cUTI is prone to recurrence. If structural abnormalities of urinary system are not corrected, more than 50% of cUTI patients will relapse 4–6 weeks after a prior treatment [13]. Repeated infections can lead to serious consequences such as urinary sepsis, renal scars, and progression to end-stage kidney diseases, seriously affecting the prognosis and long-term quality of life of patients. So far, there has been no study on prediction models for the recurrence of cUTI in pediatric patients. This study explored the risk factors for cUTI recurrence, and for the first time, constructed a nomogram model for predicting the risk of cUTI recurrence in pediatric patients. To the best of our knowledge, this cohort is the largest to study the risk factors of recurrence of cUTI that involved multiple complicating factors in pediatric patients. Through multivariate analysis, 5 independent risk factors for the recurrence of cUTI in children were found, including female gender, history of urinary tract surgery, Escherichia coli in urine culture, renal dysfunction, and VUR. These risk factors were used to construct the nomogram for estimating the risk of cUTI recurrence. As a model performance indicator, the C-index in the training dataset was 0.735, while the C-index in the validation dataset was 0.750, indicating that the easy-to-use nomogram can be used reliably to predict the recurrence of cUTI in children. The nomogram may help clinicians identify high-risk individuals of cUTI recurrence in pediatric patients for early specific interventions. This would be beneficial for the comprehensive management of cUTI in children.
Anatomical structural abnormalities of the urinary tract can easily lead to urinary tract infections in both males and females. This study showed that cUTI in children was more common in boys, with a male to female ratio of 1.54:1, which might be related to the prevalence of obstructive urinary tract diseases in males [7]. Although it was shown that boys without circumcision had a high incidence rate in the first year after birth, girls with the increase of age were more likely to suffer from urinary tract infection due to the anatomical structure of the urinary tract [14]. In particular, more than 25% of girls experienced recurrence within one year after their first urinary tract infection [15, 16]. Our study found that female gender was an independent risk factor for the recurrence of cUTI in pediatric patients, and can be used as a predictor for the recurrence of cUTI in children, considering the females’ anatomical characteristics such as short and wide urethra, proximity to the anus and vagina. But some studies suggested that the recurrence of urinary tract infection (not limited to cUTI) was not related to gender [17]. In addition, some previous studies showed that children aged 2 to 6 years, especially those aged 3 to 5 years, had a higher risk of recurrent urinary tract infections, which might be related to urinary dysfunction in this age group [18–20], whereas some other studies showed opposite finding that younger age (< 6 months) rather than older age was associated with increased risk of recurrence of urinary tract infection as reviewed by Keren et al. [21]. Our multivariate analysis showed that the age of first cUTI was not a risk factor for cUTI recurrence, consistent with Keren et al. [21].
It was revealed in this study that Escherichia coli was the most common pathogen of cUTI in children, consistent with previous studies [9, 22], and Escherichia coli in urine culture was also an independent risk factor for the recurrence of childhood cUTI. A study has shown that Escherichia coli is the main pathogen of recurrent UTI worldwide [23]. There is a complex interaction between the genetic diversity of Escherichia coli and the host's innate and adaptive immune responses during UTI [24]. About a half of recurrent UTI was caused by the same pathogenic Escherichia coli in the urinary tract during the initial UTI, indicating that urinary tract infection often failed to produce adaptive immune responses to prevent subsequent infections with the same bacterium strain [25]. Another study also showed that 61% of recurrent UTI in children was caused by antibiotic resistant pathogens, with Escherichia coli being the most common pathogen leading to recurrence [17]. Recurrent UTI is considered to be associated with the pathogenic characteristics of the bacterium itself, virulence genes afa and usp of Escherichia coli, and the resistance of Escherichia coli to antibiotics such as cefuroxime and cefazolin [26, 27].
In this study, we found that the common complicating factors for cUTI in children were hydronephrosis (211 cases, 50.1%), VUR (176 cases, 41.8%), and ureterectasis (107 cases, 25.4%). In this cohort, there were 88 cases (20.9%) having fetal development abnormalities of the urinary system, with fetal hydronephrosis (70 cases, 16.6%) being the most common. Hydronephrosis was also the most common urinary tract abnormality in newborns, occurring in 45% of newborns with urinary tract infections [28]. Yang et al. [29] found that in children with first-time febrile urinary tract infections, the most common urinary tract abnormality detected by ultrasound was hydronephrosis (9.2%), followed by ureterectasis (2.9%). Some studies found that the most common urinary tract abnormality detected by ultrasound was bladder abnormality (39.1%), followed by hydronephrosis (9.4%) [9]. The multivariate analysis in this study included more common complicating factors such as hydronephrosis, VUR (at any level), ureterectasis, and phimosis, among which only VUR (at any level) was an independent risk factor for the recurrence of cUTI in children. Keren et al.'s study suggested that any level of VUR was associated with the recurrence of urinary tract infection [21], which was basically consistent with our finding. Castro et al. found that, even after anti-reflux surgery, VUR still was associated with the increased recurrence rate of urinary tract infection due to the presence of excretory dysfunction [30]. But some studies also suggested that only high-level VUR was associated with recurrence of urinary tract infection, while low-level VUR was not associated with urinary tract infection recurrence [6, 17, 21, 31].
Urinary tract infection is the main hospital complication after pediatric urological surgery [32–34]. We found that the history of urinary tract surgery was a risk factor for cUTI recurrence in pediatric patients. Urinary tract surgery might cause changes in the physiological structure and defense mechanism of the urinary tract in children. Pathogens might breed or cause retrograde infections after urinary tract surgery, and some bacteria might not be easily cleared by antibiotics, leading to the increased risk of cUTI recurrence.
Both first-time and repeated urinary tract infection can lead to varying degrees of renal dysfunction. In this study, it was found that renal dysfunction was in turn a risk factor for the recurrence of cUTI in children. The reasons for the increased risk of cUTI recurrence might be related to underlying diseases, structural abnormalities, and weakened immunity that caused renal dysfunction in children. Further research is needed to explore the specific causes of cUTI recurrence caused by renal dysfunction.
There were certain limitations in this study. Firstly, both the internal and external validation cohorts in this study were from a single center and could not represent all pediatric patients, resulting in certain biases. Further multicenter studies are helpful in verifying the accuracy of the nomogram. Secondly, urine culture samples were collected after admission, and the use of antibiotics before admission might increase the false negative rate of urine culture. The impact of this factor on the distribution of pathogenic bacterial strains in this study was not analyzed. Thirdly, this study did not collect complete hematological indicators, and only included limited numbers of pathogenic bacterial strains and complicating factors in the analysis. Thus some other risk factors for the recurrence of cUTI in children might have been missed. Fourthly, there might be recall bias in the research data collected during the follow-up period, especially by telephone follow-ups.
In conclusion, we summarized the clinical characteristics, analyzed the risk factors for recurrence of cUTI in pediatric patients, and for the first time, constructed a clinically practical model as a nomogram for predicting the risk of cUTI recurrence in pediatric patients. Our nomogram study revealed 5 risk factors for cUTI recurrence in children: female gender, renal dysfunction, Escherichia coli in urine culture, history of urinary tract surgery, and VUR. This model showed a high predictive value. Therefore, clinical management based on this predictive model would be necessary for clinicians to timely identify high-risk individuals of cUTI recurrence and take specific interventions. The clinical decision curves reveal that targeted interventions may provide a positive influence in preventing cUTI recurrence in pediatric patients. Further large-scale multicenter studies should be conducted to validate the predictive value of the model.