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Long-term incidence of febrile UTI after DxHA treatment of VUR

      Abstract

      Purpose

      To assess the long-term incidence of febrile urinary tract infection (fUTI) in children treated by endoscopic injection of dextranomer/hyaluronic acid (DxHA) for vesicoureteral reflux (VUR).

      Materials and methods

      Prospective study from January 2002 to December 2009 in children treated at our institution for VUR by endoscopic injection of DxHA. All children underwent clinical and renal/bladder ultrasound follow up at 3 months after procedure, then annually. Post-operative voiding cystourethrogram (VCUG) control was performed only for patients with recurrent fUTI.

      Results

      227 children (177 female) were included. Mean patient age at inclusion was 4.7 years. The mean duration of follow-up was 51.6 months. During follow-up, 18.9% had one or several fUTIs, of whom 48.8% had VUR at VCUG. No recurrence of fUTI was observed after 4 years of follow-up. We identified three risk factors for fUTI recurrence: cystitis cystica at the time of injection (p = 0.007), preoperative renal scarring (p = 0.018), and the disappearance of the implant at 3-month follow-up ultrasound (p = 0.037).

      Conclusions

      The long-term incidence of recurrent fUTI after endoscopic treatment of VUR is low. Our data show that the clinical results of endoscopic treatment should be interpreted with a follow up of at least 4 years.

      Keywords

      Introduction

      Since the publication of the International Reflux Study in Children in 1992 [
      • Weiss R.
      • Duckett J.
      • Spitzer A.
      Results of a randomized clinical trial of medical versus surgical management of infants and children with grades III and IV primary vesicoureteral reflux (united states). The international reflux study in children.
      ], it is established that eliminating vesicoureteral reflux (VUR) has little impact on the prognosis of renal function, which is determined by the prior existence of renal dysplasia. However, correcting VUR significantly reduces the incidence of subsequent febrile urinary tract infection (fUTI), which represents considerable morbidity for patients and their families.
      In 2010 and 2012, the American Urology Association and the European Urology Association [
      • Peters C.A.
      • Skoog S.J.
      • Arant B.S.
      • Copp H.L.
      • Elder J.S.
      • Hudson R.G.
      • et al.
      Summary of the AUA guideline on management of primary vesicoureteral reflux in children.
      ,
      • Tekgül S.
      • Riedmiller H.
      • Hoebeke P.
      • Kočvara R.
      • Nijman R.J.
      • Radmayr C.
      • et al.
      EAU guidelines on vesicoureteral reflux in children.
      ] respectively issued guidelines for the management of VUR in children, aimed at reducing the risk of fUTI and renal scarring. The results of VUR treatment are evaluated according to three main criteria:
      • -
        Radiologic result, evaluated by a negative voiding cystourethrogram (VCUG)
      • -
        Renal prognosis, assessed by evolution of renal scars on dimercaptosuccinic acid (DMSA) scan
      • -
        Clinical outcome, evaluated by the cessation of recurrent fUTI (low economic cost and best quality of life for patients and their families).
      Most of the published studies determine the success rate of endoscopic treatment by the disappearance of reflux on VCUG (around 70–80% at initial injection for all grades) [
      • Routh J.C.
      • Inman B.A.
      • Reinberg Y.
      Dextranomer/hyaluronic acid for pediatric vesicoureteral reflux: systematic review.
      ]. However, the clinical outcome has not been extensively assessed in the literature.
      The recurrence rate of fUTI ranges from 12% to 36% after antibiotic prophylaxis [
      • Garin E.H.
      • Olavarria F.
      • Garcia Nieto V.
      • Valenciano B.
      • Campos A.
      • Young L.
      Clinical significance of primary vesicoureteral reflux and urinary antibiotic prophylaxis after acute pyelonephritis: a multicenter, randomized, controlled study.
      ,
      • Roussey-Kesler G.
      • Gadjos V.
      • Idres N.
      • Horen B.
      • Ichay L.
      • Leclair M.D.
      • et al.
      Antibiotic prophylaxis for the prevention of recurrent urinary tract infection in children with low grade vesicoureteral reflux: results from a prospective randomized study.
      ,
      • Pennesi M.
      • Travan L.
      • Peratoner L.
      • Bordugo A.
      • Cattaneo A.
      • Ronfani L.
      • et al.
      Is antibiotic prophylaxis in children with vesicoureteral reflux effective in preventing pyelonephritis and renal scars? A randomized, controlled trial.
      ], from 4.6% to 24% after surgical reimplantation [
      • Whittam B.M.
      • Thomasch J.R.
      • Makari J.H.
      • Tanaka S.T.
      • Thomas J.C.
      • Pope J.C.
      • et al.
      Febrile urinary tract infection after ureteroneocystostomy: a contemporary assessment at a single institution.
      ,
      • Elmore J.M.
      • Kirsch A.J.
      • Heiss E.A.
      • Gilchrist A.
      • Scherz H.C.
      Incidence of urinary tract infections in children after successful ureteral reimplantation versus endoscopic dextranomer/hyaluronic acid implantation.
      ] and from 0.75% to 27% [
      • Elder J.S.
      • Diaz M.
      • Caldamone A.A.
      • Cendron M.
      • Greenfield S.
      • Hurwitz R.
      • et al.
      Endoscopic therapy for vesicoureteral reflux: a meta-analysis. I. Reflux resolution and urinary tract infection.
      ,
      • Sedberry-Ross S.
      • Rice D.C.
      • Pohl H.G.
      • Belman A.B.
      • Majd M.
      • Rushton H.G.
      Febrile urinary tract infections in children with an early negative voiding cystourethrogram after treatment of vesicoureteral reflux with dextranomer/hyaluronic acid.
      ] after endoscopic treatment.
      Over the past 2 decades, endoscopic treatment has become the first-line therapy for VUR. DxHA (Deflux®, Q-Med, Uppsala, Sweden), approved by the FDA in 2001, is now the most widely used bulking agent for this indication.
      The purpose of this prospective study was to evaluate the long-term clinical outcome after endoscopic DxHA injection for VUR in children with a special focus on the recurrence rate of fUTI. The secondary aim was to identify possible risk factors for fUTI recurrence in this population.

      Materials and methods

      Patient population

      This prospective cohort study was performed from January 2002 to December 2009, in a paediatric population recruited in our university hospital. Children were included after one or several episodes of fUTI. In all children, the diagnosis of VUR was confirmed by VCUG, performed after fUTIs. VUR was graded according to the international grading system established by the International Reflux Study in Children [
      • Weiss R.
      • Duckett J.
      • Spitzer A.
      Results of a randomized clinical trial of medical versus surgical management of infants and children with grades III and IV primary vesicoureteral reflux (united states). The international reflux study in children.
      ].
      In addition to VCUG, all children underwent renal ultrasound and DMSA scan before intervention.

      Exclusion criteria

      We excluded patients with VUR associated with posterior urethral valve, neurogenic bladder, pyelo-ureteral duplication, and bladder diverticula. Furthermore we excluded children with a history of ureteral reimplantation, or endoscopic injection.

      Technique

      Endoscopic therapy consisted of a subureteral injection of DxHA according to the classical STING procedure [
      • O'Donnell B.
      • Puri P.
      Treatment of vesicoureteric reflux by endoscopic injection of teflon.
      ]. Intervention was performed under general anaesthesia using a cystoscope (Storz®) with offset lens 9.5 Charriere and/or a direct vision 11 Charriere.
      A dose of antibiotics (amoxicillin/clavulanic acid) was systematically administered at the start of the anaesthesia. After discharge, antimicrobial prophylaxis (trimethoprim–sulfamethoxazole or Cefixime) was prescribed for a limited period of 8 days.

      Follow-up

      All children underwent urinary tract ultrasound 3 months after the procedure.
      We decided not to perform systematic postoperative VCUG, except in children with high-grade VUR.
      If any anomaly was detected on pre-operative DMSA scan, repeat DMSA scan was systematically performed 3 years later. Abnormal DMSA scan was defined as the presence of scarring, single or multiple focal defects, and contribution of one kidney to total renal function <45% on DMSA Scan.
      An annual visit was scheduled at our surgical unit or with the family practitioner.
      The occurrence of each post injection fUTI was checked with the family doctor and/or parents by phone or regular mailing, and defined as fever above 38.5 °C, and blood C-reactive protein (CRP) level of >4 mg/L, and positive dipstick test (nitrite and leukocytes), and monomicrobial positive urine culture results at >100 000 colony-forming units/mL and leukocyturia>10 000/mL. Urine sample was collected with an external collector in children with uncontrolled voiding.
      The exhaustiveness and accuracy of the recorded data was verified by a questionnaire sent to parents at the end of the study (December 2009). In the case of non-response despite reminders, the family physician was contacted by phone to verify the accuracy of recorded data.

      Statistical analysis

      Quantitative data are presented as mean ± standard deviation (SD) and categorical data as number and percentage. Categorical variables were compared using the Chi square test and quantitative variables using the Student t test, as appropriate.
      Children were classified according to presence or absence of at least one episode of fUTI at follow up.
      We evaluated the risk of recurrence of fUTI based on prognostic variables identified by bivariate analysis. Variables with a p value of <0.20 were retained for inclusion in the Cox regression multivariate analysis. We plotted the risk of recurrent fUTI using the Kaplan–Meier method.
      All analyses were performed using SAS version 9.2. (SAS Institute, Cary, NC, USA).

      Results

      Patient population

      From January 2002 to December 2009, 259 patients were treated in our centre for VUR by endoscopic injection of DxHA. Among these, 32 (12.3%) were excluded due to presence of non-inclusion criteria (23 pyelo-ureteral duplication, 7 neurogenic bladder and 2 posterior urethral valves). A total of 227 patients (324 refluxing renal units) were included; 177 (78%) were girls and 50 (22%) were boys. The average age at the time of endoscopic injection was 4.7 years [range 1.4–15.5 years]. The average follow-up was 51.6 months [range 12–96 months]. The baseline characteristics of the study population are presented in Table 1. The VUR was unilateral in 130 (57.3%) and bilateral in 97 (42.7%). The VUR grading chart is shown in Fig. 1.
      Table 1Characteristics of patients with vs. without recurrent febrile urinary tract infection.
      No recurrence n = 184(%)Recurrent fUTI n = 43(%)p
      Age
      Mean age.
      (years)
      4.754.400.53
      Sex
       Female140 (76.6)83.7 (36)0.4
       Male43 (23.4)16.3 (7)
      Reflux grade0.48
       Grade I26 (14.1)8 (18.6)
       Grade 288 (47.8)17 (39.5)
       Grade 359 (32.1)17 (39.5)
       Grade 411 (6)1 (2.4)
      Dysfunctional elimination syndrome0. 36
       Yes55 (29.9)16 (37.2)
       No129 (70.1)27 (62.8)
      Ultrasound findings0.20
       Renal cortical abnormalities11 (6.1)0 (0)
       Dilation17 (9.4)3 (7)
       Normal153 (84.5)40 (93)
      Renal scars on DMSA0.04
       Yes40 (21.7)27 (37.2)
       No144 (78.3)27 (62.8)
      Trabeculated bladder0.48
       Yes65 (35.3)18 (41.9)
       No119 (64.7)25 (58.1)
      Cystitis cystica0.17
       Yes10 (5.4)5 (11.6)
       No174 (94.6)38 (88.4)
      Position of ureteral orifice0.90
       Normal6 (3.8)2 (5.4)
       Laterally displaced106 (67.5)25 (67.6)
       Severely laterally displaced45 (28.7)10 (27)
      Implant visible at 3 months0.02
       Yes59 (41)8 (21.1)
       No85 (59)30 (78.9)
      Mean volume of DxHA injected (mL)0.720.830.14
      a Mean age.
      Figure thumbnail gr1
      Figure 1Distribution of refluxing ureters by grade.
      Pre-operative renal/bladder ultrasound (RBUS) showed dilation of the urinary tract in 8.9%, and renal cortical abnormalities in 4.9%. Pre-operative DMSA scan revealed renal scars in 56 children (24.7%). Seventy-one children (31.3%) presented dysfunctional elimination syndrome (DES) at diagnosis. During the endoscopic procedure, trabeculated bladder was found in 36.6% and bladder wall inflammation or cystitis cystica in 18.9%. The mean (±SD) volume of DxHA injected per ureter was 0.78 (±0.44) mL. The analysis of volume of DxHA injected by grade of VUR showed a mean volume of DxHA injected per ureter of 0.73 (±0.38) mL for grade I, 0.71 (±0.29) mL for grade II, 0.88 (±0.45) mL for grade III and 1.15 (±0.96) mL for grade IV.
      At 3 months' follow up, the clinical status and ultrasonography were uneventful in 209 (92.1%) patients and mild upper tract dilatation was observed in 17 (7.5%). RBUS showed new renal scarring in one patient (0.4%).

      Recurrence of fUTI

      During post-operative follow-up, 43 children (18.9%) presented recurrent fUTI, of whom 21 (48.8%) had several episodes. Among children with recurrent fUTI, VCUG showed VUR in half (21/43).
      The Kaplan–Meier estimates of the risk of recurrence of fUTI over time are shown in Fig. 2.
      Figure thumbnail gr2
      Figure 2Kaplan–Meier curves of time to occurrence of recurrent febrile urinary tract infection (fUTI) (pyelonephritis-free survival).
      50% Of recurrences occurred within the first 24 months after endoscopy treatment. Beyond 4 years of follow up, the risk of recurrence was almost nil.
      The factors significantly associated with recurrent fUTI by Cox multivariate regression analysis (Table 2) were renal scarring on DMSA scan, bladder wall alteration, low volume of DxHA injected, and the disappearance of the implant on 3-month ultrasound. Age, reflux grade and impaired renal function (defined as contribution of one kidney to total renal function <45% on DMSA scan) were not shown to be predictive factors of recurrent fUTI. DES did not significantly increase the risk of recurrent fUTI.
      Table 2Risk factors for recurrent febrile urinary tract infection with odds ratios (OR) and 95% confidence interval (95%CI).
      Unadjusted OR [95% CI]pAdjusted OR [95% CI]p
      Male sex0.69 [0.30; 1.56]0.378
      Age <3 years0.83 [0.46; 1.48]0.543
      High reflux grade1.26 [0.68; 2.31]0.451
      DES1.36 [0.73; 2.52]0.333
      Abnormal ultrasound2.31 [0.71; 7,47]0.162
      Contribution of one kidney to total RF on DMSA scan <45%1.58 [0.86; 2.91]0.137
      Renal scars on DMSA2.03 [1.09; 3.76]0.0262.22 [1.14; 4.32]0.018
      Trabeculated bladder1.34 [0.73; 2.46]0.343
      Cystitis cystica1.83 [0.90; 3.73]0.0922.88 [1.34; 6.20]0.007
      Dx/HA volume injected <0.5 mL2.17 [1.09; 4.32]0.0272.86 [1.32; 6.17]0.007
      Implant vanishing on 3 m RBUS2.05 [0.97; 4.33]0.0602.42 [1.05; 5.57]0.037
      DES = dysfunctional elimination syndrome; RBUS = renal/bladder ultrasound; RF = renal function.
      Recurrent fUTI with radiologic VUR led to a second endoscopic injection of DxHA in 8 patients, and ureteral Cohen's reimplantation in 13.
      In all children with high grade of VUR (>III) (n = 12), postoperative VCUG was normal. Among these, only one child presented 2 recurrent fUTI. VCUG showed recurrent VUR and Cohen's reimplantation was performed.

      Discussion

      We observed a rate of recurrence of fUTI of almost 19%, which is comparable to previous reports [
      • Sedberry-Ross S.
      • Rice D.C.
      • Pohl H.G.
      • Belman A.B.
      • Majd M.
      • Rushton H.G.
      Febrile urinary tract infections in children with an early negative voiding cystourethrogram after treatment of vesicoureteral reflux with dextranomer/hyaluronic acid.
      ,
      • Traxel E.
      • DeFoor W.
      • Reddy P.
      • Sheldon C.
      • Minevich E.
      Risk factors for urinary tract infection after dextranomer/hyaluronic acid endoscopic injection.
      ], but higher than the average recurrence rate after endoscopic DxHA treatment, reported to be around 12% (although ranging from 0.75% to 27%) [
      • Sedberry-Ross S.
      • Rice D.C.
      • Pohl H.G.
      • Belman A.B.
      • Majd M.
      • Rushton H.G.
      Febrile urinary tract infections in children with an early negative voiding cystourethrogram after treatment of vesicoureteral reflux with dextranomer/hyaluronic acid.
      ,
      • Traxel E.
      • DeFoor W.
      • Reddy P.
      • Sheldon C.
      • Minevich E.
      Risk factors for urinary tract infection after dextranomer/hyaluronic acid endoscopic injection.
      ,
      • Puri P.
      • Kutasy B.
      • Colhoun E.
      • Hunziker M.
      Single center experience with endoscopic subureteral dextranomer/hyaluronic acid injection as first line treatment in 1,551 children with intermediate and high grade vesicoureteral reflux.
      ,
      • Brandström P.
      • Esbjörner E.
      • Herthelius M.
      • Swerkersson S.
      • Jodal U.
      • Hansson S.
      The swedish reflux trial in children: III. Urinary tract infection pattern.
      ]. This wide variation in the rate of recurrent fUTI can be explained by the heterogeneity between reports and, often, the lack of distinction between febrile and non-febrile urinary infection. Indeed, most studies were retrospective, except the study by Brandström et al. [
      • Brandström P.
      • Esbjörner E.
      • Herthelius M.
      • Swerkersson S.
      • Jodal U.
      • Hansson S.
      The swedish reflux trial in children: III. Urinary tract infection pattern.
      ], a prospective multicentre study in 203 children, randomised to three different treatment approaches. Among the 66 children in the endoscopic treatment arm, the authors observed a fUTI recurrence rate of 21% [
      • Brandström P.
      • Esbjörner E.
      • Herthelius M.
      • Swerkersson S.
      • Jodal U.
      • Hansson S.
      The swedish reflux trial in children: III. Urinary tract infection pattern.
      ]. Likewise, in a monocentric study of 100 children, Wadie et al. [
      • Wadie G.M.
      • Tirabassi M.V.
      • Courtney R.A.
      • Moriarty K.P.
      The deflux procedure reduces the incidence of urinary tract infections in patients with vesicoureteral reflux.
      ] observed a recurrence rate of 13%. Puri et al. [
      • Puri P.
      • Pirker M.
      • Mohanan N.
      • Dawrant M.
      • Dass L.
      • Colhoun E.
      Subureteral dextranomer/hyaluronic acid injection as first line treatment in the management of high grade vesicoureteral reflux.
      ] reported an exceptionally low rate of recurrent UTI of only 2.6% after successful correction of VUR using DxHA, but without distinguishing between upper and lower urinary tract infection.
      We decided not to perform systematic post injection VCUG, except in cases of recurring fUTI. Indeed, the aim of our study was to evaluate the clinical result of DxHA injection. This approach is debatable but preserves the minimally invasive nature of the endoscopic treatment of VUR. Harper et al. [
      • Harper L.
      • Boutchkova S.
      • Lavrand F.
      • Vergnes P.
      • Semjen F.
      • Dobremez E.
      Postoperative cystography and endoscopic treatment of low-grade vesicoureteral reflux.
      ] also supported this option in a series of 41 patients presenting a low grade of VUR (I–III) treated by endoscopic DxHA injection. In this study, 2 children presented a postoperative recurrence of fUTI with a normal postoperative VCUG. Despite the AUA recommendation advocating postoperative VCUG, we note that post-operative follow up varies greatly between centres in the literature and in clinical practice. This post-operative management depends largely on the surgeon's experience and on the patients' clinical characteristics. In a recent study, Kalisaart [
      • Kalisvaart J.F.
      • Scherz H.C.
      • Cuda S.
      • Kaye J.D.
      • Kirsch A.J.
      Intermediate to long-term follow-up indicates low risk of recurrence after double HIT endoscopic treatment for primary vesico-ureteral reflux.
      ] also questioned the need for VCUG in asymptomatic patients after endoscopic treatment of VCUG. In accordance with Harper, we feel that postoperative VCUG should be reserved for children who present recurrent fUTIs or were treated for high grade of VUR. VCUG is very unpopular among children and their families.
      Thus, for children and parents, the absence of fUTI is the main criterion for successful intervention. As previously pointed out by Capozza [
      • Capozza N.
      • Lais A.
      • Matarazzo E.
      • Nappo S.
      • Patricolo M.
      • Caione P.
      Treatment of vesico-ureteric reflux: a new algorithm based on parental preference.
      ], recurrent fUTI is the primary concern for parents. Indeed recurrent fUTI can cause great anxiety for the family, particularly when the patient is aged less than 3 years. In a recent study, Schwentner et al. [
      • Schwentner C.
      • Oswald J.
      • Lunacek A.
      • Schlenck B.
      • Pelzer A.E.
      • Schwentner I.
      • et al.
      Health-related quality of life in children with vesicoureteral reflux – impact of successful endoscopic therapy.
      ] evaluated health-related quality of life in 100 children cured of VUR by endoscopic therapy using the Glasgow Children's Benefit Inventory questionnaire. With a response rate of 88%, they observed a significant and durable improvement in children's quality of life, with a significant difference (p = 0.001) between the score at one year post treatment (average 23.95) and at four years (average 59.72).
      In our study, we assessed whether the volume of injected DxHA ureter could be a risk factor for recurrent fUTI. Our analysis confirmed this hypothesis by showing that an injected volume <0.5 mL was a risk factor for recurrent fUTI. Indeed, it has been previously reported [
      • McMann L.P.
      • Scherz H.C.
      • Kirsch A.J.
      Long-term preservation of dextranomer/hyaluronic acid copolymer implants after endoscopic treatment of vesicoureteral reflux in children: a sonographic volumetric analysis.
      ] that there is a decrease in the volume of DxHA over time, particularly in the first two weeks after injection. It is possible that the residual volume is therefore insufficient, leading to a loss of efficacy of the initial injection over time. Other risk factors for recurrence appeared to be: renal scarring on initial DMSA scan, bladder wall alteration at endoscopy, low volume of DxHA injected, and the disappearance of the implant at 3 months. However, these factors are controversial. Particularly, while DES did not seem to increase the risk of recurrent fUTI, our systematic management of associated constipation probably explains this by the establishment of a toilet training programme. It is clear that this specific management caused a positive bias in the interpretation of the results of endoscopic treatment.
      The disappearance of the implant on follow-up ultrasound at 3 months as a risk factor for recurrent fUTI can be explained by the absorption of the dextranomer, or the possible migration of the implant. Kirsch and colleagues were alerted by the risk of migration, and this prompted them to develop their modified version of the original endoscopic STING technique, which they named the HIT procedure, particularly for high-grade VUR [
      • Kirsch A.J.
      • Perez-Brayfield M.
      • Smith E.A.
      • Scherz H.C.
      The modified sting procedure to correct vesicoureteral reflux: improved results with submucosal implantation within the intramural ureter.
      ].
      Our study shows that minimally invasive treatment of VUR by endoscopic injection of DxHA requires at least four years of clinical follow-up to be able to draw firm conclusions regarding outcome. These results are comparable with Puri's recent retrospective series of 1551 patients over 9 years in which no fUTI was recorded beyond 3 years [
      • Puri P.
      • Kutasy B.
      • Colhoun E.
      • Hunziker M.
      Single center experience with endoscopic subureteral dextranomer/hyaluronic acid injection as first line treatment in 1,551 children with intermediate and high grade vesicoureteral reflux.
      ].
      In our view and in accordance with Kaye et al. [
      • Kaye J.D.
      • Srinivasan A.K.
      • Delaney C.
      • Cerwinka W.H.
      • Elmore J.M.
      • Scherz H.C.
      • et al.
      Clinical and radiographic results of endoscopic injection for vesicoureteral reflux: defining measures of success.
      ], the success of endoscopic treatment of VUR should be interpreted not only through radiologic resolution, but must importantly on clinical outcomes, especially disappearance of fUTI.
      However, for long-term evaluation, the difficulties in identifying fUTI amongst other febrile affections, especially in children aged less than 3 years, are the principal weakness. Indeed, it has been reported that among children presenting an unexplained fever, only 7% of them have pyelonephritis [
      • Shaikh N.
      • Morone N.E.
      • Bost J.E.
      • Farrell M.H.
      Prevalence of urinary tract infection in childhood: a meta-analysis.
      ].
      The prospective method, long-term outcomes, and contact with parents and physicians to guarantee exhaustiveness are the strong points of our study. The small number of patients, which did not allow subgroup analysis (high or low grade of reflux), and the lack of control group may represent limitations of our study.

      Conclusion

      In this prospective study performed over 8 years, we observed a risk of recurrent fUTI after endoscopic treatment of 19%, of which half occurred in the first 24 months after endoscopic treatment. Our data show that the clinical results of endoscopic treatment should be interpreted with a minimum follow up of 4 years.

      Funding sources

      None.

      Conflict of interest

      None.

      Ethical approval

      Approved by French human protection Committee East Area II.

      Acknowledgements

      The authors thank Marie-Christine Woronoff (PharmD, PhD) for her help in the methodology and for extensive advice; Fiona Ecarnot for translation and editorial assistance; and Marc Puyraveau for statistical analysis.

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