Risk factors associated with recurrent febrile urinary tract infection in children with neurogenic bladder who perform clean intermittent catheterization
Guanglun Zhou and Man Jiang contributed equally to this study.
Abstract
Objective
To identify the clinical and urodynamic risk factors associated with the development of recurrent febrile urinary tract infections (FUTIs) in children with neurogenic bladder (NB) who perform clean intermittent catheterization (CIC).
Methods
Children with NB receiving CIC were prospectively enrolled from January to December 2019 and followed up prospectively for 2 years. All data were compared between occasional (0–1 FUTI) and recurrent FUTIs (≥2 FUTI) groups. In addition, the risk factors for recurrent FUTIs in children were evaluated.
Results
Complete data from 321 children were analyzed. Occasional FUTIs occurred in 223 patients, and 98 patients experienced recurrent FUTIs. Univariate and multivariate analyses, showed late-initiation and low-frequency CIC, vesicoureteral reflux (VUR), small bladder capacity and low compliance, and detrusor overactivity were associated with an increased risk of recurrent FUTIs. Children with high-grade VUR (grades IV‒V) had a higher risk of recurrent FUTIs than those with low-grade VUR (grades I‒III) (odds ratio [OR]: 26.95 vs. OR: 4.78, p < 0.001).
Conclusions
Our study suggests that late-initiation and low-frequency CIC, VUR, small bladder capacity and low compliance, and detrusor overactivity were associated with recurrent FUTIs in patients with NB. In addition, high-grade VUR is a crucial risk factor for recurrent FUTIs.
1 INTRODUCTION
Neurogenic bladder (NB) can develop due to lesions at any nervous system level.1 It may lead to urinary tract infections (UTIs), vesicoureteral reflux (VUR), kidney scarring, and kidney failure.2 Nonsurgical treatment is the first choice in the first year of life.3 Patients who do not receive proper management typically develop severe complications in the upper urinary tract.3
Clean intermittent catheterization (CIC) is recommended for patients with NB to prevent deterioration of kidney function.4 CIC increases the possibility of bacteriuria in these patients by introducing microorganisms into the bladder during long-term catheterization.5 Some children are prone to recurrent febrile urinary tract infections (FUTI), while others have little or no FUTI in clinical practice. FUTI is a well-recognized predisposing risk factor for kidney damage and kidney scarring, especially recurrent FUTIs.6 Shaikh et al. reported that each new FUTI increases the risk of kidney scarring in children without NB, the incidence of 2.8% and 25.7% after the first and second infections, respectively, and up to 28.6% after three or more FUTIs.6 Therefore, the risk of recurrent FUTIs must be minimized.
There are few studies on recurrent FUTIs in children with NB. Accordingly, we aimed to identify potential risk factors associated with the development of recurrent FUTIs in children with NB during CIC.
2 MATERIALS AND METHODS
2.1 Study design
This single-center study collected information of children diagnosed with NB from January to December 2019 at our institution. The inclusion criteria for this study were the following: (1) children with a clear history of congenital neurological diseases and diagnosed with NB, (2) patients undergoing CIC, and (3) patients with complete data required to assess potential risk factors. The participants were followed up prospectively for approximately 2 years. Informed consent was obtained from the guardians or parents of all patients before examination/treatment. This prospective observational study was approved by the Institutional Review Board of our hospital (no. 2018031).
Episodes of FUTI were recorded during the 2 years follow-up period. A FUTI was defined as a recorded temperature ≥38°C within 24 h of UTI diagnosis, pyuria on urinalysis, and ≥50 000 colony-forming unit/mL of a single organism on culture by catheterization.6 The cure criteria for FUTI are as follows: (1) disappearance of clinical symptoms and signs, (2) absence of pyuria during urine analysis, and (3) negative urine culture. The number of FUTI episodes was calculated during this study period for each participant. Based on the frequency of FUTI, children were classified into the occasional FUTI (<2 FUTI) and recurrent FUTIs (≥2 FUTI) groups. Patients with missing data, less than two clinic visits, and those who underwent urological procedures during the follow-up were excluded from this study.
Clinical and urodynamic parameters, including age, sex, antibiotic prophylaxis, anticholinergic therapy, constipation, initial age at CIC, CIC frequency (times/day), VUR, hydronephrosis based on the SFU grading scale, urinary incontinence, bladder compliance, bladder wall thickness, pressure detrusor (end-fill Pdet), bladder trabeculation, bladder capacity (BC), detrusor leak-point pressure (DLPP), and detrusor overactivity (DO) were analyzed as potential risk factors at baseline for developing recurrent FUTIs. The treatment regimen was formulated based on the urodynamic results of each NB patients. Patients with VUR and recurrent UTIs were treated with prophylactic antibiotics. For patients who received an invasive procedure, a conventional treatment dose of antibiotics was administered for approximately 2 days to prevent UTI. Patients who experienced one FUTI do not take antibiotics after they are cured. For patients with >2 UTIs, especially those with combined VUR, prophylactic antibiotics should be administered.
The grading of VUR was based on voiding cystourethrography, performed according to international standards, and, in bilateral cases, the patients were categorized by the side with the highest reflux. The VUR grades included grades I‒V; patients with grades IV–V were defined as high-grade reflux, and grades I‒III as low-grade reflux. The bladder wall thickness was defined as the average bladder wall thickness of the anterior and posterior walls when the bladder was full by ultrasonography. The urodynamic examination was conducted according to the method recommended by the International Continence Society Association.7 Expected BC was calculated using the equation (age + 1) × 30 = milliliters. High BC was defined as ≥150% of the expected BC, and low BC was defined as <65% of the expected BC. DO and bladder compliance were defined as “yes” or “no,” and “normal (≥10.0)” or “low (<10.0),” respectively. DLPP was defined as ≤40 cmH2O, >40 cmH2O, or no leak. Pdet was defined as the maximum detrusor pressure at the end of the filling period, and its values were divided into low-Pdet (<10.0 cmH2O) and high-Pdet (≥10.0 cmH2O) groups.
2.2 Statistics
Continuous data were analyzed using the Student's t test and categorical variables were analyzed using Pearson's χ2. A univariate analysis was performed on all variables to determine their relationships with recurrent FUTIs. Variables with p < 0.05 in the univariate analysis were included in the subsequent multivariate analysis. A multivariate logistic regression analysis was performed to determine the association between various potential risk factors and the development of recurrent FUTIs. Statistical analyses were performed using the SPSS version 21.0.
3 RESULTS
3.1 Cohort description
In total, 386 children met the inclusion criteria. Among these, 14 did not participate in the study owing to objections from their guardians, and four others did not participate because they changed their places of residence. A total of 368 patients were enrolled in this study, among whom 47 were excluded due to surgery, missing data, or loss of follow-up. Therefore, 321 patients (129 with and 192 without VUR) were included in the final analysis. Occasional FUTI occurred in 223 (69.5%) patients, and 98 (30.5%) experienced recurrent FUTIs. In the occasional FUTI group, two cases of UTI occurred after undergoing invasive procedures (urodynamic study and voiding cystourethrography), whereas one case of UTI occurred after undergoing an invasive procedure (voiding cystourethrography) in the recurrent FUTIs group. In the occasional FUTI group, 34 children had no FUTI, and 189 had one. In the recurrent FUTIs group, 62 children had two FUTIs, 29 had three, and 7 had four. In the occasional FUTI group, two children had VUR grade I, 22 had grade II, 29 had grade III, 3 had grade IV, and 2 had grade V. In the recurrent FUTIs group, 3 children had VUR grade I, 16 had grade II, 19 had grade III, 23 had grade IV, and 10 had grade V. The basic data of the patients are listed in Table 1.
| Variable | Occasional FUTI group | Recurrent FUTIs group | p Value |
|---|---|---|---|
| No. patients | 223 | 98 | |
| Neurological diseases | 0.791a | ||
| Myelomeningocele (spina bifida aperta) | 136 (61.0%) | 61 (62.2%) | |
| Spina bifida (spina bifida occulta) | 86 (38.6%) | 37 (37.8%) | |
| Meningocele | 1 (0.4) | 0 (0%) | |
| Age (months) | 44.2 ± 21.3 | 45.3 ± 26.8 | 0.648b |
| Sex | 0.865a | ||
| Boys | 132 (59.2%) | 59 (60.2%) | |
| Girls | 91 (40.8%) | 39 (39.8%) | |
| Anticholinergic therapy | 0.838a | ||
| Yes | 68 (30.5%) | 31 (31.6%) | |
| No | 155 (69.5%) | 67 (68.4%) | |
| Antibiotic prophylaxis | 0.218a | ||
| Yes | 60 (26.9%) | 33 (33.7%) | |
| No | 163 (73.1%) | 65 (66.3%) | |
| The initial age of CIC | 25.25 ± 8.86 | 38.56 ± 9.49 | <0.001b |
| CIC frequency | <0.001a | ||
| 1–2 times/day | 9 (4.0%) | 45 (45.9%) | |
| 3–4 times/day | 108 (48.4%) | 26 (26.5%) | |
| ≥5 times/day | 106 (47.5%) | 27 (27.6%) | |
| Vesicoureteral reflux | <0.001a | ||
| No reflux | 165 (74.0%) | 27 (27.6%) | |
| Low-grade reflux | 53 (23.8%) | 38 (38.8%) | |
| High-grade reflux | 5 (2.2%) | 33 (33.6%) | |
| Hydronephrosis | 0.08a | ||
| Yes | 44 (19.7%) | 28 (28.6%) | |
| No | 179 (80.3%) | 70 (71.4%) | |
| Incontinence | 0.197a | ||
| Yes | 72 (32.3%) | 27 (27.6%) | |
| No | 151 (67.7%) | 71 (72.4%) | |
| Bladder trabeculation | 0.041a | ||
| Yes | 115 (51.6%) | 62 (63.3%) | |
| No | 108 (48.4%) | 35 (35.7%) | |
| Bladder wall thickness (mm) | 3.38 ± 2.21 | 3.71 ± 2.37 | 0.026b |
| Constipation | 0.769a | ||
| Yes | 103 (46.2%) | 47 (48.0%) | |
| No | 120 (53.8%) | 51 (52.0%) | |
| BC | <0.001a | ||
| Low | 51 (22.9%) | 47 (48.0%) | |
| Normal | 119 (53.3%) | 37 (37.7%) | |
| High | 53 (23.8%) | 14 (14.3%) | |
| Bladder compliance | 0.002a | ||
| Normal | 97 (43.5%) | 25 (25.5%) | |
| low (<10.0 mL/cmH2O) | 126 (56.5%) | 73 (74.5%) | |
| DO | <0.001a | ||
| Yes | 94 (42.2%) | 68 (69.4%) | |
| No | 129 (57.8%) | 30 (30.6%) | |
| Pdet (cmH2O) | 0.001a | ||
| Low (<10.0) | 130 (58.3%) | 38 (38.8%) | |
| High (≥10.0) | 93 (41.7%) | 60 (61.2%) | |
| DLPP | 0.783a | ||
| ≤40 mmH2O | 72 (32.3%) | 35 (35.7%) | |
| >40 mmH2O | 75 (33.6%) | 33 (33.7%) | |
| No leak | 76 (34.1%) | 30 (30.6%) |
- Abbreviations: BC, bladder capacity; CIC, clean intermittent catheterization; DLPP, detrusor leak point pressure; DO, detrusor overactivity; FUTI, febrile urinary tract infection; Pdet, pressure detrusor.
- a χ2 test.
- b t test.
3.2 Univariate analysis
The initial age at CIC, the frequency of CIC, bladder trabeculation, bladder wall thickness, and VUR were associated with an increased risk of recurrent FUTIs (Tables 1 and 2). Late-initiation and low-frequency CIC were significantly associated with risk of recurrent FUTIs (p < 0.05). Bladder trabeculation and VUR were risk factors for recurrent FUTIs (p < 0.05). A large bladder wall thickness was associated with a higher risk of recurrent FUTIs (p < 0.05). However, age, sex, anticholinergic therapy, antibiotic prophylaxis, constipation, urinary incontinence, or hydronephrosis were not associated with recurrent FUTIs.
| Adjusted OR | 95% CI | p Value | |
|---|---|---|---|
| The initial age of CIC (months) | 1.13 | 1.01–1.38 | <0.001 |
| CIC Frequency | 0.018 | ||
| 1–2 times/day | 3.14 | 2.52–4.38 | |
| 3–4 times/day | 1.01 | 0.98–1.03 | |
| ≥5 times/day (referent) | |||
| BC | 0.02 | ||
| Low | 1.66 | 1.29–2.15 | |
| High | 0.96 | 0.80–1.01 | |
| Normal (referent) | |||
| Vesicoureteral reflux | <0.001 | ||
| Low-grade reflux | 4.78 | 2.76–6.84 | |
| High-grade reflux | 26.95 | 14.76–49.21 | |
| No-reflux (referent) | |||
| Bladder compliance | 3.29 | 2.33–5.41 | 0.009 |
| DO | 2.13 | 1.56–4.12 | 0.013 |
- Abbreviations: BC, bladder capacity; CI, confidence interval; CIC, clean intermittent catheterization; DO, detrusor overactivity; OR, odds ratio.
High Pdet, low bladder compliance, DO, and low BC were significantly associated with risk of recurrent FUTIs (Table 1). DLPP was not associated with an increased risk of recurrent FUTIs.
3.3 Multivariate analysis
Late-initiation and low-frequency CIC, VUR, low bladder compliance, low BC, and DO were identified as risk factors for recurrent FUTIs (Table 2). High-grade reflux had a higher risk of recurrent FUTIs than those with low-grade reflux (hazard ratio [odds ratio, OR] = 26.95, p < 0.001, Table 2). However, bladder trabeculation, bladder wall thickness, and Pdet were not associated with an increased risk of recurrent FUTIs (Table 2).
4 DISCUSSION
The main management objectives for NB are to prevent UTIs and slow upper urinary tract deterioration to protect kidney function.8 However, the risk of kidney scarring increases substantially with recurrent FUTIs.6 Therefore, preventing recurrent FUTIs and the consequent kidney scarring is vital in patients with NB. Our data suggested that the initial age of CIC, CIC frequency, VUR, BC, and compliance, and DO were associated with recurrent FUTIs in patients with NB.
VUR was associated with a significant risk of recurrent FUTIs, which increased with high-grade VUR. Hum et al. found that high-grade VUR was a significant risk factor for recurrent FUTIs in children without NB.9 VUR may resolve with age in this population, and only few adults still have VUR.10 However, VUR often results from long-term bladder dysfunction in patients with NB, and urodynamic characteristics may deteriorate over time.11 Persistent functional obstruction can lead to changes in the anatomy of the ureterovesical and bladder junction, resulting in the development and persistence of VUR.12 Moreover, long-term CIC increases the risk of bacteria entering the bladder because keeping CIC clean techniques are not easy for children, and reflux allows bacteria to reach the renal, leading to recurrent pyelonephritis.13 Seki et al. reported that VUR with bacteriuria is a risk factor for FUTI.11 Therefore, we believe that improving bladder dysfunction can delay the onset or avoid the rapid progression of VUR, which can prevent recurrent FUTIs.
Chaudhry et al. reported that the CIC frequency was not associated with frequent UTIs in a retrospective study of 83 children with NB.14 However, in this study, CIC frequency was an independent risk factor for recurrent FUTIs, and a low CIC frequency led to an increased risk of recurrent FUTIs. Similarly, Shigemura et al. demonstrated that the number of CICs was associated with FUTI occurrence in a retrospective study of 141 adult patients.15 CIC four to six times a day is recommended for NB children, and it helps to empty the bladder regularly.15 Elevated storage pressures can develop if the bladder is not emptied regularly, which may put the upper tract at risk of subsequent deterioration.11 A lower frequency CIC can result in more residual urine volume remaining for a longer period.15 This condition may increase the chance of reflux from the bladder and pyelonephritis.15 Lee et al. reported that a small amount of residual urine could lead to FUTI and make treatment more difficult in children with NB.16 Therefore, ensuring a certain frequency of CIC can help prevent recurrent FUTIs in patients with NB.
CIC allows the bladder to remain empty and reduces bladder pressure. In previous studies, delay-start CIC was a significant risk factor for kidney function deterioration.17, 18 However, whether delay-start CIC is associated with recurrent FUTIs remains unclear. Our data showed that delay-start CIC is associated with recurrent FUTIs. This finding may be attributed to the gradual deterioration of the urodynamic characteristics caused by delayed CIC, which partly reflects the cumulative risk of recurrent FUTIs. Patients who cannot promptly receive CIC must be counseled about the increased risk of renal complications and the need for later augmentation owing to the delayed initiation of CIC. Nonetheless, we recommend assisted urination (Valsalva action) as an alternative to promote bladder emptying in such patients.
Over time, many patients experience reduced BC despite the proactive approach.19 If BC is decreased, bladder pressure can elevate, leading to upper urinary tract deterioration.11 This study showed a direct correlation between low BC and recurrent FUTIs. Sekido et al. reported that decreased BC was a risk factor for symptomatic UTI in patients with spinal cord injury.20
In this study, low bladder compliance and DO were associated with the incidence of recurrent FUTIs. Similarly, Seki et al. found that both low bladder compliance and DO were independently risk factors associated with the incidence of FUTI.11 Low bladder compliance or DO during voiding lead to increase bladder pressure, which can responsible for bladder mucosal ischemia and results in a decrease in bladder mucosal immunity, increasing the risk of FUTI.11
This study fully included clinical and urodynamic parameters. In addition, the number of participants in this study was relatively large. However, our study had several limitations. First, clinical indicators were affected by patient compliance, thus limiting the analysis. Second, urinary biomarkers were not included as potential risk factors. Third, the exclusion of the surgical cohort from the study is based on the possibility that the postoperative clinical course can significantly influence the frequency of FUTI and may constitute bias. Fourth, divide the study patients into two groups (instead of three groups) based on the number and frequency of UTIs.
5 CONCLUSIONS
Our data demonstrated that late-initiation and low-frequency CIC, VUR, low BC, low bladder compliance, and DO were associated with an increased risk of recurrent FUTIs. Patients with VUR have the highest risk of recurrent FUTIs, especially high-grade VUR. Therefore, we recommend early CIC interventions in patients with NB.
AUTHOR CONTRIBUTIONS
All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Guanglun Zhou, Man Jiang, Xiaodong Liu, Shoulin Li, and Jinjun Chen. The first draft of the manuscript was written by Guanglun Zhou and all authors commented on previous versions of the manuscript. Guanglun Zhou and Jinjun Chen read and approved the final manuscript.
ACKNOWLEDGMENTS
We thank Wenbin Zhu and Yingtian Zhang for revising this manuscript. This study is supported by the Shenzhen Fund for Guangdong Provincial High-level Clinical Key Specialties (SZXK035), Natural Science Foundation of China (No. U1904208), and Guangdong High-level Hospital Construction Fund Clinical Research Project of Shenzhen Children's Hospital (LCYJ2022082).
CONFLICT OF INTEREST STATEMENT
The authors declare no conflict of interest.
ETHICS STATEMENT
The study was approved by the Bioethics Committee of Shenzhen Children's Hospital. Informed consent was obtained from legal guardians.
Open Research
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
