Clinical manifestations, laboratory markers, and renal ultrasonographic examinations in 1-month to 12-year-old Iranian children with pyelonephritis: a six-year cross-sectional retrospective study

Febrile urinary tract infections (UTIs) or acute pyelonephritis (AP) is one of the most common bacterial infections of the renal pelvis and kidney among children and young adult women [1]. It has been reported that the annual cost of treating this disease in France and the US was about €58 million and $2.47 billion, respectively [2, 3]. In childhood, this disease usually occurs in boy infants due to congenital anomalies of kidneys and urinary tract, while AP is observed in girls at older ages [4‐6]. Escherichia coli is the main responsible pathogen for AP. This pathogen often causes severe inflammation and short-term (e.g., fever, dysuria, and flank pain) and long-term (e.g., irreversible renal scarring) morbidities [7, 8]. The renal scarring significantly develops the risk of hypertension, proteinuria, vesicoureteral reflux (VUR), chronic kidney disease, and end-stage renal disease [9, 10]. Since renal scarring is observed in 37% of AP children after two years from the infection onset, the rapid diagnosis and implementation of effective therapeutic measures are necessary to manage this disease among children [4, 11‐13].

Although some complications such as dysuria, urgency, hesitancy, small-volume voids, or lower abdominal pain were recognized in children with UTI at older ages, infants involved with this disease usually appear non-specific symptoms like fever, failure to thrive, jaundice, irritability, and vomiting [14, 15]. On the other hand, the definitive analysis among infants with UTI involves bladder catheterization due to the nonspecific signs and symptoms of UTI in pediatric populations. Besides, clinical strategies driven by antibiotic prophylaxis or imaging tools have been recently implemented for hospitalized children with UTIs. Accordingly, several imaging techniques such as ultrasound, micturition cystourethrogram, and Tc-99 m dimercaptosuccinic acid along with a broad spectrum of intravenous prophylactic antibiotics were recommended to monitor and treat febrile UTIs (e.g., VUR and renal scarring) in children [8, 16].

Although there are many studies on the association between demographic and laboratory factors and the AP severity in children, little evidence on the combination of findings obtained from clinical manifestations, markers, and renal sonography among Iranian children within a wide age range has been published. For the first time, the efficiency of ultrasonographic examinations and antibiotics to diagnose and treat AP among Iranian infants and children was first conducted based on a high number of clinical manifestations, laboratory markers, and complications. As a result, the objective of this six-year cross-sectional study was to scrutinize the febrile UTI in 1-month to 12-year-old Iranian children based on clinical outcomes and signs, as well as renal ultrasound findings to adopt clinical practices and diagnostic tools/markers for a notable contribution to the early disease prognosis, monitoring, and treatment in the future.

The average age of 104 patients with AP was 47.08 years. Nighty-five (91.34%) of the studied patients were girls. The minimum, mean, and maximum values of patients’ height and weight were 52 cm and 3.3 kg, 94.26 cm and 15.77 kg, and 147 cm and 69.9 kg, respectively. The highest and lowest BMI were respectively calculated to be 10 and 28 kg/m², while the mean BMI of the total population with AP was 16.29 kg/m² (Table 1). Table 2 exhibits the frequency of BMI classes as a function of gender differences and age groups (< 1, 1–5, and >  5 years old). Most children (girls, 62.1%; boys, 44.4%) had a normal range of BMI. Also, almost equal numbers of children were in different age ranges (31.73–34.61%, Table 2). Based on the age group classification, most overweight children had an age of less than one-year-old (n = 23) and over 5 years old (n = 23) (Table 2).

The minimum and maximum time of hospitalization stay were 2 days (n = 9) and 16 days (n = 1), respectively (Table 1). In general, 75% of the patients with AP were symptomatic. A high number of girls (78.9%) were symptomatic, while most boys (66.7%) were asymptomatic (Fig. 1a). This finding indicates that UTIs may occur in boys with fewer clinical symptoms. Thus, this population group needs further laboratory investigations. Also, the percentage of asymptomatic children in three age groups of < 1, 1–5, and >  5 years old was 47.2, 12.1, and 14.3%, respectively (Fig. 1b). Hence, asymptomatic was more common at younger ages. The symptomatology rate was increased with increasing age, although there was no significant difference in this index between age groups of 1–5 and > 5 years old. As 20.19% (n = 21) of the patients with AP complained of constipation, this symptom can be considered as a risk factor for UTIs. Fever as the main inclusion criterion for all patients averagely was at 39.4 °C, at admission time, while the minimum and maximum temperature degrees were 38.5 and 41.0 °C, respectively. The shortest and longest fever durations before the treatment were 1 day (n = 10) and 7 days (n = 6), respectively (Table 1). Although the child’s fever duration before starting the antimicrobial therapy does not play a role in confirming or rejecting a UTI, a delay in beginning the treatment can significantly have consequences like renal scarring. Three cases did not show fever after the treatment, while fever in the two other cases continued for up to 5 days after the treatment, showing a necessity to change the used antibiotic type. As dysuria was observed among 30 patients with AP (28.84%), the absence of dysuria does not rule out a UTI. Abdominal pain and vomiting were detected in 33.65% (n = 35) and 40.38% (n = 42) of the subjects, respectively (Table 3). Based on Pearson’s Chi-square analysis, there were significant associations between patients’ age and symptoms of dysuria (p = 0.003) and abdominal pain (p = 0.0001).

Pyuria and hematuria usually respectively are the presence of ≥10 WBCs/mm³ and ≥ 5RBCs/HPF in a urine specimen. Pyuria, hematuria, and positive nitrite were respectively diagnosed in 88.46% (n = 92), 38.46% (n = 40) and 45.19% (n = 47) of urine tests of patients with AP (Table 3). As a result, not only pyuria can be one of the most important symptoms of UTI, but also not having hematuria and urine nitrite do not rule out this disease. Figure 1c shows that these abnormal urinary changes were increased by increasing the age from < 1 to > 5 years old. In addition, there was a negative correlation between and eGFR and patients’ age (r = 0.754, p = 0.001). Results proved that this increase in the urine nitrite (50.0%) was more evident than hematuria (36.36%) and pyuria (10.12%) (Fig. 1c). E. coli was the most frequent pathogen in urine samples so that this bacterium was present in samples of 96 patients (92.31%). Other bacteria such as Gram-negative Bacillus (2 cases), Group-B Streptococcus (2 cases), Klebsiella pneumoniae (1 case), Acinetobacter (1 case), Enterococcus (1 case), and Staphylococcus aureus (1 case) were observed in urine samples taken from patients less than one-year-old (Table 4). Ceftizoxime was the most common intravenous antibiotic to treat patients with AP (n = 78, 75.0%). Other used antibiotics were ceftriaxone (n = 12, 11.53%), amikacin (n = 7, 6.73%), cefotaxime (n = 2, 1.92%), cefepime (n = 2, 1.92%), vancomycin (n = 1, 0.96%), meropenem (n = 1, 0.96%), and gentamicin (n = 1, 0.96%) (Table 4). Patients receiving two antibiotics of vancomycin and meropenem had abnormal ultrasound results. But, the administration of other antibiotics led to more normal sonographic findings. Pearson’s Chi-square analysis also showed that there were significant correlations between gender and antibiotic type (p = 0.0001) and hospitalization stay (p = 0.001). Thus, a proper choice of used antibiotics can significantly reduce fever degree and duration, and subsequently, the hospitalization stay of children with AP.

Overall, ESR and CRP values had recorded for 91 and 99 patients with AP, respectively. The minimum, mean, and maximum levels of ESR and CRP were 3 mm/h and 1 mg/L, 46.5 mm/h and 58.7 mg/L, and 108 mm/h and 118 mg/L, respectively (Table 1). The elevated ESR (> 10 mm/h) and CRP (> 10 mg/L) levels [22] were observed in 84 (92.30%) and 82 (82.82%) patients, respectively. Therefore, only 7 and 17 patients respectively had an ESR and CRP within a normal range. Accordingly, high amounts of these hematological factors may be effective in the diagnosis of patients with AP. The minimum, mean, and maximum amounts of BUN and SCr were 5 and 0.05 mg/dL, 11.31 and 0.57 mg/dL, and 62 and 2.4 mg/dL, respectively. Also, the minimum and maximum eGFR amounts respectively were 17.2 and 134 mL/min/1.73 m², while the average value of this index was calculated to be 68.94 mL/min/1.73 m² (Table 1). Also, the lowest, average, and highest values of WBCs and Hb were 3.6/mm³and 7.6 ng/mL, 14.90/mm³and 11.02 ng/mL, and 34/mm³and 14.7 ng/mL, respectively (Table 1). The frequency of leukocytosis and anemia in the studied population was 81.73% (n = 85) and 36.53% (n = 38), respectively. The mean Na and K amounts in blood samples were 140.7 and 4.36 mEq/L, respectively. The lowest and highest values of Na and K were 131 and 3.5 mEq/L, and 152 and 5.8 mEq/L, respectively (Table 1).

In general, 67.3% of the patients had normal sonographic examinations. A good inter-observer agreement was found for ultrasound imaging in the study years (kappa value: 0.751–0.837). Sonographic findings showed the presence of hydronephrosis, cystitis, and renal anomalies in 22 (21.15%), 9 (8.65%), and 2 (1.92%) patients with AP, respectively (Table 3). However, none of the patients showed ureteral stones on their ultrasound images. Consequently, hydronephrosis was the most common abnormality detected in the ultrasonography of kidneys and urinary tract. Since sonography results of 70 patients (67.3%) were not in favor of pyelonephritis, ultrasound alone cannot be a valid diagnostic technique for this disease.

A particular interest in the field of pediatric studies is early diagnosis and discrimination of AP from other UTIs such as cystitis because of long-term morbidities and serious complications. Girls than boys are more susceptible to get involved in AP due to their shorter urethras [23]. However, boy populations with UTIs typically have underlying anatomical or functional abnormalities of the genitourinary tract with a higher primary scarring rate [23]. E. coli is the most common AP-causing pathogen in children. It was previously shown that this Gram-negative rod bacterium was present in 69% of the English patients with AP, while K. pneumoniae, E. faecalis, Proteus mirabilis, and Pseudomonas aeruginosa caused 3–6% of AP in other patients [24]. Mahmoudi et al. [25] and Sarvari et al. [26] earlier reported the frequent presence of E. coli in urine samples collected from Iranian pediatric populations with AP. Since E. coli is the main pathogen responsible for AP, the antimicrobial sensitivity profile of this member of the family Enterobacteriaceae should be considered as a principle in determining the empirical therapeutic protocols [17]. The number of symptomatic patients with AP in this study was higher compared to that of in the study of Mahmoudi et al. (12.8%) [25]. Although Muhammad et al. [27] explained that constipation is a frequent and overlooked problem in children with UTI symptoms, most patients in this study (79.81%) did not show constipation complications. Pelvic floor dynamics are significantly worsened with this complication. The existence of large stool masses accompanied by volitional holding delays/prevents the complete bladder emptying because of pain with defecation. This mechanism leads to the high accumulation of post-void residuals facilitating bacterial colonization (such as E. coli) in the bladder [28, 29]. The guideline available in the American Academy of Pediatrics recommends pyuria as a clinical factor to diagnose UTIs [30]. Pyuria was the common factor in most children with AP in the present study (88.46%). The pyuria percentage in this research was in agreement with the findings of Nickavar and Sadeghi-Bojd [31] and Shaikh et al. [32] who respectively reported 81 and 87% pyuria among Iranian and American children with AP. Also, Renata et al. [33] pointed out that the frequency of pyuria among the studied Israeli infants and children was 93.5%. They also showed that patients with pyuria significantly had higher concentrations of urinary interleukin-6 (UIL-6) and interleukin-8 (UIL-8) [33]. As a laboratory factor in diagnosing AP in children, we found that the presence of nitrite in urine samples was more pronounced than hematuria. The positive nitrite reaction is a specific test so that it only detects Gram-negative coliforms, whereas atypical pathogens (such as Pseudomonas and Gram-positive organisms) cannot be identified [34]. Moreover, high urine-specific gravity can remarkably reduce the sensitivity of this test [35]. However, as the presence of atypical pathogens in urine samples was insignificant, this factor in our study was relatively appropriate to detect children with AP. The prevalence rate of leukocytosis as a common feature of inflammatory reaction in the current study (81.73%) was much more than that of (56%) in Ayazi et al. [22]. Lee et al. [36] also mentioned leukocytosis as an important risk factor for renal scar formation in Korean infants with the first episode of AP. Shah and Upadhyay [37] earlier reported a significant increase in leukocytosis among children with AP. CRP is synthesized by the liver in response to inflammatory cytokines, particularly UIL-6. ESR shows the complete acute phase process mainly as a response to the production of fibrinogen [38]. The levels of CRP and ESR also were much more than the measured amounts in studies conducted by Ayazi et al. [22] and Naseri [39]. This fact showed that the high amounts of these hematological factors were risk factors to develop renal scars in the long-term follow-up. Jung and Lee [40] proved that UTI infants with a higher CRP significantly had higher cortical defect on an acute dimercaptosuccinic acid (DMSA) scan. Rodríguez et al. [41] revealed that CRP can be considered a valid test to diagnose febrile UTI with high sensitivity (83.3%) compared to UIL-6 (77.8%). In contrast, Lin et al. [42] reported that ESR and CRP had a relatively low sensitivity to diagnose UTI in febrile infants.

Ultrasound not only is a non-invasive, easily repeatable, safe, and relatively cheap technique to diagnose infectious diseases but also it does not require any sedation and is easy to examine bedside [43]. Other benefits of ultrasound are the lack of ionizing radiation hazards, general availability, and patient acceptability [44]. Sonography examinations showed that only 34 patients were in favor of AP with a more appearance of hydronephrosis. The size of kidneys during AP may be enlarged so that they have hypoechoic parenchyma with a loss of the normal corticomedullary junction [45]. Our ultrasonographic findings demonstrated that this imaging tool did not have sufficient adequacy to diagnose AP as it may miss parenchymal and perinephric abnormalities [46]. Thus, other diagnostic methods in combination with ultrasound should be used to monitor AP in pediatric patients due to the disadvantages such as the accepted low sensitivity, high operator dependence, and required expertise for the data interpretation [47, 48]. It has been recently reported that the combined use of ultrasound with DMSA scintigraphy [49], voiding cystourethrogram [50], and technetium-99 m DMSA (^99mTc-DMSA) scintigraphy [51, 52] can highly improve the diagnostic accuracy of AP among pediatric patients.