques.3,4 Among these causes, several occult sources such as Chlamydia pneumonia infections,5 clotted old non-functioning arterial-venous grafts,6 and periodontal diseases7 have been reported as contributors to the chronic inflammation in MHD patients. When considering occult infections during the diagnostic workup of inflammation in MHD patients, the urine-deprived bladder is frequently dismissed as a potential site of infection. It was demonstrated that the urinary tract, even in ESKD patients on hemodialysis8,9 and peritoneal dialysis (PD) patients,10 may represent a significant reservoir for infection. Contributing factors to asymptomatic urinary tract infection (UTI) in MHD patients include the presence of low urine volume, bladder stasis, and the fact that UTI symptoms are mostly related to voiding, which is reduced or absent in MHD population.11 Presumably, persistence of UTI in asymptomatic MHD patients, with positive urine cultures as the only expression of the infection, may be related to higher levels of inflammatory markers. In this context, serum IL-6 and CRP were correlated with measurements of clinical activity of symptomatic UTI in the general population.12 However, there is no information in the literature about the relationship between asymptomatic bacteriuria and chronic inflammation in MHD patients. We hypothesized that the presence of asymptomatic bacteriuria as a sole clinical manifestation of UTI in asymptomatic MHD patient may contribute to the chronic inflammatory response. The aim of this study was therefore to explore the relationship between asymptomatic bacteriuria and elevated levels of inflammatory markers in patients with ESKD on MHD therapy. Such a finding would provide a potential link between a treatable infection and a powerful risk factor in the MHD population.
METHODS Patients The study was approved by the Ethics Committee of Assaf Harofeh Medical Center (Zerifin, affiliated with the Sackler Faculty of Medicine, Tel Aviv University, Israel). Inclusion criteria were outpatients who underwent MHD for at least 3 months, were 18 years or older and signed a local institutional review board-approved consent form. Patients with an indwelling urinary catheter, with an Hemodialysis International 2018; 22:110–118
active malignant disease, with any diagnosed infectious disease including symptomatic UTI, diabetic foot, and severe periodontal diseases and patients with severe heart failure (NYHA class III-IV) were excluded. The patients were recruited from December 2011 through July 2015. All patients underwent regular dialysis via their vascular access, 4 to 5 hours 3 times per week at a blood flow rate of 250 to 300 mL/minute and at a dialysis solution flow rate of 500 mL/minute. Dialysis treatments were performed with a low flux biocompatible dialyzer membrane with a surface area of 1.4 to 1.8 m2.
Study design This study was a randomized open-label parallel group single center study (Clinical Trials ID No. NCT01570556). After meeting all inclusion criteria, the study participants underwent examinations including a physical examination, laboratory tests (predialysis), and bioimpedance analysis (BIA) postdialysis in all scheduled study visits. Before the hemodialysis session, random mid-stream urine specimens were collected from study patients in a sterile container and sent to the laboratory immediately. A typical medical urinalysis employing a urine dip stick, microscopic examination, and bacteriological culture were included according to standard methods. Laboratory criteria for the diagnosis of asymptomatic bacteriuria were as follows: 2 consecutive voided urine specimens with isolation of the same bacterial strain in quantitative counts 105 cfu/mL in women and a single urine specimen with 1 bacterial species isolated in a quantitative count 105cfu/mL in men.13 Pyuria was defined as the presence of 10 or more white cells per cubic millimeter in a urine specimen.14 A urine culture that was reported as no growth in 48 hours was considered negative without the need to repeat the urine culture according to the study protocol. Urine output was expressed as mL/24 hours. Residual renal function (RRF) was defined as measured urine volume >200 mL/day. A flow chart of the study is presented in Figure 1. In total, 114 MHD patients were enrolled in the study. Forty-one subjects were excluded: 5 due to exclusion criteria (2 patients had an active malignancy, 2 patients had symptoms of active infection at the time of sampling, and 1 patient was with an indwelling urinary catheter); 1 because of transfer to PD immediately after sampling; 1 patient withdrew consent; 16 subjects had mixed urine culture, or different bacterial species in the first and second culture. Eighteen participants were not able to provide midstream samples for analysis. Of the remaining 73 participants, 46 presented negative urine culture and 111
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Figure 1 Flow diagram of the study.
27 patients fulfilled the criteria for having asymptomatic bacteriuria. Thus, the prevalence of asymptomatic bacteriuria in this study was 37.0% among the 73 MHD patients with midstream samples (43.5% in women and 34.0% in men). Escherichia coli was the most prevalent bacterial species in the urine cultures in women (8/10, 80.0%), whereas Enterococcus faecalis was the most prevalent bacterial species in the urine cultures in men (12/17, 70.6%). Patients with asymptomatic bacteriuria were randomized to 2 study groups: the treatment group, with 7 days of antibiotic treatment given according to the bacteriogram sensitivity (13 MHD patients), and the observational group (14 subjects) who were only observed without antibiotic treatment. Treatment was followed by a 3 month followup period, during which none of the patients received any specific treatment. At the end of the follow-up, we repeated all the measurements of the study. The primary end point was change in inflammatory biomarkers (CRP, IL-6) from baseline by the end of the study.
Laboratory evaluation Predialysis blood samples and postdialysis serum urea nitrogen were obtained from non-fasting patients on a 112
mid-week day. All biochemical analyses were measured by an automatic analyzer. Serum high sensitivity Creactive protein (CRP) was measured by a turbidimetric immunoassay. IL-6 levels were measured in plasma samples using commercially available enzyme-linked immunosorbent assay (ELISA) kits (R&D System, Minneapolis, MN) according to the manufacturer’s protocol. After sampling, urine was immediately analyzed with a dip stick, microscopic examination, and bacteriological analysis were performed according to standard methods.
Body composition analysis Body composition was determined by body impedance analysis (B.I.A. Nutriguard-M, Data-Input, Frankfurt, Germany). Following the recommendations for clinical application of bioelectrical impedance analysis,15 we performed BIA at approximately 30 minutes postdialysis. The multi-frequency technique (using 3 frequencies: 5, 50, and 100 kHz) were used to estimate the total body water (TBW) and extracellular water (ECW). These estimates were obtained using the NutriPlus software, version 5.1 (Data Input GmbH, Germany). Hemodialysis International 2018; 22:110–118
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Table 1 Baseline demographic and clinical characteristics of the randomized MHD patients (n 5 27) Characteristics
All (n 5 27)
Demographic and clinical characteristics Age (y) 71.5 6 12.2 Gender (male %) 63.0 HD Vintage (mo) 36.0 (16.5–45.0) DM (yes %) 66.7 Co-morbidity index 9.0 (6.5–11.0) Access (A-V Fistula %) 59.3 Urine volume/24 h (mL) 350 (200–500) RRF (yes %) 77.8 SBP (mmHg) 145.4 6 22.7 DBP (mmHg) 66.3 6 15.0 Periodontal disease index 1.20 (0.5–2.5) Kt/V 1.38 6 0.30 Hb (g/dL) 10.9 6 1.4 Biochemical characteristics Albumin (g/dL) 3.70 6 0.35 Creatinine (mg/dL) 6.97 6 2.10 Bicarbonate (mmol/L) 23.8 6 2.2 Body composition and volume status 28.7 6 3.8 BMI (kg/m2) Phase angle (8) 4.42 6 1.0 ECW/TBW 0.39 6 0.06 Pyuria Urine WBC (WBCs/hdf) 25.0 (7.5–200.0) Inflammatory markers 6.8 (5.6–8.4) WBC (3109/L) Ferritin (ng/mL) 674.3 (339.4–937.9) CRP (mg/L) 12.4 (3.0–22.2) IL-6 (pg/mL) 11.8 (5.1–17.5)
Treatment group (n 5 13)
Observation group (n 5 14)
P value
71.6 6 11.7 61.5 34.5 (17.0–47.3) 76.9 8.0 (7.0–12.0) 53.8 350 (175–500) 76.9 150.5 6 15.7 65.9 6 16.0 1.0 (0.0–2.0) 1.37 6 0.15 11.0 6 1.3
71.3 6 13.1 64.3 37.0 (14.0–44.0) 57.1 9.0 (5.3–10.8) 64.3 425 (187.5–800) 78.6 140.9 6 27.2 66.6 6 14.7 1.20 (0.5–2.0) 1.38 6 0.43 10.5 6 1.6
0.96 1.0 0.65 0.42 0.92 0.59 0.28 0.92 0.29 0.91 0.58 0.97 0.41
3.64 6 0.39 7.04 6 2.12 23.1 6 2.2
3.76 6 0.32 6.90 6 2.16 24.1 6 2.1
0.40 0.87 0.25
28.8 6 4.4 4.31 6 1.1 0.39 6 0.03
28.9 6 3.2 4.52 6 1.0 0.39 6 0.05
0.97 0.65 0.57
25.0 (6.5–100.0)
262.5 (25.0–500.0)
0.40
6.0 (4.6–8.5) 621.8 (378.4–882.6) 18.1 (4.3–24.8) 12.1 (5.3–25.7)
7.5 (6.0–8.4) 770.8 (280.5–974.2) 5.6 (2.1–19.7) 9.0 (5.1–13.1)
0.24 0.88 0.17 0.35
Continuous variables are expressed as mean 6 SD or median with an interquartile range (Q1–Q3) for non-normally distributed data, and categorical variables are expressed as a percentage. HD 5 hemodialysis; DM 5 diabetes mellitus; A-V 5 arterial-venous; RRF 5 residual renal function; SBP 5 systolic blood pressure; DBP 5 diastolic blood pressure; Hb 5 hemoglobin; BMI 5 body mass index; ECW/TBW 5 extra-cellular water to total body water ratio; WBC 5 white blood cells; CRP 5 C-reactive protein; IL-6 5 interleukin-6.
Co-morbidity index and periodontal disease index We determined the co-morbidity index, recently developed by Liu et al.16 and validated specifically for dialysis patient populations, as a measure of co-morbid conditions. Periodontal disease index was applied to indicate oral health status in each patient according to a previously described method.7
Statistical analysis The power calculation was restricted to IL-6 changes from baseline because of recruitment difficulties. A Hemodialysis International 2018; 22:110–118
sample size of 13 patients in each arm of the study enabled us to have a statistical power of 90% with a twosided a-error rate of 5% for detecting a difference in IL-6 of 4.0 pg/mL between the study groups. Data are expressed as mean 6 standard deviation (SD), or as median with interquartile range (IQR) for variables that do not follow a normal distribution, or as frequencies for categorical data. Baseline parameters were compared between the study groups by using chi-square tests for categorical variables, a two-sided t test and the non-parametric Mann-Whitney U test on the basis of whether the data were normally distributed. Changes in inflammatory parameters from baseline to the end of the study (expressed as both an 113
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Table 2 Mean difference in changes of inflammatory markers between the study groups
Changes in markers Absolute difference D WBC (3109/L) D Ferritin (ng/mL) D CRP (mg/L) D IL-6 (pg/mL) Transformed difference D WBC (3109/L) D Ferritin (ng/mL) D CRP (mg/L D IL-6 (pg/mL)
Treatment group (n 5 13)
Observation group (n 5 14)
Mean difference between groups (95% CI)
P value
0.05 (20.85 to 1.00) 246.4 (2332.0 to 80.9) 1.43 (21.58 to 6.47) 2.25 (28.85 to 16.6)
20.80 (22.10 to 0.33) 473.6 (18.8 to 972.7) 20.82 (21.02 to 18.1) 22.87 (210.2 to 20.99)
0.43 (21.16 to 2.01) 209.0 (294.6 to 570.2) 221.2 (265.9 to 23.6) 10.1 (24.48 to 24.7)
0.27 0.09 0.90 0.14
20.01 (20.19 to 0.19) 20.89 (26.27 to 1.63) 0.26 (20.75 to 0.41) 20.22 (22.28 to 1.31)
0.13 (20.06 to 0.40) 4.13 (21.24 to 1.00) 0.14 (21.61 to 0.29) 0.46 (0.31 to 1.51)
20.08 (20.39 to 0.23) 6.35 (20.96 to 13.96) 1.36 (22.02 to 4.75) 21.28 (23.22 to 0/66)
0.41 0.07 0.90 0.15
Variables in the study groups are expressed as medians with an interquartile (Q1–Q3) range and compared by a Mann-Whitney U test. CI 5 confidence interval; WBC 5 white blood cells; CRP 5 C-reactive protein; IL-6 5 interleukin-6.
absolute difference and square root transformed difference) were compared by using the non-parametric Mann-Whitney U test for independent groups or by the Wilcoxon rank sum test for matched groups. All statistical analyses were performed using SPSS software, version 16.0 (SPSS Inc., Chicago, IL).
RESULTS Participant characteristics Of the 73 participants who provide valid midstream samples for analysis, 46 presented negative urine culture. The 27 MHD patients with asymptomatic bacteriuria (mean age of 71.5 6 12.2 years) randomized for this study included 63% men. Two-thirds of the participants (66.7%) had diabetes mellitus (DM) and a median dialysis vintage of 36.0 months. Six of the 13 randomized patients in the treatment group were treated by ciprofloxacin, 5 by cefuroxim and 2 by ampicillin/sulbactam. No treatmentrelated adverse events were reported by the study participants. Baseline demographics and clinical characteristics of the randomized patients are shown in Table 1 and were balanced overall across the study groups. Baseline characteristics of all 73 patients with valid midstream samples stratified by the presence of asymptomatic bacteriuria are shown in Table S1. Of note, no differences in demographic and clinical characteristics were observed across these groups with an exception in dialysis vintage which was higher in urine culturenegative patients. 114
Inflammatory markers changes in the study groups Changes in inflammatory parameters during the study are shown in Table 2. There were no statistically significant differences in changes of WBC, ferritin, CRP, and IL-6 levels between the groups from baseline to the end of the study. Inflammatory marker trajectories within the study groups are shown in Figure 2. Overall, levels of these parameters did not change from baseline in both groups. No significant differences were observed between the groups in WBC, ferritin, CRP, or IL-6 levels at the end of the study as well (Figure 3).
Cross-sectional observations Although the presented study is a randomized controlled trial, we additionally analyzed the data to find the possible association between asymptomatic bacteriuria and inflammation in our population. Table 3 shows the univariate and multivariate associations between asymptomatic bacteriuria and mediators of inflammation at baseline. Asymptomatic bacteriuria did not predict higher levels of CRP and IL-6 according to this analysis. Levels of WBC, ferritin, CRP, and IL-6 did not change significantly during the study, neither in the group with sterile urine nor in the group with asymptomatic bacteriuria (Figure S1). Of the 13 MHD patients in the treatment group, 10 patients presented negative urine culture on repeated sampling (after treatment). However, inflammatory marker levels Hemodialysis International 2018; 22:110–118
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Figure 2 Observed median (with 95% CI) levels of inflammatory markers over the study period in the treatment and control (observation only) groups. No differences between these parameters were observed from baseline to the end of the study in both treatment and control groups. (a) WBC (3109/L): Treatment group—6.0 (4.6–8.5) vs. 6.7 (5.1–9.1), P 5 0.94; Control group—7.5 (6.0–8.4) vs. 8.2 (6.7–9.3), P 5 0.26. (b) Ferritin (ng/mL): Treatment group—674.0 (430.6–830.6) vs. 474.0 (350.6–571.3), P 5 0.09; Control group—674.0 (313.4–962.5) vs. 790.0 (224.0–1328), P 5 0.31. (c) CRP (mg/L): Treatment group—18.1 (4.3–24.8) vs. 7.6 (2.0–16.0), P 5 0.61; Control group—6.4 (2.1–14.1) vs. 7.6 (3.0–15.9), P 5 0.87. (d) IL-6 (pg/mL): Treatment group—12.1 (5.3–25.7) vs. 9.5 (3.2–25.3), P 5 0.68; Control group—9.0 (5.1–13.1) vs. 12.2 (6.8– 23.3), P 5 0.10. The inflammatory parameters levels are given here as medians with an interquartile (Q1–Q3) range and compared by a Wilcoxon rank sum test.
did not change significantly in these patients from baseline to the end of the study (Figure S2).
DISCUSSION We studied whether asymptomatic bacteriuria is a modifiable risk factor for chronic inflammation in the MHD population and should therefore be screened for and treated. The rate of positive urine culture in ESKD patients receiving MHD treatment reported in the literature is about 25% to 58%9,17,18 and our study falls within these results. The distribution of IL-6 levels at baseline in our population is also similar to previously reported levels in MHD patients.1,2 Finding a difference of 4 pg/mL in IL-6 levels between the study groups would give us the Hemodialysis International 2018; 22:110–118
opportunity to distinguish differences in the one point of the inflammation score that was previously composed as a measure of the overall inflammation burden in MHD patients.19 Contrary to our hypothesis, no impact of asymptomatic bacteriuria was confirmed on the inflammatory parameters levels in our population. Failure to find a link between asymptomatic bacteriuria and chronic inflammation in our patients can be mostly explained by the following 2 ways: First, infections of the lower urinary tract are not characterized by extremely high levels of inflammatory mediators which makes it very difficult to discern significant differences in their levels before and after intervention. In support of this, significantly higher serum and urine IL-6 and IL-8 levels were found in children with acute 115
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Figure 3 Box and whisker plots of inflammatory parameters at the end of the study in the study groups. The treatment and observation groups were similar according to inflammatory markers levels. (a) WBC (3109/L): 6.7 (5.1–9.1) vs. 8.2 (6.7– 9.3), P 5 0.24. (b) Ferritin (ng/mL): 474.0 (350.6–571.3) vs. 790.0 (224.0–1328), P 5 0.55. (c) CRP (mg/L): 7.6 (2.0–16.0) vs. 7.6 (3.0–15.9), P 5 1.0. (d) IL-6 (pg/mL): 9.5 (3.2–25.3) vs. 12.2 (6.8–23.3), P 5 0.60.
pyelonephritis than in those with lower UTI.20,21 However, the literature is mixed on this issue, even in studies with similar populations and design.22 Overall, a majority of clinical studies on serum or urinary IL-6 as a biomarker
for UTI has been performed in pediatric populations. Another population studied in this respect is the elderly. IL-6 median-urine levels were reported in this population as significantly elevated in the acute pyelonephritis group,
Table 3 Association between asymptomatic bacteriuria and inflammatory mediators (CRP, IL-6) at baseline in the study population (n 5 73) according to univariate and multivariate logistic regression models Descriptive 1. 2. 3. 4.
Bacteriuria(yes) 11Age and Gender 21Vintage1DM 31BMI1urine vol.
CRP (mg/L) OR (95% CI) 0.51 0.58 0.44 0.36
(0.19–1.38) (0.21–1.63) (0.14–1.38) (0.11–1.17)
P value 0.18 0.30 0.16 0.09
IL-6 (pg/mL) OR (95% CI) 0.63 0.64 0.64 0.73
(0.21–1.88) (0.21–2.00) (0.18–2.34) (0.19–2.75)
P value 0.41 0.44 0.50 0.64
CRP and IL-6 levels were dichotomized (according to their median levels) and modeled as dependent variables, whereas asymptomatic bacteriuria was an independent variable. All covariates included in the regression models are continuous except for categorical variables. OR 5 odds ratio; CI 5 confidence interval; CRP 5 C-reactive protein; IL-6 5 interleukin-6; DM 5 diabetes mellitus; BMI 5 body mass index.
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compared to those with asymptomatic bacteriuria and negative controls.23 Of interest, median-urine IL-6 levels were the same in both asymptomatic bacteriuria and negative control groups in the aforementioned study.23 Second, despite our assumption regarding asymptomatic bacteriuria as a sole indicator of latent infection, it does not reflect a real infection of the urinary tract and therefore cannot cause an inflammatory response. It should be noted that the causal link between asymptomatic and symptomatic episodes of UTI in MHD population is unknown. Asymptomatic bacteriuria may therefore only be a risk marker for symptomatic UTIs, regardless of the prior asymptomatic infection having been treated or not, as reported in patients after kidney transplantation.24 Levels of IL-6 and IL-8 in serum were reported as higher in children with UTI with fever compared to those with asymptomatic bacteriuria.25 Along the same line, urinary IL-6 is a useful biomarker to discriminate between acute cystitis and asymptomatic bacteriuria in elderly subjects.26 Overall, no benefits besides bacteriological cure were reported in the literature between antibiotics vs. no treatment of asymptomatic bacteriuria in women below 60 years old, patients with diabetes, the elderly,27 as well as in kidney transplant recipients.28 Developing resistance to antibiotic treatment by comparing resistance of grown bacteria in the urine before and after therapy by antibiotics is also an important issue. According to current consensus guidelines, asymptomatic bacteriuria should not be treated with antibiotics with the exception of pregnant women and patients undergoing urologic procedures.13 In spite of a large number of studies with varied protocols and target populations, no information regarding asymptomatic bacteriuria in MHD patients was provided in the literature. In this regard, our study is the first to our knowledge, to address the specific question of relationship between the presence of asymptomatic bacteriuria and chronic inflammation in adult ESKD patients on MHD treatment. This study has some limitations. First, the conclusions of this study are based on a small sample from a single center that does not allow for an evaluation of more subtle differences in serum IL-6 levels between the study groups. Second, we did not measure RRF that may have an impact on inflammatory markers levels in our study. Another limitation is the short duration of the study that precludes assessing the effect of asymptomatic bacteriuria on inflammatory mediator levels over a longer period. A cutoff point above which bacteriuria was diagnosed as positive (quantitative counts 105cfu/mL) may have also limited the results of the study. In general, evaluating patients Hemodialysis International 2018; 22:110–118
with quantitative counts of bacteriuria below 105 cfu/mL is a common clinical dilemma. In conclusion, our data show that asymptomatic bacteriuria has no clinical impact on chronic inflammation in MHD patients. It should not be tested as a routine component of chronic inflammation work up and should not be treated for the purpose of relieving inflammation in the MHD population. A larger size and longer duration study is warranted to investigate whether our findings translate into bacteriuria-related complications and mortality risk profile in this patient population.
ACKNOWLEDGMENT The authors would like to thank Dr. Mechael Kanovsky for his language editing which has greatly improved the manuscript. Manuscript received November 2016; revised January 2017.
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SUPPORTING INFORMATION Additional Supporting Information may be found online in the supporting information tab for this article. Table S1 Baseline characteristics of study participants (n573) stratified by presence of asymptomatic bacteriuria Figure S1 Observed median (with 95% CI) levels of inflammatory markers over the study period in the study participants with negative urine culture (n546) compared to patients with asymptomatic bacteriuria (n527). No differences between these parameters were observed from baseline to the end of the study in both groups. a. WBC (x109/L): Bacteriuria - 6.9 (5.2 to 8.4) vs 7.5 (6.0 to 9.3), P50.14. Sterile urine - 6.7 (5.5 to 8.0) vs 5.9 (5.1 to 8.8), P50.68. b. Ferritin (ng/ml): Bacteriutia - 674,3 (339.4 to 937.9) vs 602.7 (415.4 to 1203.8), P50.31. Sterile urine 466.4 (302.9 to 882.0) vs 379.0 (196.0 to 704,3), P50.37. c. CRP (mg/L): Bacteriuria - 14.1 (3.2 to 21.7) vs 10.5 (3.4 to 17.4), P50.20. Sterile urine - 6.2 (2.7 to 12.3) vs 5.1 (3.1 to 14.2), P50.81. d. IL-6 (pg/ml): Bacteriuria 12.0 (4.5 to 21.1) vs 11.9 (6.7 to 23.6), P50.10. Sterile urine – 8.8 (6.2 to 15.8) vs 8.9 (5.3 to 14.9), P50.36. The inflammatory parameters levels are given here as medians with interquartile (Q1 to Q3) range and compared by the Wilcoxon rank sum test. Figure S2 Box and whisker plots of inflammatory markers levels at baseline (before antibacterial treatment) and at the end of the study in the participants who achieved eradication of bacteriuria (n510). No significant differences were noted between these markers before and after treatment. a. WBC (x109/L) - 5.5 (4.7 to 6.9) vs 5.6 (5.1 to 7.1), P50.72. b. Ferritin (ng/ml) - 667.1 (430.1 to 1391.5) vs 551.8 (379.1-619.7), P50.29. c. CRP (mg/L) - 19.8 (10.6 to 32.7) vs 19.0 (7.6 to 37.7), P50.72. d. IL-6 (pg/ml) 11.0 (7.0 to 13.9) vs 12.2 (9.5 to 18.1), P50.11. The inflammatory parameters levels are given here as medians with interquartile (Q1 to Q3) range and compared by the Wilcoxon rank sum test.
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