Summary
Introduction
In 2011, the American Academy of Pediatrics (AAP) published guidelines regarding diagnosis and management of children 2-to-24-months-old with initial febrile urinary tract infection (fUTI). Available data were insufficient to determine whether evidence from studies of 2-to-24-month-olds applies to those <2-months-old, so they were excluded.
Objective
This study aimed to 1) compare demographic, clinical, imaging and outcomes between patients <2-months-old and those 2-to-24-months-old hospitalized with fUTI, and 2) assess whether diagnostic and imaging recommendations of the AAP 2011 guidelines apply to those <2-months-old.
Study Design
A cohort study of patients ≤24-months-old hospitalized at a children’s hospital with fUTI from 2016–2018 was conducted. Data were collected via a prospectively generated electronic medical record note template, supplemented with retrospective chart review. Primary outcomes included differences in demographics, clinical presentation, urine culture results, and imaging utilization/results by age group. Secondary outcomes included surgical procedures, UTI recurrence, and 90-day all-cause readmissions and emergency department (ED) revisits. Univariate and bivariate statistics were utilized to compare age groups.
Results
Overall, 137 patients were included (median age 70 days, 55.5% male [92.1% uncircumcised], 53.3% Hispanic/Latino, 89.8% 1st fUTI). There were no demographic differences between groups, except children <2-months-old were more frequently male (71.2 vs 43.6%, p=0.002). The Summary Table compares clinical factors and imaging utilization by age. There were no differences in urinalysis or urine culture results between groups. Patients <2-months-old had shorter fever duration, lower maximum temperature, and lower white blood cell counts. Voiding cystourethrograms (VCUGs) were recommended and obtained more frequently in patients <2-months-old, but there were no differences in renal and bladder ultrasound (RBUS) or VCUG results between age groups. There were no differences in UTI recurrence (13.6% of <2-months-old vs 14.1% of 2-to-24-months-old, p=1.00) or fUTI recurrence (13.6 vs 7.7%, p=0.40) within 1 year, 90-day readmission (6.8 vs 6.4%, p=1.00), or 90-day ED revisit (22.0 vs 20.5%, p=1.00).
Discussion
There were minimal differences between the <2-months-old and 2-to-24-months-old age groups in demographics, laboratory (including microbial) or imaging results, or clinical outcomes. Patients <2-months-old were more frequently male and less ill. These data support applying urinalysis and urine culture diagnostic criteria, and universal RBUS, from the AAP guidelines to patients <2-months-old. Given utilization differences, applicability of VCUG guideline recommendations requires further clarification for patients <2-months-old.
Conclusion
Laboratory testing and RBUS recommendations from the AAP guidelines may be safely applied to infants <2-months-old. Further studies are needed to clarify optimal VCUG recommendations.
Keywords: Urinary Tract Infections, Infant, Evidence-based Practice, Practice Guidelines
Introduction
Urinary tract infections (UTI) are the most common cause of serious bacterial infection among febrile infants and young children[1], and frequently lead to Emergency Department (ED) visits and inpatient admissions. The prevalence of UTI among febrile infants <24-months-old is ~7.0% while the prevalence for those <2-months-old may be up to 13.6%[2]. Pediatric UTI is also associated with congenital urinary tract abnormalities, e.g., vesicoureteral reflux (VUR)[3], which puts infants at increased risk of acute pyelonephritis, recurrent UTIs, and renal scarring[4]. Thus, prompt UTI diagnosis and treatment, and diagnosis of potential underlying structural abnormalities, are critically important, with early detection and treatment potentially reducing renal scarring risk[4, 5].
There is abundant evidence available regarding febrile UTI (fUTI) evaluation and management in children 2-to-24-months-old. However, data to guide care for infants <2-months-old are more limited. Infants <2-months-old are often aggregated with older infants (e.g., grouped as all those <6-months-old), or excluded from studies[6]. In 2011, the American Academy of Pediatrics (AAP) published guidelines on evaluation and management of infants with fUTIs, but excluded children <2-months-old due to insufficient data[1]. The lack of evidenced based recommendations for those <2-months-old is especially concerning given that this age group, relative to those 2-to-24-months-old, may have a greater fUTI prevalence and greater risk of renal damage secondary to fUTIs, though evidence for the latter is somewhat conflicting[7–9].
Emerging evidence suggests that some aspects of the AAP UTI guidelines may also apply to patients <2-months-old. Specifically, the present study focuses on the urine testing and imaging recommendation components of the guidelines. Additionally, there are limited data comparing clinical outcomes between these age groups, such as recurrent UTIs, ED revisits, and inpatient readmissions. One recent study indicated that infants <2-months-old with fUTI were clinically similar to older infants, with the exception of being less ill and predominately males[8].
In this present study, the aims were to: 1) to compare demographics and clinical characteristics, laboratory data, uropathogens, antibiotic resistance patterns, imaging and clinical outcomes between patients <2-months-old and those 2-to-24-months-old hospitalized with fUTI and 2) assess whether the diagnostic and imaging recommendations of the 2011 AAP UTI guidelines are applicable to infants <2-months-old. We hypothesized that children <2-months-old would receive more diagnostic testing and experience poorer clinical outcomes (i.e., higher UTI recurrence and readmission rates).
Material and Methods
Study Design & Data Source
This was a retrospective cohort study conducted within the context of our institution’s participation in the Quality Improvement for the Management of Children Hospitalized with Urinary Tract Infection (Q-UTI) initiative. This initiative aimed to implement and evaluate the uptake of 2011 AAP UTI guidelines at hospitals nationwide. Data were abstracted from patient electronic health records (EHR) via a prospectively generated EHR note template, supplemented with manual retrospective EHR review. Institutional review board approval (IRB 2019–2478) was obtained from Ann & Robert H. Lurie Children’s Hospital of Chicago.
Study Population
The cohort consisted of patients ≤24-months-old hospitalized with a fUTI at a single tertiary-care, free-standing children’s hospital from 07-01-2016 to 06-30-2018. Patients were identified through a prospectively maintained database that included all patients eligible for the Q-UTI initiative during the study period. We defined fUTI as positive urinalysis (UA; positive leukocytes, nitrites, or >3 WBC per high power field), urine culture growing ≥10 000 organism colony forming units (CFUs) per mL of a single uropathgen regardless of collection method, and temperature ≥100.4F. Exclusion criteria included genitourinary anomalies, neurogenic bladder (including spina bifida), prior genitourinary operative procedures (excluding circumcision), indwelling urinary catheters, intensive care unit admission, urinalysis or urine culture obtained >48 hours after admission, afebrile UTI, or admission unrelated to UTI. Patients transferred from another institution were eligible for inclusion.
Measures
The independent variable was patient age, comparing patients <2-months-old to those 2-to-24-months-old. Dependent variables included: 1) demographics: age (in days), median household income by zip code (US dollars), transferred (yes/no), sex, parent-reported race (White, Black, Asian, other, unknown) and ethnicity (Hispanic/Latino, Non-Hispanic/Latino, unknown), insurance (private, public, other, unknown. Those with insurance pending at the time of hospital admission were classified as public); 2) clinical characteristics: Incidence of fUTI (e.g., 1st, 2nd, 3rd), circumcision status, presence of phimosis (any of the following: unable to visualize meatus, noted in physical exam or elsewhere in EHR, steroid cream recommended, circumcision recommended), urinalysis characteristics (bacteriuria, leukocytes, nitrites, WBC >3), length-of-stay (LOS) (in days), fever duration (in days), maximum temperature (Fahrenheit), serum white blood cell count (WBC) (K/μL), blood culture obtained (yes/no), blood culture result (No Growth, Growth (e.g., E. Coli)); 3) urine culture results: source of urine culture (bagged, catheterized, clean catch, unknown), isolated urinary organism type and CFUs/mL, antibiotic resistance patterns; 4) imaging utilization and results: obtained prenatal ultrasound (yes/no), results of prenatal ultrasound (normal/abnormal), RBUS obtained at or after index hospitalization (yes/no), any hydronephrosis on RBUS (yes/no), hydronephrosis or hydroureter laterality on RBUS (i.e., none, unilateral, bilateral), Society of Fetal Urology (SFU) hydronephrosis grade (none, trace/minimal = SFU 1, mild = SFU 2 or Urinary Tract Dilation (UTD) 1, moderate = SFU 3 or UTD 2, severe = SFU 4 or UTD 3), VCUG recommended by any clinician (yes/no), VCUG obtained at or after index hospitalization (yes/no), any VUR on VCUG (yes/no), VUR laterality (none, unilateral, bilateral), VUR grade by International Reflux Grading System (none, 1, 2, 3, 4, 5); and 5) physician recommendation for antibiotic prophylaxis (yes/no), antibiotic prophylaxis utilization at any time (yes/no), time on antibiotic prophylaxis (in days), and 1-year on antibiotic prophylaxis (yes/no).
Primary outcomes included differences in demographics, clinical factors, urine culture results, and imaging utilization and results. Secondary outcomes included surgical procedures performed (i.e., circumcision and ureteral reimplant), recurrence of UTI or fUTI within 1-year of index encounter (yes/no), 90-day all-cause readmission (yes/no), 90-day all-cause ED revisit (yes/no), and 90-day UTI-related ED revisit (yes/no).
Statistical Analysis
The unit of measurement for analyses was the individual patient (instead of hospital encounter). Primary and secondary outcomes were compared by age: <2-months-old versus 2-to-24-months-old. Statistical analyses were performed using R[10] and RStudio[11]. Univariate and bivariate statistics were performed. Chi-Square tests and Student’s t-test were used for parametric data, and Fisher Exact test or Mann-Whitney U test were used for non-parametric data. A two-tailed alpha of 0.05 defined statistical significance.
Results
Primary Outcomes – Demographics, Clinical Presentation, Imaging Utilization/Results, and Antibiotic Prophylaxis
Overall, 137 of 175 (78.3%) patients that qualified for the Q-UTI initiative were included; Table 1 shows demographics. Most patients were male (55.5%), Hispanic/Latino (53.3%) and publicly insured (58.4%). Patients <2-months-old were more frequently male compared to those 2-to-24-months-old. There were no other demographic differences between age groups.
Table 1.
Demographics
| Total (N = 137) | <2-Months-Old (N = 59) | 2–24-Months-Old (N = 78) | P-Value | |
|---|---|---|---|---|
| Age (Days)a Mean, Median [Range] | 122.8, 70 [7 – 594] | 32.29, 34 [7 – 60] | 191.3, 120, [63 – 594] | <0.001 |
| Median Household Income by Zip Code (dollars)a Mean, Median [Range] | $66 602.00, $60 073.00 [$22 992.00 – $166 262.00] | $65 181.00, $60 073.00 [$27 262.00 – $135 146.00] | $67 676.00, $60 073.00 [$22 992.00 – $166 262.00] | 0.945 |
| Transferred | 0.401 | |||
| Yes | 29 (21.2%) | 10 (16.9%) | 19 (24.4%) | |
| No | 108 (78.8%) | 49 (83.1%) | 59 (75.6%) | |
| Sex | 0.002 | |||
| Female | 61 (44.5%) | 17 (28.8%) | 44 (56.4%) | |
| Male | 76 (55.5%) | 42 (71.2%) | 34 (43.6%) | |
| Raceb | 0.644 | |||
| White | 44 (32.1%) | 23 (39.0%) | 21 (27.0%) | |
| Black | 8 (5.8%) | 3 (5.1%) | 5 (6.4%) | |
| Asian | 7 (5.0%) | 2 (3.4%) | 5 (6.4%) | |
| Other | 75 (54.7%) | 30 (50.8%) | 45 (57.7%) | |
| Refused/Unknown | 3 (2.2%) | 1 (1.7%) | 2 (2.6%) | |
| Ethnicityb | 0.832 | |||
| Hispanic/Latino | 73 (53.3%) | 30 (50.8%) | 43 (55.1%) | |
| Non-Hispanic/Latino | 61 (44.5%) | 28 (47.5%) | 33 (42.3%) | |
| Unknown | 3 (2.2%) | 1 (1.7%) | 2 (2.6%) | |
| Insuranceb | 0.214 | |||
| Private | 55 (40.1%) | 26 (44.1%) | 29 (37.2%) | |
| Public | 80 (58.4%) | 31 (52.5%) | 49 (62.8%) | |
| Military | 1 (0.7%) | 1 (1.7%) | 0 (0.0%) | |
| Unknown | 1 (0.7%) | 1 (1.7%) | 0 (0.0%) |
Mann-Whitney U test
Fisher Exact test
Clinically, most patients presented with their 1st fUTI (89.8%) and most males were uncircumcised (92.1%) with phimosis (59/72, 81.9%). Patients <2-months-old, relative to those 2-to-24-months-old, had greater LOS, but lower fever duration, maximum temperature, and serum WBC count (Table 2). There were no statistically significant differences in UA results between age groups (Table 2). Urine samples were mostly collected via catheterization (83.9%) and urine culture results yielded no statistically significant differences between age groups (Table 3), with E. Coli predominance (79.6%). Antibiotic resistance patterns also did not differ between age groups (Table A.1). In particular, there was no difference between age groups in E. Coli antimicrobial resistance patterns (data not shown). Every infant <2-months-old had a blood culture obtained (100%), and E. Coli bacteremia occurred in 2 (1.8%) infants <2-months-old.
Table 2.
Clinical Factors
| Total (N = 137) | <2-Months-Old (N = 59) | 2–24-Months-Old (N = 78) | P-Value | |
|---|---|---|---|---|
| Length-of-Stay (days)a Mean, Median [Range] | 4.04, 3 [1 – 21] | 4.9, 3 [1 – 14] | 3.2, 2, [1 – 21] | 0.007 |
| Fever Duration (days)a Mean, Median [Range] | 3.0, 2 [1 – 11] | 2, 2 [1 – 7] | 3.8, 3 [1 – 11] | <0.001 |
| Max Temp (F)a Mean, Median [Range] | 102.7, 102.6 [100.4 – 107] | 101.8, 101.8 [100.4 – 104.2] | 103.3, 103.2 [100.5 – 107] | <0.001 |
| Serum WBC (K/μL)a Mean, Median [Range] | 15.3, 14.1 [2.6 – 36.7] | 13.3, 12.2 [2.6 – 30.8] | 16.9, 16.2 [4.1 – 36.7] | 0.005 |
| 1st UTIb | 123 (89.8%) | 56 (94.9%) | 67 (85.9%) | 0.225 |
| Circumcisedb | 4 (5.3%) | 4 (9.5%) | 0 (0.0%) | 0.099 |
| Phimotic foreskinb | 59 (77.6%) | 34 (81.0%) | 25 (73.5%) | 0.361 |
| Urinalysis Bacteriuriab | 100 (75.2%) | 46 (82.1%) | 54 (70.1%) | 0.196 |
| Urinalysis Leukocytesb | 115 (86.5%) | 50 (89.3%) | 65 (84.4%) | 0.772 |
| Urinalysis Nitritesb | 41 (30.8%) | 16 (28.6%) | 25 (32.5%) | 0.291 |
| Urinalysis WBC >3b | 108 (81.2%) | 50 (89.3%) | 58 (75.3%) | 0.165 |
Mann-Whitney U test
Fisher Exact test
Table 3.
Urine Culture Results
| Total (N = 137) | <2-Months-Old (N = 59) | 2–24-Months-Old (N = 78) | P-Value | |
|---|---|---|---|---|
| Source of Urine Culturea | 0.743 | |||
| Bagged | 6 (4.3%) | 2 (3.4%) | 4 (5.1%) | |
| Catheterized | 115 (83.9%) | 52 (88.1%) | 63 (80.8%) | |
| Clean Catch Urine | 8 (5.8%) | 3 (5.1%) | 5 (6.4%) | |
| Unknown | 8 (5.8%) | 2 (3.4%) | 6 (7.7%) | |
| Organismsa,b | 0.799 | |||
| E. Coli | 109 (79.6%) | 48 (78.7%) | 61 (75.3%) | |
| Klebsiella | 11 (8.0%) | 3 (4.9%) | 8 (9.9%) | |
| Enterococcus | 7 (5.1%) | 4 (6.6%) | 3 (3.7%) | |
| Citrobacter | 5 (3.6%) | 2 (3.3%) | 3 (3.7%) | |
| Otherc | 10 (7.3%) | 4 (6.6%) | 6 (7.4%) | |
| Organism CFU Counta,b | 0.512 | |||
| >1k – 10k | 5 (3.5%) | 3 (4.9%) | 2 (2.4%) | |
| >10k – 25k | 9 (6.3%) | 2 (3.3%) | 7 (8.4%) | |
| >25k – 50k | 7 (4.9%) | 4 (6.6%) | 4 (4.8%) | |
| >50k – 100k | 44 (30.6%) | 21 (34.4%) | 22 (26.5%) | |
| >100k | 77 (53.5%) | 31 (50.8%) | 46 (55.4%) | |
| Unknown | 2 (1.4%) | 0 (0.0%) | 2 (2.4%) |
Fisher Exact Test
Some patients may have had multiple organisms on urine culture.
Staph Aureus (N = 3), Non-speciated Gram Negative (N = 2), Gardenerella Vaginalis (N = 1), Pseudomonas, (N = 1), Enterobacter (N = 1), Enterobacter Cloacae (N = 1), Streptococcus Anginosus (N = 1) and unknown (N = 2).
Imaging utilization and results are shown in Table 4. Nearly all patients (98.5%) underwent RBUS at the index encounter. Most patients (64.2%) were recommended to undergo, and 51.1% underwent, a voiding cystourethrography (VCUG) with higher rates in those <2-months-old, relative to those 2-to-24-months-old (Table 4). There were no differences in RBUS or VCUG results between age groups (Table 4). There was no difference between age groups for physician recommendation for antibiotic prophylaxis (62.7% [37/59] <2-months-old versus 50.0% [39/78] 2-to-24-months-old, p=0.191). There was a statistically significant difference between age groups in utilization of antibiotic prophylaxis at any time (54.2% [32/59] vs 35.9% [28/78], p=0.049). The median time on antibiotic prophylaxis was 54.5 days (IQR of 25.8–123, mean = 216.77, range = 2–1486). There was no difference between age groups in days on antibiotic prophylaxis (Median 56.5 days for those <2-months-old vs 51.5 days for those 2-to-24-months-old, p=0.926). Lastly, it was found that there was no statistically significant difference in 1-year antibiotic prophylaxis between age groups (8.5% [5/54] <2-months-old vs 2.6% [2/76] 2-to-24-months-old, p=0.14). All those on antibiotic prophylaxis for ≥1-year had VUR on VCUG (n=7).
Table 4.
Imaging Utilization and Results
| Total (N = 137) | <2-Months-Old (N = 59) | 2–24-Months-Old (N = 78) | P-Value | |
|---|---|---|---|---|
| Prenatal Ultrasound Obtaineda | 0.619 | |||
| Yes | 4 (3.9%) | 1 (2.0%) | 3 (5.6%) | |
| No | 99 (96.1%) | 48 (98.0%) | 51 (94.4%) | |
| Prenatal Ultrasound Resultsa | 0.438 | |||
| Abnormalc | 7 (7.1%) | 2 (4.2%) | 5 (9.8%) | |
| Normal | 92 (92.9%) | 46 (95.8%) | 46 (90.2%) | |
| RBUS Obtaineda | 1.000 | |||
| Yes | 135 (98.5%) | 58 (98.3%) | 77 (98.7%) | |
| No | 2 (1.5%) | 1 (1.7%) | 1 (1.3%) | |
| Hydronephrosis on RBUS | 0.511 | |||
| Yes | 83 (61.5%) | 38 (65.5%) | 45 (58.4%) | |
| No | 52 (38.5%) | 20 (34.5%) | 32 (41.6%) | |
| Hydronephrosis Laterality on RBUS | 0.289 | |||
| None | 52 (38.5%) | 20 (34.5%) | 32 (41.6%) | |
| Unilateral | 48 (35.6%) | 19 (32.8%) | 29 (37.7%) | |
| Bilateral | 35 (25.9%) | 19 (32.8%) | 16 (20.8%) | |
| Hydroureter Lateralitya | 0.254 | |||
| None | 119 (88.1%) | 54 (93.1%) | 65 (84.4%) | |
| Unilateral | 13 (9.6%) | 4 (6.9%) | 9 (11.7%) | |
| Bilateral | 3 (2.2%) | 0 (0.0%) | 3 (3.9%) | |
| Hydronephrosis Gradea,b | 0.692 | |||
| None | 52 (38.5%) | 20 (34.5%) | 32 (41.6%) | |
| Trace/Minimal | 25 (18.5%) | 12 (20.7%) | 13 (16.9%) | |
| Mild | 53 (39.3%) | 25 (43.1%) | 28 (36.4%) | |
| Moderate | 5 (3.7%) | 1 (1.7%) | 4 (5.2%) | |
| Severe | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | |
| VCUG Recommended | 0.017 | |||
| Yes | 88 (64.2%) | 45 (76.3%) | 43 (55.1%) | |
| No | 49 (35.8%) | 14 (23.7%) | 35 (44.9%) | |
| VCUG Obtained | 0.011 | |||
| Yes | 70 (51.1%) | 38 (64.4%) | 32 (41.0%) | |
| No | 67 (48.9%) | 21 (35.6%) | 46 (59.0%) | |
| VUR on VCUG | 1.000 | |||
| Yes | 16 (22.9%) | 9 (23.7%) | 7 (21.9%) | |
| No | 54 (77.1%) | 29 (76.3%) | 25 (78.1%) | |
| VUR Lateralitya | 0.921 | |||
| None | 54 (77.2%) | 29 (76.3%) | 25 (78.1%) | |
| Unilateral | 8 (11.4%) | 4 (10.5%) | 4 (12.5%) | |
| Bilateral | 8 (11.4%) | 5 (13.2%) | 3 (9.4%) | |
| VUR Gradea,b | 0.987 | |||
| None | 54 (77.1%) | 29 (76.3%) | 25 (78.1%) | |
| 1 | 1 (1.4%) | 0 (0.0%) | 1 (3.1%) | |
| 2 | 4 (5.7%) | 2 (5.3%) | 2 (6.3%) | |
| 3 | 5 (7.1%) | 3 (7.9%) | 2 (6.3%) | |
| 4 | 5 (7.1%) | 3 (7.9%) | 2 (6.3%) | |
| 5 | 1 (1.4%) | 1 (2.6%) | 0 (0.0%) |
Fisher Exact Test
Highest grading on either kidney was used as overall grade for hydronephrosis on RBUS and vesicoureteral reflux on VCUG.
Abnormal prenatal ultrasound results included: left hydronephrosis (n=1), bilateral hydronephrosis (L>R) (n=1), duplicate aortic arch (n=1), enlarged kidney (n=2), bilateral pelviectasis (n=1), and hepatosplenomegaly (n=1).
Interestingly, all circumcised boys (n=4) were in the <2-months-old age group, presented with their first fUTI, and had normal prenatal ultrasounds. All were recommended to undergo VCUG. One did not obtain a VCUG after a normal RBUS and this patient had a re-operative clamp circumcision, potentially indicating enough residual foreskin to maintain preputial colonization. Of the three with abnormal RBUS findings, one had possible prostatic utricle, one had mild hydronephrosis and hydroureter, and one child had left trace/minimal hydronephrosis. The boy with hydroureter on RBUS had an abnormal VCUG with grade 5 VUR on the right and grade 2 on the left.
Secondary Outcomes – Circumcision, UTI Recurrence, and Readmissions
Only 36.8% of males were recommended to undergo circumcision with no difference between age groups (35.7% for those <2-months-old vs 38.2% for those 2-to-24-months-old, p=1.00). However, those <2-months-old, relative to those 2-to-24-months-old, more frequently had a circumcision performed (19.0 vs 2.9%, p=0.04). One patient in the <2-months-old group and 2 patients in the 2-to-24-months old group had a ureteral reimplant (1.7 vs 2.6%, p=1.00). There was also no difference between age groups regarding UTI recurrence within 1 year (13.6 vs 14.1%, p=1.00), fUTI recurrence within 1 year (13.6 vs 7.7%, p=0.40), 90-day readmission (6.8 vs 6.4%, p=1.00), all-cause 90-day ED revisit (22.0 vs 20.5%, p=1.00), or UTI-related 90-day ED revisit (1.7% <2-months-old vs 2.6% 2-to-24-months-old, p=1.00).
Discussion
In this retrospective cohort study of children hospitalized for fUTI, we found that patients <2-months-old, relative to those 2-to-24-months-old, were more likely to be male, were less ill, and were more likely to receive a recommendation for and obtain a VCUG. Thus, our hypothesis of more aggressive testing in the younger age group was supported. There were no other differences between age groups related to demographics and clinical factors, laboratory, or imaging results. Contrary to our hypothesis, there were no differences between age groups in UTI or fUTI recurrence within 1-year, and there were no differences in 90-day all-cause readmission or 90-day all-cause ED revisit.
The demographic and clinical characteristics of patients <2-months-old are overall similar to prior studies of very young infants with fUTI, including the finding that those <2-months-old are less ill compared to those 2-to-24-months-old. Our study found no demographic differences between age groups, except patients <2-months-old were more often male. Similar to our findings, a prospective study of 388 patients, including 255 (65.7%) boys, found that those <2-months-old with an initial fUTI, compared to children 2-to-24-months-old, were also more likely to be boys—all of whom were uncircumcised—and patients in both age groups had similar clinical, microbial, and imaging characteristics[8]. Other studies also show a predominance of uncircumcised boys among younger infants with a UTI, similar to our cohort[2, 8, 9, 12–15]. Our study also found that those <2-months-old, relative to those 2-to-24-months-old, were more likely to have a lower maximum temperature and total fever duration and lower serum WBC count, all similar to other studies [8, 9]. Hsu et al. hypothesized that infants may be less ill at time of admission due to parents being more sensitive to fevers in younger infants[8], prompting quicker emergency care and thus more timely diagnosis and treatment. Additionally, at the time of this study, our institution was following published recommendations indicating that most infants <2-months-old seeking emergency care for fever should be hospitalized[16], which may contribute to younger infants being less ill overall.
Our results showed no difference between age groups regarding UA and urine culture results. It was once thought that UA was inaccurate for young infants secondary to rapid bladder emptying, inability to concentrate urine, and immature immune systems[17]. Therefore, those <2-months-old with a positive urine culture and negative UA were often treated for UTI. However, a recent prospective study showed that positive urinalysis (i.e., any LE, >5 WBC/HPF, or nitrite) for those ≤60-days old was highly predictive of UTI when CFUs/mL threshold was ≥50 000 (sensitivity and specificity of 0.94 [95%CI: 0.91–0.97] and 0.91 [95%CI: 0.90–0.91], respectively)[18]. Additionally, there was no difference in the results of that study between those ≤28 days versus those >29–60 days of age. After the CFUs/mL threshold was reduced to 10 000 for sensitivity analysis, results remained similar, though with a slightly lower sensitivity of 0.87 [95%CI: 0.83–0.90] when compared to the ≥50 000 CFUs/mL threshold. Our results show similar rate of positive UA between age groups, which support the recommendation from Chang et al. that UA results should be incorporated into the diagnoses of UTIs among infants <2-months-old[17]. Furthermore, in our study, most of the cohort had ≥50 000 CFUs/mL (84.1%) on urine culture and there were no differences in CFU counts between age groups. However, a cut-off point for CFUs/mL for a UTI has not been well defined in pediatric populations more broadly, with variations in cut-off points by urine collection methods and across international guidelines. E. Coli was the predominant organism in our study with no difference between age groups, which is consistent with multiple other studies[8, 9, 19]. There was also no difference between age groups in resistance patterns among those with E. Coli, which is a similar finding within the literature[8]. Overall, our findings suggest that the UA and urine culture results are similar between those <2-months-old and those 2-to-24-months-old. However, these data do not provide sufficient evidence on whether diagnostic criteria recommendations provided by the 2011 AAP Guidelines for diagnosis, i.e., CFU thresholds, are appropriate for either age group.
Our study determined that, relative to those 2-to-24-months-old, those <2-months-old had a greater likelihood of receiving a recommendation for and obtaining a VCUG, though ultrasonographic findings were similar between age groups, and those <2-months-old were not more likely to have higher grade reflux. Most patients in the full cohort had hydronephrosis on RBUS (61.5%). This abnormal finding rate is slightly higher, but similar compared to the existing range in the literature of around 19–55%[8, 20, 21]. Also, there were no differences between age groups in terms of RBUS results, similar to findings by prior studies[8].
In our study, 23.7% of patients <2-months-old were found to have VUR, which is within the range of reported VUR rates in existing literature (14–33.5%)[8, 9, 13, 15]. There was also no difference between age groups in differing grades (i.e., I-V) of VUR, which is supported by available data[8]. There was also no difference between age groups in presence of VUR on VCUG and existing literature on this topic provides conflicting findings. In support of our findings, one study found that there was no difference in incidence of VUR between those that were <1-month-old and those 1–24-months-old[9]. However, another study by Hsu et al. found those <2-months-old, relative to those 2-to-24-months-old, were more likely to have VUR on VCUG[8]. The entire cohort from the Hsu et al. study obtained a RBUS and VCUG, while only 51.1% of participants underwent VCUG in our study. The variation in results may be stemming from this discrepancy, and—in addition to this—that our cohort only focused on hospitalized patients. The AAP guidelines recommend not obtaining a routine VCUG for initial fUTI for those 2-to-24-months-old and it is believed that this “avoids, for the vast majority of febrile infants with UTIs, radiation exposure, expense, and discomfort.”[1] Currently, evidence is emerging that suggests that infants <2-months-old may not require more vigilance for VUR detection than those 2-to-24-months-old[17]. However, this evidence is far from definitive. It seems reasonable to apply the AAP recommendation for universal RBUS to children <2-months-old but the safety of applying the VCUG recommendation to those <2-months-old remains uncertain and requires additional research.
Overall, the fUTI and UTI recurrence rates within 1-year in our study were 10.2% and 13.9%, respectively, with no difference between age groups. Prior studies have reported a wide range of UTI recurrence (1–28%), and our findings are within this same range[15, 20, 22]. Additionally, it is common at our institution to start antibiotic prophylaxis before a VCUG is obtained, with results guiding further antibiotic utilization – those with VUR continue prophylaxis and those without VUR discontinue prophylaxis. Thus, the lack of difference between age groups in outcomes does not appear to be due to initial antibiotic utilization differences among groups.
Our study does have limitations that warrant mention. Findings from a single free-standing, tertiary-care, urban children’s hospital may not be generalizable to community hospitals, or the US national population. Only hospitalized patients were included, which likely confers an element of selection bias due to different admission criteria for those <2-months-old. This differential admission criteria may partly explain why the younger age group was less ill than the 2-to-24-months-old age group. UTI and fUTI recurrence rates could have been impacted by circumcision status, a possibility that is being explored more comprehensively in a complementary study at our hospital. Additionally, the sample size was small such that multivariable analyses were not able to be performed. Lastly, there was only one DMSA scan (0.72%) obtained among this cohort, so we were unable to determine incidence of renal scarring.
Conclusions
Overall, there was little variation between those <2-months-old and those 2-to-24-months-old hospitalized at our tertiary-care center with fUTI in demographic and clinical factors, laboratory (including microbial) or imaging results, and clinical outcomes, except for greater recommendations for and receipt of VCUG among the younger age group. Thus, our hypothesis that patients <2-months-old would have a lower threshold for testing was supported. These data support application of UA and urine culture diagnostic recommendations, and the recommendation of universal RBUS, from the AAP fUTI Guidelines to infants <2-months-old with an initial fUTI. However, the applicability of the Guideline VCUG recommendation to those <2-months-old requires further investigation.
Supplementary Material
Summary Table.
Clinical Factors and Imaging Utilization
| Total (N = 137) | <2-Months-Old (N = 59) | 2–24-Months-Old (N = 78) | P-Value | |
|---|---|---|---|---|
| Length-of-Stay (days)a Mean, Median [Range] | 4.04, 3 [1 – 21] | 4.9, 3 [1 – 14] | 3.2, 2, [1 – 21] | 0.007 |
| Fever Duration (days)a Mean, Median [Range] | 3.0, 2 [1 – 11] | 2, 2 [1 – 7] | 3.8, 3 [1 – 11] | <0.001 |
| Max T emp (F)a Mean, Median [Range] | 102.7, 102.6 [100.4 – 107] | 101.8, 101.8 [100.4 – 104.2] | 103.3, 103.2 [100.5 – 107] | <0.001 |
| Serum WBC (K/μL)a Mean, Median [Range] | 15.3, 14.1 [2.6 – 36.7] | 13.3, 12.2 [2.6 – 30.8] | 16.9, 16.2 [4.1 – 36.7] | 0.005 |
| Index VCUG Recommended by a Clinician | 0.017 | |||
| Yes | 88 (64.2%) | 45 (76.3%) | 43 (55.1%) | |
| No | 49 (35.8%) | 14 (23.7%) | 35 (44.9%) | |
| Index VCUG Obtained | 0.011 | |||
| Yes | 70 (51.1%) | 38 (64.4%) | 32 (41.0%) | |
| No | 67 (48.9%) | 21 (35.6%) | 46 (59.0%) |
Mann-Whitney U test
Funding:
This work was supported in part by research grants from the National Institute of Diabetes and Digestive and Kidney Diseases (K23 DK125670) to Dr. David I. Chu. The NIH and NIDDK had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. The views expressed in this article are those of the authors and do not necessarily represent the official view of the NIH or NIDDK.
Appendix A
Supplemental Table A.1.
Antibiotic Resistance Patterns
| Total (N = 137) | <2-Months-Old (N = 59) | 2–24-Months-Old (N = 78) | P-Value | |
|---|---|---|---|---|
| Ampicillin | 66 (48.2%) | 29 (49.2%) | 37 (47.4%) | 0.979 |
| Othera | 43 (31.4%) | 17 (28.8%) | 26 (33.3%) | 0.705 |
| Ampicillin/Sulbactam | 41 (29.9%) | 18 (30.5%) | 23 (29.5%) | 1.000 |
| Ancef | 35 (25.5%) | 13 (22.0%) | 22 (28.2%) | 0.534 |
| Bactrim | 32 (23.3%) | 16 (27.1%) | 16 (20.5%) | 0.483 |
| Ceftriaxoneb | 8 (5.8%) | 5 (8.5%) | 3 (3.8%) | 0.289 |
| Ciprob | 8 (5.8%) | 3 (5.1%) | 5 (6.4%) | 1.000 |
| Gentamicinb | 7 (5.1%) | 2 (3.4%) | 5 (6.4%) | 0.699 |
| Not Available | 11 (8.0%) | 3 (5.1%) | 8 (10.3%) | 0.350 |
Amoxicillin/K Clavanate (N = 10), Tobramycin (N = 9), Aztreonam (N = 9), Cefuroxime (N = 9), Ceftazidime (N = 8), Cefotaxime (N = 7), Cefepime (N = 7), Cephalothin (N = 7), Cefuroxime (Oral) (N = 6), Levofloxacin (N = 5), Cefoxitin (N = 6), Cefuroxime (Parenteral) (N = 3), Tetracycline (N = 3), Nitrofurantoin (N=3), Amoxicillin (N=3), Gentamicin (N = 2), Penicillin (N = 1), Rifampin (N = 1), Penicillin G (N = 1), Keflex (N=1), Tazo (N=1), Vancomycin (N=1), Amikacin (N=0), Omnicef (N=0), Cefixime (N=0), Clindamycin (N=0), Fluconazole (N=0).
Fisher Exact Test
Footnotes
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References
- [1].Roberts KB. Urinary tract infection: clinical practice guideline for the diagnosis and management of the initial UTI in febrile infants and children 2 to 24 months. Pediatrics. 2011;128:595–610. 10.1542/peds.2011-1330 [DOI] [PubMed] [Google Scholar]
- [2].Shaikh N, Morone NE, Bost JE, Farrell MH. Prevalence of urinary tract infection in childhood: a meta-analysis. The Pediatric infectious disease journal. 2008;27:302–8. 10.1097/INF.0b013e31815e4122 [DOI] [PubMed] [Google Scholar]
- [3].Stefanidis CJ, Siomou E. Imaging strategies for vesicoureteral reflux diagnosis. Pediatric nephrology (Berlin, West). 2007;22:937–47. 10.1007/s00467-006-0396-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
- [4].Rushton HG. The evaluation of acute pyelonephritis and renal scarring with technetium 99m-dimercaptosuccinic acid renal scintigraphy: evolving concepts and future directions. Pediatric nephrology (Berlin, West). 1997;11:108–20. 10.1007/s004670050243 [DOI] [PubMed] [Google Scholar]
- [5].Karavanaki KA, Soldatou A, Koufadaki AM, Tsentidis C, Haliotis FA, Stefanidis CJ. Delayed treatment of the first febrile urinary tract infection in early childhood increased the risk of renal scarring. Acta Paediatrica. 2017;106:149–54. 10.1111/apa.13636 [DOI] [PubMed] [Google Scholar]
- [6].Keren R, Shaikh N, Pohl H, Gravens-Mueller L, Ivanova A, Zaoutis L, et al. Risk Factors for Recurrent Urinary Tract Infection and Renal Scarring. Pediatrics. 2015;136:e13–21. 10.1542/peds.2015-0409 [DOI] [PMC free article] [PubMed] [Google Scholar]
- [7].Pecile P, Miorin E, Romanello C, Vidal E, Contardo M, Valent F, et al. Age-Related Renal Parenchymal Lesions in Children With First Febrile Urinary Tract Infections. Pediatrics (Evanston). 2009;124:23–9. 10.1542/peds.2008-1192 [DOI] [PubMed] [Google Scholar]
- [8].Hsu C-C, Tsai J-D, Ku M-S, Chen S-M, Liao P-F, Hung T-W, et al. Antimicrobial Resistance and Diagnostic Imaging in Infants Younger Than 2 Months Old Hospitalized with a First Febrile Urinary Tract Infection: A Population-based Comparative Study. The Pediatric infectious disease journal. 2016;35:840–5. 10.1097/INF.0000000000001184 [DOI] [PubMed] [Google Scholar]
- [9].Kanellopoulos TA, Salakos C, Spiliopoulou I, Ellina A, Nikolakopoulou NM, Papanastasiou DA. First urinary tract infection in neonates, infants and young children: a comparative study. Pediatric nephrology (Berlin, West). 2006;21:1131–7. 10.1007/s00467-006-0158-7 [DOI] [PubMed] [Google Scholar]
- [10].R Core Team. R: A language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing; 2021. [Google Scholar]
- [11].RStudio Team. RStudio: Integrated Development Environment for R. 2021.9.0.351 ed. Boston, MA: RStudio, PBC; 2021. [Google Scholar]
- [12].Arshad M, Seed PC. Urinary tract infections in the infant. Clinics in perinatology. 2015;42:17–28, vii. 10.1016/j.clp.2014.10.003 [DOI] [PMC free article] [PubMed] [Google Scholar]
- [13].Tsai JD, Huang CT, Lin PY, Chang JH, Lee MD, Huang FY, et al. Screening high-grade vesicoureteral reflux in young infants with a febrile urinary tract infection. Pediatric nephrology (Berlin, Germany). 2012;27:955–63. 10.1007/s00467-012-2104-1 [DOI] [PubMed] [Google Scholar]
- [14].Bachur R, Harper MB. Reliability of the urinalysis for predicting urinary tract infections in young febrile children. Archives of pediatrics & adolescent medicine. 2001;155:60–5. 10.1001/archpedi.155.1.60 [DOI] [PubMed] [Google Scholar]
- [15].Vachharajani A, Vricella GJ, Najaf T, Coplen DE. Prevalence of upper urinary tract anomalies in hospitalized premature infants with urinary tract infection. Journal of perinatology. 2015;35:362–6. 10.1038/jp.2014.209 [DOI] [PubMed] [Google Scholar]
- [16].Pantell RH, Roberts KB, Adams WG, Dreyer BP, Kuppermann N, O’Leary ST, et al. Evaluation and Management of Well-Appearing Febrile Infants 8 to 60 Days Old. Pediatrics. 2021;148. 10.1542/peds.2021-052228 [DOI] [PubMed] [Google Scholar]
- [17].Chang PW, Wang ME, Schroeder AR. Diagnosis and Management of UTI in Febrile Infants Age 0–2 Months: Applicability of the AAP Guideline. Journal of hospital medicine. 2020;15:e1–e5. 10.12788/jhm.3349 [DOI] [PubMed] [Google Scholar]
- [18].Tzimenatos L, Mahajan P, Dayan PS, Vitale M, Linakis JG, Blumberg S, et al. Accuracy of the Urinalysis for Urinary Tract Infections in Febrile Infants 60 Days and Younger. Pediatrics. 2018;141. 10.1542/peds.2017-3068 [DOI] [PMC free article] [PubMed] [Google Scholar]
- [19].Tanaka Y, Oishi T, Ono S, Kono M, Kato A, Miyata I, et al. Epidemiology of urinary tract infections in children: Causative bacteria and antimicrobial therapy. Pediatrics international : official journal of the Japan Pediatric Society. 2021;63:1198–204. 10.1111/ped.14639 [DOI] [PubMed] [Google Scholar]
- [20].Wang SF, Huang FY, Chiu NC, Tsai TC, Ho UY, Kao HA, et al. Urinary tract infection in infants less than 2 months of age. Zhonghua Minguo xiao er ke yi xue hui za zhi [Journal] Zhonghua Minguo xiao er ke yi xue hui. 1994;35:294–300. [PubMed] [Google Scholar]
- [21].Bahat H, Ben-Ari M, Ziv-Baran T, Neheman A, Youngster I, Goldman MJPN. Predictors of grade 3–5 vesicoureteral reflux in infants≤ 2 months of age with pyelonephritis. 2019;34:907–15. [DOI] [PubMed] [Google Scholar]
- [22].Biyikli NK, Alpay H, Ozek E, Akman I, Bilgen H. Neonatal urinary tract infections: Analysis of the patients and recurrences. Pediatrics international. 2004;46:21–5. 10.1111/j.1442-200X.2004.01837.x [DOI] [PubMed] [Google Scholar]
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