Accepted Article
Received Date : 20-Jan-2014 Revised Date : 21-Apr-2014 Accepted Date : 23-May-2014 Article type
: Regular Article
Clinical and laboratory indices of severe renal lesions in children with febrile urinary tract infection
Koufadaki AM1, Karavanaki KA1, Soldatou A1, Tsentidis Ch1, Sourani MP2, Sdogou T1, Haliotis FA2, Stefanidis CJ 3.
1
Second Department of Pediatrics, University of Athens, “P. & A. Kyriakou” Children’s
Hospital, Athens, Greece. 2
Second Department of Pediatrics, “Aghia Sophia” Children’s Hospital, Athens, Greece,
3
Department of Pediatric Nephrology, “P. & A. Kyriakou” Children’s Hospital, Athens,
Greece.
Address for correspondence: Kyriaki Karavanaki, MD, PhD, Associate Professor in Pediatrics Second University Department of Pediatrics, “P. & A. Kyriakou” Children’s Hospital Goudi 11527, Athens, Greece Tel: +30-210-7726488; Fax: +30-210-777-4383 e-mail: [email protected]
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/apa.12706 This article is protected by copyright. All rights reserved.
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Abstract: Aim: To evaluate the predictive value of various clinical and laboratory parameters on the identification of acute extensive and/or multifocal renal involvement in children with febrile UTI. Methods: The medical records of 148 children (median age:2.4 months,range:11 days24 months), who were admitted during a three year-period with a first episode of febrile UTI, were analyzed. Acute dimercaptosuccinic acid (DMSA) scintigraphy, clinical and laboratory parameters were evaluated. Results: Seventy six children (51%) had abnormal findings on the acute DMSA. Of them, 20 had DMSA grade 2, while 56 had grade 3 and 4. Patients with a DMSA grade 3 and 4 were more likely to have shivering (OR 3.4), WBC ≥ 18,000/μL (OR 2.4), absolute neutrophil count (ANC) ≥ 9,300/μL (OR 4.4), CRP ≥ 50mg/L (OR 2.7) and PCT ≥ 1.64 ng/ml (OR diagnostic). There was a significant difference of WBC (p=0.004), ANC, CRP and PCT levels (P105 colony forming units/ml for midstream clean-catch collection, >104 for catheterization, >103 for suprapubic collection) (9, 12). Children who had received antibiotics prior to admission and those without an aDMSA were excluded from the study. Finally, 148 children met the study criteria (Figure 1). Detailed medical history, physical examination and laboratory data were obtained from all children. Clinical features such as shivering, sleepiness, irritability, vomiting and diarrhea were recorded and analyzed. Laboratory indices including white blood count (WBC), absolute neutrophil count (ANC), C-reactive protein (CRP) and procalcitonin (PCT) levels were measured on admission and two days after treatment initiation. A whole blood autoanalyser (CellTac a, Nihon Kohden Corporation, Tokyo, Japan) was used for the estimation of WBC and ANC. The serum concentration of CRP was measured by particle-enhanced immunonephelometric assays (BN ProSpect nephelometer, Dade Behring, Liederbach,Germany) and PCT levels (Brahms Diagnostica, Berlin, Germany) were measured by chemiluminescence on the LIAISON® random access analyser (DiaSorin, Saluggia, Italy). Antibiotic treatment was given a) intravenously, b) initially intravenously and completed orally, or c) exclusively orally for 7-14 days depending on patients’ age, clinical condition and bacterial susceptibility.
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All patients underwent renal ultrasonography within the first 5 days of admission. An US was considered abnormal according to the criteria of Jakobsson B et al. (13). Voiding cystourethrogram (VCUG) for the detection of vesicouretal reflux (VUR) was performed within one month. VUR was classified according to the international grading system (14). Renal involvement was assessed with aDMSA within the first 10 days of infection by investigators who were blinded to laboratory markers and clinical information. Both acute and follow-up DMSA findings were graded as follows; grade 1: absence of lesion, grade 2: mild (defect only in one kidney), grade 3: moderate (defect in one or both kidneys), grade 4: severe renal parenchymal lesions (in both kidneys). The primary outcome of the study was the presence of moderate or severe renal lesions (defined as ≥3rd grade) on aDMSA. If the aDMSA was abnormal, a follow-up scan was obtained 6 months to one year later.
Statistical methods STATA for Windows v 8.5, (StataCorp, Texas, USA, 2006) was used for data management and statistical analyses. All data were expressed as median (range) in numerical variables and as proportions in categorical variables. Group numerical data were compared using non parametric Mann-Whitney U test (independent samples) and categorical data were compared using Fisher’s exact test. P0.5 ng/ml were considered abnormal, based on the analysis of different cut-off levels (0.5, 0.8, 1 ng/mL) of a previous study (5). The smaller value of PCT in children with severe acute pyelonephritis (DMSA grade ≥3 findings) was 1.64 ng/ml and this value was selected to dichotomize PCT. For ANC, CRP, and
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WBC the values with the optimal combination of sensitivity and specificity were selected after performing sensitivity analysis using ROC curves.
Results The study included 148 children with a first episode of febrile UTI, with a median age of 2.4 months (range:11 days-24 months). The gender distribution was 54 boys (36.5%) and 94 girls (63.5%). Urine cultures were collected by suprapubic aspiration (n=106), catheterization (n=22) and “midstream clean-catches” (n=20). The most frequently identified pathogen was Escherichia coli (n=130, 87.8%), followed by Klebsiella (n=5, 3.4%), Proteus (7, 4.7%) Enterobacter (n=4, 2.7%), and Pseudomonas (n=2, 1.35%). Thirty patients (20.3%) had VUR; 9 (6.1%) grade 1 and 2 and 21 (14.2%) grade 3 and 4. Renal ultrasound was abnormal in 43 patients (29.9%). Acute DMSA was abnormal in 76 patients (51.4%). Lesions grade 2 were found in 20 (13.5%), grade 3 in 48 (32.4%) and grade 4 in 8 children (5.4%). In total, 92 patients (62.2%) had aDMSA grade 1 and 2, while 56 (37.8%) had grade 3 and 4.
In table 1 the characteristics of patients with aDMSA grade 3 and 4 are compared with grade 1 and 2. It was observed that children with aDMSA grade 3 and 4 tended to have shivering more frequently (16.3%) compared to those with aDMSA grade 1 and 2 (5.4%) (p=0.057), although the difference was not statistically significant. However, the number of children with shivering was significantly higher in the group with renal lesions on aDMSA scan compared to those with normal aDMSA [9/63 (14.28%) vs 2/54 (3.7%), p=0.047, Fisher’s exact test]. There was a significant difference of WBC (p=0.004), ANC, PCT and CRP levels (P 1.0 ng/ml. Table 3 shows the selected cut-off values for laboratory parameters with their best combination of sensitivity and specificity, as derived from sensitivity analysis using ROC curves. WBC > 18,000 had 50.0% sensitivity and 70.9% specificity for the prediction of aDMSA grade 3 and 4 lesions ≥ 3. PCT had the highest sensitivity and specificity (100%) at the cut-off level of 1.64 ng/ml. CRP at the cut-off level of 50 mg/dl had lower sensitivity (49.3%) and specificity (73.3%) than PCT for the prediction of aDMSA grade 3 and 4 lesions. Comparing the CRP and PCT ROC curves at the cut-off levels of CRP ≥ 50 mg/L and PCT ≥ 1.64 ng/ml (AUC 0.651 vs. 1.0 respectively) it was found that PCT is a more reliable marker than CRP for the prediction of severe acute renal lesions. Figure 2 shows the sensitivity analyses of each numerical laboratory parameter in the prediction of severe acute pyelonephritis (grade ≥ 3). Table 4 shows the follow-up DMSA scanning in relation to acute DMSA lesions. It is observed that 6/10 (60%) of the children with aDMSA grade 2 lesions had a normal DMSA at follow-up, in comparison with only 10/40 (25%) of those with aDMSA grade >/3 (p=0.043, Fisher’s exact test). It is noteworthy that all these 10 patients had aDMSA grade 3 lesions, while none of those with aDMSA grade 4 lesions had normal follow-up DMSA. However, the number of patients with aDMSA grade 2 was rather small to draw safe conclusions.
Discussion In the present study clinical features and inflammatory indices in children with febrile UTI were evaluated, in order to help clinicians discern which patients are at high risk of severe acute renal involvement. There are only a handful of previous studies on this topic (7,8,9,15). The novelty of the present study lies on the assessment of clinical and laboratory factors potentially predictive of the development of moderate or severe renal lesions in aDMSA. In addition, we included patients younger than two years, in This article is protected by copyright. All rights reserved.
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compliance with recent clinical practice guidelines (16, 17). The limitation of this study is its retrospective nature. In our study, we assume that the percentage of infants with asymptomatic bacteriuria, i.e. bacteriuria and fever due to an unrelated viral infection (18), is limited since only 13 of the 148 children had coexisting symptoms of a viral-like infection. Although clean-catch urine collection has been advocated as an appropriate collection method in the NICE guideline (19) and recent Italian recommendations (20), in order to eliminate the risk of contamination with faecal bacteria (21), the majority of the cultures in our study were collected by suprapubic inspiration (71.6%) and catheterization (14.9%); only 13.5% of the specimens were clean catch collections, performed immediately after cleansing of the perineum (22).
Among several common symptoms associated with febrile UTI in our study population, shivering was the only clinical sign predictive (OR=4.3) of acute renal lesions. To the best of our knowledge this is the first study to highlight the importance of shivering as a predictor of acute renal involvement. In our study population parental report of shivering correlated well with the presence of serious illness with renal lesions, and was not influenced by other confounding factors (patients’ age, duration of fever, frequency of prolonged fever). In our population, WBC ≥ 18,000/μL and ANC ≥ 9,300/μL were significant risk factors for the development of acute extensive and/or multifocal DMSA lesions. Moreover WBC and ANC values were significantly higher in the group with moderate and severe versus mild aDMSA renal lesions . Different cut-off levels of WBC, ranging from 13,500 to 19,000/μL, have been proposed as predictive of the development of acute DMSA lesions (7, 8, 9, 15), probably reflecting different age-ranges (23). All previous studies agree on the ANC cut-off levels of >9,000/μL (10, 24), however cut-off levels were not correlated to the severity of renal lesions. In the present study, both PCT and CRP increased according to the severity of renal lesions. In addition, PCT could differentiate the group with severe from that with mild renal lesions, as there is no overlap of PCT levels between the groups with different degrees of severity of aDMSA lesions. Thus, PCT is a reliable marker of the presence of acute pyelonephritis and a predictor of the severity of renal lesions.
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Previous studies also report that PCT is superior to CRP as an indicator of acute renal involvement (5,8,15,24,25), that its levels are markedly higher in the group with moderate/severe versus mild aDMSA renal lesions (8,25) and is able to differentiate between totally and partially reversible renal lesions (5). Apart from infection, PCT levels have been correlated with the extent of tissue injury in patients with trauma (26). This observation might explain why PCT in our study was markedly increased in the group with severe renal lesions. In our study, the PPVs of PCT and CRP were 100% and 64.29% for the specific cut-off values mentioned above, while their NPVs were 100% and 59.78% respectively. PCT has been proven to be a more reliable marker than CRP, because high PCT levels on admission are predictive of the development of renal lesions, whereas high levels of CRP are not. Inversely, both inflammatory markers are useful for the exclusion of pyelonephritis because low levels on admission indicate low risk of long-term renal lesions.
Different cut-off levels for PCT have been suggested as markers of the development of acute renal lesions, ranging from 0.5-2.0 ng/ml (5, 8, 15, 25, 26, 27), most agreeing on cut-off levels of 0.8-1 ng/ml (5, 8, 15). In the present study PCT values ≥ 1.64 ng/ml were predictive of severe renal lesions. In a previous study we have shown that PCT levels above 1 ng/ml were predictive of acute renal involvement (5). This is the first time that a cut-off level of PCT for severe renal involvement is proposed. Leroy et al in a meta-analysis on the role of PCT in children with febrile UTI concluded that algorithms for the identification of children at high risk of acute pyelonephritis should be built, in order to limit early DMSA (11). Our data indicate that PCT levels on admission could be incorporated in proper algorithms to predict the presence and the severity of renal lesions in acute pyelonephritis, since it is an excellent marker of acute kidney involvement.
The primary outcome of this study was to evaluate the predictive value of various clinical and laboratory parameters on the identification of extensive and/or multifocal pyelonephritis. Children with aDMSA grade ≥ 3 developed renal scars at the followup DMSA significantly more frequently, compared to those with aDMSA grade 2 renal lesions. Therefore, the prediction of moderate and severe lesions in aDMSA by clinical and laboratory indices is important for late renal sequelae. This article is protected by copyright. All rights reserved.
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Conclusions Clinical signs and laboratory markers can be used as predictors of renal involvement documented by acute DMSA scanning in children under two years old with a first episode of febrile UTI. Children who present with shivering are more likely to have moderate to severe renal lesions of one or both kidneys. PCT levels ≥ 1.64 ng/ml, CRP ≥ 50 mg/L, WBC ≥ 18000/μL and/or ANC ≥ 9300/μL might predict the presence of moderate and severe renal lesions. Moreover our data confirm that PCT is superior to CRP as an indicator of acute renal involvement as it could differentiate the group with severe renal lesions.
References: 1.
Smellie JM, Prescod NP, Shaw PJ, Risdon RA, Bryant TN. Childhood reflux
and urinary infection:a follow-up of 10-41 years in 226 adults. Pediatr Nephrol 1998; 12:727. 2.
Zorc JJ, Kiddoo DA, Shaw KN. Diagnosis and management of pediatric
urinary tract infections. Clin Microbiol Rev 2005;18:417. 3.
Shaikh N, Ewing AL, Bhatnagar S, Hoberman A. Risk of renal scarring in
children with first urinary tract infection:a systematic review. Pediatrics 2010; 126(6): 1084-91. 4.
Majd M, Rushton HG. Renal cortical scintigraphy in the diagnosis of acute
pyelonephritis. Semin Nucl Med 1992; 22(2):98-111. 5.
Karavanaki K, Haliotis A, Sourani M, Kariyiannis C, Hantzi E, Zachariadou L
et al. DMSA scintigraphy in febrile urinary tract infections could be omitted in children with low procalcitonin levels. Inf Dis Clin Pract 2007; 15(6):377-381. 6.
Montini G, Zucchetta P, Tomasi L, Talenti E, Rigamonti W, Picco G, et al.
Value of imaging studies after a first febrile urinary tract infection in young children:data from Italian renal study 1.Pediatrics 2009; 123 (2): e 239-246. 7.
Gilani KA, Esfeh JM, Gholamrezanezhad A, Gholami A, Mamishi S,
Eftekhari M, et al. Predictors of abnormal renal cortical scintigraphy in children with
This article is protected by copyright. All rights reserved.
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first urinary tract infection: the importance of time factor. Int Urol Nephrol 2010; 42: 1041-1047. 8.
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 2009; 124;23-29. 9.
Fernandez-Menendez JM, Malaga S, Matezans JL, Solis G, Alonso S, Perez-
Mendez C et al. Risk factors in the development of early technetium-99m dimercaptosuccinic acid renal scintigraphy lesions during first urinary tract infection in children. Acta Paediatr 2003; 92:21-26. 10.
Donoso RG, Lobo SG, Arnello VF, Arteaga VMP, Coll CC, Hevia JP, et al.
Renal scars after one year of follow up in children with a first episode of acute pyelonephritis. Rev Med Chil. 2006; 134(3): 305-311. 11.
29.
Leroy S, Fernandez-Lopez A, Nikfar R, Romanello C, Bouissou F,
Gervaix A, et al. Association of procalcitonin with acute pyelonephritis and renal scars in pediatric UTI. Pediatrics 2013;131(5):870-9 12.
Practice parameter: the diagnosis, treatment, and evaluation of the initial
urinary tract infection in febrile infants and young children. American Academy of Pediatrics, Committee on Quality improvement. Subcommittee on Urinary Tract Infection. Pediatrics, 1999 Apr; 103 (4 Pt 1): 843-52 13.
Birgir Jakobsson, Lennart Nolstedt, Leif Svensson, Stefan Soderlundh and
Ulla Berg. 99m Technetium-dimercaptosuccinic acid scan in the diagnosis of acute pyelonephritis in children: relation to clinical and radiological findings. Pediatr Nephrol (1992)6: 328-334 14.
Lebowitz RL, Olbing H, Parkkulainen KV, Smellie JM, Tamminen – Mobius
TE. International system of radiographic grading of vesicoureteric reflux. International Reflux Study in Children.Pediatr Radiol 1985;15(2):105-9 15.
Kotoula A, Gardikis S, Tsalkidis A, Mantadakis E, Zissimopoulos A,
Kambouri K, et al.
Procalcitonin for the early prediction of renal parenchymal
involvement in children with UTI: preliminary results. Int Urol Nephrol. 2009; 41(2):393-399. This article is protected by copyright. All rights reserved.
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16.
American Academy of Pediatrics. 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 September 2011;128 (3):595-611. 17.
Dorien H. F. Geurts & Willem Vos & Henriette A. Moll & Rianne
Oostenbrink. Impact analysis of an evidence-based guideline on diagnosis of urinary tract infection in infants and young children with unexplained fever. Eur J Pediatr (2014) 173:463–468. 18.
Kjell Tullus. Difficulties in diagnosing urinary tract infections in small
children. Pediatr Nephrol. 2011; 26:1923-1926. 19.
National Institute for Health and Clinical Excellence. Urinary Tract Infection
In Children: Diagnosis, Treatment and Long Term Management. Clinical Guideline no.54,2007. Available from:http://www.nice.org.uk/CG54 [accessed March 2012]. 20.
Ammenti A, Cataldi L, Chimenz R, Fanos V et al. Febrile urinary tract
infections in young children: recommendations for the diagnosis, treatment and follow-up. Acta Paediatr. 2012 May;101 (5):451-7. 21.
Etoubleau C, Reveret M, Brouet D, Badier I, Brosset P, Fourcade L, et al.
Moving from bag to catheter for urine collection in non-toilet-trained children suspected of having urinary tract infection: a paired comparison of urine cultures. J Pediatr 2009;154:803–806. 22.
Pryles CV, Luders D, Alkan MK. A comparative study of bacterial cultures
and colony counts in aired specimens of urine obtained by catheter versus voiding from normal infants and infants with urinary tract infection. Pediatrics 1961; 27: 1728 23.
Hulstaert F, Hannet I, Deneys V, Munhyeshuli V, Reichert T, DeBruyere M,
et al. Age-related changes in human blood lymphocyte subpopulations. II. Varyring kinetics of
percentage
and absolute
count
measurements.
Clin Immunol
Immunopathol 1994; 70(2): 152-158. 24.
Benador N, Siegrist CA, Gendrel D, Greder C, Benador D, Assicot M, et al.
Procalcitonin is a marker of severity of renal lesions in pyelonephritis. Pediatrics 1998; 102(6):1422-1425 This article is protected by copyright. All rights reserved.
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25.
Prat C, Dominguez J, Rodrigo C, Gimenez M, Azuara M Jiménez O, et al.
Elevated serum procalcitonin values correlate with renal scarring in children with urinary tract infection. Pediatr Infect Dis J 2003;22(5):438-442. 26.
Shahangian S, Ash KO, Wahlstrom NO Jr, Warden GD, Saffle JR, Taylor A
Jr, et al. Creatinine kinase and lactate dehydrogenase isoenzymes in serum of patients suffering burns, blunt trauma or myocardial infarction. Clin Chem 1984;30:1332– 1338. 27.
Ng PC. Diagnostic markers of infection in neonates. Arch Dis Child Fetal
Neotatal Ed 2004; 89: F229-235.
Table 1: Descriptive characteristics of clinical and laboratory parameters on admission in predictive of moderate/severe acute renal lesions. DMSA score
1 and 2 (n=92)
3 and 4 (n=56)
Median (range)
Median (range)
3.0
4.0
(0.5-24.0)
(0.3-24.0)
48.0
72.0
fever (hours)
(3.0-180.0)
(6.0-180.0)
Prolonged fever
6/92(6.52%)
7/56(12.5%)
0.84**
Shivering
4/74(5.4%)
7/43(16.3%)
0.057*
15,300
18,900
0.001*
(2,300-31,700)
(2,600-38,100)
7,134
11,200
(500-26,311)
(119.9-23,638)
44.0
105.0
(0.3-202.0)
(5.0-336.0)
0.40
9.58
(0.10-8.25)
(4.0-28.68)
Age (months)
Total duration of
WBC (/μL)
ANC (/μL)
CRP (mg/L)
PCT (ng/ml)
Prolonged fever: Duration of fever ≥3 days after treatment initiation
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P value
0.991*
0.438*
Received Date : 20-Jan-2014 Revised Date : 21-Apr-2014 Accepted Date : 23-May-2014 Article type
: Regular Article
Clinical and laboratory indices of severe renal lesions in children with febrile urinary tract infection
Koufadaki AM1, Karavanaki KA1, Soldatou A1, Tsentidis Ch1, Sourani MP2, Sdogou T1, Haliotis FA2, Stefanidis CJ 3.
1
Second Department of Pediatrics, University of Athens, “P. & A. Kyriakou” Children’s
Hospital, Athens, Greece. 2
Second Department of Pediatrics, “Aghia Sophia” Children’s Hospital, Athens, Greece,
3
Department of Pediatric Nephrology, “P. & A. Kyriakou” Children’s Hospital, Athens,
Greece.
Address for correspondence: Kyriaki Karavanaki, MD, PhD, Associate Professor in Pediatrics Second University Department of Pediatrics, “P. & A. Kyriakou” Children’s Hospital Goudi 11527, Athens, Greece Tel: +30-210-7726488; Fax: +30-210-777-4383 e-mail: [email protected]
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/apa.12706 This article is protected by copyright. All rights reserved.
Accepted Article
Abstract: Aim: To evaluate the predictive value of various clinical and laboratory parameters on the identification of acute extensive and/or multifocal renal involvement in children with febrile UTI. Methods: The medical records of 148 children (median age:2.4 months,range:11 days24 months), who were admitted during a three year-period with a first episode of febrile UTI, were analyzed. Acute dimercaptosuccinic acid (DMSA) scintigraphy, clinical and laboratory parameters were evaluated. Results: Seventy six children (51%) had abnormal findings on the acute DMSA. Of them, 20 had DMSA grade 2, while 56 had grade 3 and 4. Patients with a DMSA grade 3 and 4 were more likely to have shivering (OR 3.4), WBC ≥ 18,000/μL (OR 2.4), absolute neutrophil count (ANC) ≥ 9,300/μL (OR 4.4), CRP ≥ 50mg/L (OR 2.7) and PCT ≥ 1.64 ng/ml (OR diagnostic). There was a significant difference of WBC (p=0.004), ANC, CRP and PCT levels (P105 colony forming units/ml for midstream clean-catch collection, >104 for catheterization, >103 for suprapubic collection) (9, 12). Children who had received antibiotics prior to admission and those without an aDMSA were excluded from the study. Finally, 148 children met the study criteria (Figure 1). Detailed medical history, physical examination and laboratory data were obtained from all children. Clinical features such as shivering, sleepiness, irritability, vomiting and diarrhea were recorded and analyzed. Laboratory indices including white blood count (WBC), absolute neutrophil count (ANC), C-reactive protein (CRP) and procalcitonin (PCT) levels were measured on admission and two days after treatment initiation. A whole blood autoanalyser (CellTac a, Nihon Kohden Corporation, Tokyo, Japan) was used for the estimation of WBC and ANC. The serum concentration of CRP was measured by particle-enhanced immunonephelometric assays (BN ProSpect nephelometer, Dade Behring, Liederbach,Germany) and PCT levels (Brahms Diagnostica, Berlin, Germany) were measured by chemiluminescence on the LIAISON® random access analyser (DiaSorin, Saluggia, Italy). Antibiotic treatment was given a) intravenously, b) initially intravenously and completed orally, or c) exclusively orally for 7-14 days depending on patients’ age, clinical condition and bacterial susceptibility.
This article is protected by copyright. All rights reserved.
Accepted Article
All patients underwent renal ultrasonography within the first 5 days of admission. An US was considered abnormal according to the criteria of Jakobsson B et al. (13). Voiding cystourethrogram (VCUG) for the detection of vesicouretal reflux (VUR) was performed within one month. VUR was classified according to the international grading system (14). Renal involvement was assessed with aDMSA within the first 10 days of infection by investigators who were blinded to laboratory markers and clinical information. Both acute and follow-up DMSA findings were graded as follows; grade 1: absence of lesion, grade 2: mild (defect only in one kidney), grade 3: moderate (defect in one or both kidneys), grade 4: severe renal parenchymal lesions (in both kidneys). The primary outcome of the study was the presence of moderate or severe renal lesions (defined as ≥3rd grade) on aDMSA. If the aDMSA was abnormal, a follow-up scan was obtained 6 months to one year later.
Statistical methods STATA for Windows v 8.5, (StataCorp, Texas, USA, 2006) was used for data management and statistical analyses. All data were expressed as median (range) in numerical variables and as proportions in categorical variables. Group numerical data were compared using non parametric Mann-Whitney U test (independent samples) and categorical data were compared using Fisher’s exact test. P0.5 ng/ml were considered abnormal, based on the analysis of different cut-off levels (0.5, 0.8, 1 ng/mL) of a previous study (5). The smaller value of PCT in children with severe acute pyelonephritis (DMSA grade ≥3 findings) was 1.64 ng/ml and this value was selected to dichotomize PCT. For ANC, CRP, and
This article is protected by copyright. All rights reserved.
Accepted Article
WBC the values with the optimal combination of sensitivity and specificity were selected after performing sensitivity analysis using ROC curves.
Results The study included 148 children with a first episode of febrile UTI, with a median age of 2.4 months (range:11 days-24 months). The gender distribution was 54 boys (36.5%) and 94 girls (63.5%). Urine cultures were collected by suprapubic aspiration (n=106), catheterization (n=22) and “midstream clean-catches” (n=20). The most frequently identified pathogen was Escherichia coli (n=130, 87.8%), followed by Klebsiella (n=5, 3.4%), Proteus (7, 4.7%) Enterobacter (n=4, 2.7%), and Pseudomonas (n=2, 1.35%). Thirty patients (20.3%) had VUR; 9 (6.1%) grade 1 and 2 and 21 (14.2%) grade 3 and 4. Renal ultrasound was abnormal in 43 patients (29.9%). Acute DMSA was abnormal in 76 patients (51.4%). Lesions grade 2 were found in 20 (13.5%), grade 3 in 48 (32.4%) and grade 4 in 8 children (5.4%). In total, 92 patients (62.2%) had aDMSA grade 1 and 2, while 56 (37.8%) had grade 3 and 4.
In table 1 the characteristics of patients with aDMSA grade 3 and 4 are compared with grade 1 and 2. It was observed that children with aDMSA grade 3 and 4 tended to have shivering more frequently (16.3%) compared to those with aDMSA grade 1 and 2 (5.4%) (p=0.057), although the difference was not statistically significant. However, the number of children with shivering was significantly higher in the group with renal lesions on aDMSA scan compared to those with normal aDMSA [9/63 (14.28%) vs 2/54 (3.7%), p=0.047, Fisher’s exact test]. There was a significant difference of WBC (p=0.004), ANC, PCT and CRP levels (P 1.0 ng/ml. Table 3 shows the selected cut-off values for laboratory parameters with their best combination of sensitivity and specificity, as derived from sensitivity analysis using ROC curves. WBC > 18,000 had 50.0% sensitivity and 70.9% specificity for the prediction of aDMSA grade 3 and 4 lesions ≥ 3. PCT had the highest sensitivity and specificity (100%) at the cut-off level of 1.64 ng/ml. CRP at the cut-off level of 50 mg/dl had lower sensitivity (49.3%) and specificity (73.3%) than PCT for the prediction of aDMSA grade 3 and 4 lesions. Comparing the CRP and PCT ROC curves at the cut-off levels of CRP ≥ 50 mg/L and PCT ≥ 1.64 ng/ml (AUC 0.651 vs. 1.0 respectively) it was found that PCT is a more reliable marker than CRP for the prediction of severe acute renal lesions. Figure 2 shows the sensitivity analyses of each numerical laboratory parameter in the prediction of severe acute pyelonephritis (grade ≥ 3). Table 4 shows the follow-up DMSA scanning in relation to acute DMSA lesions. It is observed that 6/10 (60%) of the children with aDMSA grade 2 lesions had a normal DMSA at follow-up, in comparison with only 10/40 (25%) of those with aDMSA grade >/3 (p=0.043, Fisher’s exact test). It is noteworthy that all these 10 patients had aDMSA grade 3 lesions, while none of those with aDMSA grade 4 lesions had normal follow-up DMSA. However, the number of patients with aDMSA grade 2 was rather small to draw safe conclusions.
Discussion In the present study clinical features and inflammatory indices in children with febrile UTI were evaluated, in order to help clinicians discern which patients are at high risk of severe acute renal involvement. There are only a handful of previous studies on this topic (7,8,9,15). The novelty of the present study lies on the assessment of clinical and laboratory factors potentially predictive of the development of moderate or severe renal lesions in aDMSA. In addition, we included patients younger than two years, in This article is protected by copyright. All rights reserved.
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compliance with recent clinical practice guidelines (16, 17). The limitation of this study is its retrospective nature. In our study, we assume that the percentage of infants with asymptomatic bacteriuria, i.e. bacteriuria and fever due to an unrelated viral infection (18), is limited since only 13 of the 148 children had coexisting symptoms of a viral-like infection. Although clean-catch urine collection has been advocated as an appropriate collection method in the NICE guideline (19) and recent Italian recommendations (20), in order to eliminate the risk of contamination with faecal bacteria (21), the majority of the cultures in our study were collected by suprapubic inspiration (71.6%) and catheterization (14.9%); only 13.5% of the specimens were clean catch collections, performed immediately after cleansing of the perineum (22).
Among several common symptoms associated with febrile UTI in our study population, shivering was the only clinical sign predictive (OR=4.3) of acute renal lesions. To the best of our knowledge this is the first study to highlight the importance of shivering as a predictor of acute renal involvement. In our study population parental report of shivering correlated well with the presence of serious illness with renal lesions, and was not influenced by other confounding factors (patients’ age, duration of fever, frequency of prolonged fever). In our population, WBC ≥ 18,000/μL and ANC ≥ 9,300/μL were significant risk factors for the development of acute extensive and/or multifocal DMSA lesions. Moreover WBC and ANC values were significantly higher in the group with moderate and severe versus mild aDMSA renal lesions . Different cut-off levels of WBC, ranging from 13,500 to 19,000/μL, have been proposed as predictive of the development of acute DMSA lesions (7, 8, 9, 15), probably reflecting different age-ranges (23). All previous studies agree on the ANC cut-off levels of >9,000/μL (10, 24), however cut-off levels were not correlated to the severity of renal lesions. In the present study, both PCT and CRP increased according to the severity of renal lesions. In addition, PCT could differentiate the group with severe from that with mild renal lesions, as there is no overlap of PCT levels between the groups with different degrees of severity of aDMSA lesions. Thus, PCT is a reliable marker of the presence of acute pyelonephritis and a predictor of the severity of renal lesions.
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Previous studies also report that PCT is superior to CRP as an indicator of acute renal involvement (5,8,15,24,25), that its levels are markedly higher in the group with moderate/severe versus mild aDMSA renal lesions (8,25) and is able to differentiate between totally and partially reversible renal lesions (5). Apart from infection, PCT levels have been correlated with the extent of tissue injury in patients with trauma (26). This observation might explain why PCT in our study was markedly increased in the group with severe renal lesions. In our study, the PPVs of PCT and CRP were 100% and 64.29% for the specific cut-off values mentioned above, while their NPVs were 100% and 59.78% respectively. PCT has been proven to be a more reliable marker than CRP, because high PCT levels on admission are predictive of the development of renal lesions, whereas high levels of CRP are not. Inversely, both inflammatory markers are useful for the exclusion of pyelonephritis because low levels on admission indicate low risk of long-term renal lesions.
Different cut-off levels for PCT have been suggested as markers of the development of acute renal lesions, ranging from 0.5-2.0 ng/ml (5, 8, 15, 25, 26, 27), most agreeing on cut-off levels of 0.8-1 ng/ml (5, 8, 15). In the present study PCT values ≥ 1.64 ng/ml were predictive of severe renal lesions. In a previous study we have shown that PCT levels above 1 ng/ml were predictive of acute renal involvement (5). This is the first time that a cut-off level of PCT for severe renal involvement is proposed. Leroy et al in a meta-analysis on the role of PCT in children with febrile UTI concluded that algorithms for the identification of children at high risk of acute pyelonephritis should be built, in order to limit early DMSA (11). Our data indicate that PCT levels on admission could be incorporated in proper algorithms to predict the presence and the severity of renal lesions in acute pyelonephritis, since it is an excellent marker of acute kidney involvement.
The primary outcome of this study was to evaluate the predictive value of various clinical and laboratory parameters on the identification of extensive and/or multifocal pyelonephritis. Children with aDMSA grade ≥ 3 developed renal scars at the followup DMSA significantly more frequently, compared to those with aDMSA grade 2 renal lesions. Therefore, the prediction of moderate and severe lesions in aDMSA by clinical and laboratory indices is important for late renal sequelae. This article is protected by copyright. All rights reserved.
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Conclusions Clinical signs and laboratory markers can be used as predictors of renal involvement documented by acute DMSA scanning in children under two years old with a first episode of febrile UTI. Children who present with shivering are more likely to have moderate to severe renal lesions of one or both kidneys. PCT levels ≥ 1.64 ng/ml, CRP ≥ 50 mg/L, WBC ≥ 18000/μL and/or ANC ≥ 9300/μL might predict the presence of moderate and severe renal lesions. Moreover our data confirm that PCT is superior to CRP as an indicator of acute renal involvement as it could differentiate the group with severe renal lesions.
References: 1.
Smellie JM, Prescod NP, Shaw PJ, Risdon RA, Bryant TN. Childhood reflux
and urinary infection:a follow-up of 10-41 years in 226 adults. Pediatr Nephrol 1998; 12:727. 2.
Zorc JJ, Kiddoo DA, Shaw KN. Diagnosis and management of pediatric
urinary tract infections. Clin Microbiol Rev 2005;18:417. 3.
Shaikh N, Ewing AL, Bhatnagar S, Hoberman A. Risk of renal scarring in
children with first urinary tract infection:a systematic review. Pediatrics 2010; 126(6): 1084-91. 4.
Majd M, Rushton HG. Renal cortical scintigraphy in the diagnosis of acute
pyelonephritis. Semin Nucl Med 1992; 22(2):98-111. 5.
Karavanaki K, Haliotis A, Sourani M, Kariyiannis C, Hantzi E, Zachariadou L
et al. DMSA scintigraphy in febrile urinary tract infections could be omitted in children with low procalcitonin levels. Inf Dis Clin Pract 2007; 15(6):377-381. 6.
Montini G, Zucchetta P, Tomasi L, Talenti E, Rigamonti W, Picco G, et al.
Value of imaging studies after a first febrile urinary tract infection in young children:data from Italian renal study 1.Pediatrics 2009; 123 (2): e 239-246. 7.
Gilani KA, Esfeh JM, Gholamrezanezhad A, Gholami A, Mamishi S,
Eftekhari M, et al. Predictors of abnormal renal cortical scintigraphy in children with
This article is protected by copyright. All rights reserved.
Accepted Article
first urinary tract infection: the importance of time factor. Int Urol Nephrol 2010; 42: 1041-1047. 8.
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 2009; 124;23-29. 9.
Fernandez-Menendez JM, Malaga S, Matezans JL, Solis G, Alonso S, Perez-
Mendez C et al. Risk factors in the development of early technetium-99m dimercaptosuccinic acid renal scintigraphy lesions during first urinary tract infection in children. Acta Paediatr 2003; 92:21-26. 10.
Donoso RG, Lobo SG, Arnello VF, Arteaga VMP, Coll CC, Hevia JP, et al.
Renal scars after one year of follow up in children with a first episode of acute pyelonephritis. Rev Med Chil. 2006; 134(3): 305-311. 11.
29.
Leroy S, Fernandez-Lopez A, Nikfar R, Romanello C, Bouissou F,
Gervaix A, et al. Association of procalcitonin with acute pyelonephritis and renal scars in pediatric UTI. Pediatrics 2013;131(5):870-9 12.
Practice parameter: the diagnosis, treatment, and evaluation of the initial
urinary tract infection in febrile infants and young children. American Academy of Pediatrics, Committee on Quality improvement. Subcommittee on Urinary Tract Infection. Pediatrics, 1999 Apr; 103 (4 Pt 1): 843-52 13.
Birgir Jakobsson, Lennart Nolstedt, Leif Svensson, Stefan Soderlundh and
Ulla Berg. 99m Technetium-dimercaptosuccinic acid scan in the diagnosis of acute pyelonephritis in children: relation to clinical and radiological findings. Pediatr Nephrol (1992)6: 328-334 14.
Lebowitz RL, Olbing H, Parkkulainen KV, Smellie JM, Tamminen – Mobius
TE. International system of radiographic grading of vesicoureteric reflux. International Reflux Study in Children.Pediatr Radiol 1985;15(2):105-9 15.
Kotoula A, Gardikis S, Tsalkidis A, Mantadakis E, Zissimopoulos A,
Kambouri K, et al.
Procalcitonin for the early prediction of renal parenchymal
involvement in children with UTI: preliminary results. Int Urol Nephrol. 2009; 41(2):393-399. This article is protected by copyright. All rights reserved.
Accepted Article
16.
American Academy of Pediatrics. 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 September 2011;128 (3):595-611. 17.
Dorien H. F. Geurts & Willem Vos & Henriette A. Moll & Rianne
Oostenbrink. Impact analysis of an evidence-based guideline on diagnosis of urinary tract infection in infants and young children with unexplained fever. Eur J Pediatr (2014) 173:463–468. 18.
Kjell Tullus. Difficulties in diagnosing urinary tract infections in small
children. Pediatr Nephrol. 2011; 26:1923-1926. 19.
National Institute for Health and Clinical Excellence. Urinary Tract Infection
In Children: Diagnosis, Treatment and Long Term Management. Clinical Guideline no.54,2007. Available from:http://www.nice.org.uk/CG54 [accessed March 2012]. 20.
Ammenti A, Cataldi L, Chimenz R, Fanos V et al. Febrile urinary tract
infections in young children: recommendations for the diagnosis, treatment and follow-up. Acta Paediatr. 2012 May;101 (5):451-7. 21.
Etoubleau C, Reveret M, Brouet D, Badier I, Brosset P, Fourcade L, et al.
Moving from bag to catheter for urine collection in non-toilet-trained children suspected of having urinary tract infection: a paired comparison of urine cultures. J Pediatr 2009;154:803–806. 22.
Pryles CV, Luders D, Alkan MK. A comparative study of bacterial cultures
and colony counts in aired specimens of urine obtained by catheter versus voiding from normal infants and infants with urinary tract infection. Pediatrics 1961; 27: 1728 23.
Hulstaert F, Hannet I, Deneys V, Munhyeshuli V, Reichert T, DeBruyere M,
et al. Age-related changes in human blood lymphocyte subpopulations. II. Varyring kinetics of
percentage
and absolute
count
measurements.
Clin Immunol
Immunopathol 1994; 70(2): 152-158. 24.
Benador N, Siegrist CA, Gendrel D, Greder C, Benador D, Assicot M, et al.
Procalcitonin is a marker of severity of renal lesions in pyelonephritis. Pediatrics 1998; 102(6):1422-1425 This article is protected by copyright. All rights reserved.
Accepted Article
25.
Prat C, Dominguez J, Rodrigo C, Gimenez M, Azuara M Jiménez O, et al.
Elevated serum procalcitonin values correlate with renal scarring in children with urinary tract infection. Pediatr Infect Dis J 2003;22(5):438-442. 26.
Shahangian S, Ash KO, Wahlstrom NO Jr, Warden GD, Saffle JR, Taylor A
Jr, et al. Creatinine kinase and lactate dehydrogenase isoenzymes in serum of patients suffering burns, blunt trauma or myocardial infarction. Clin Chem 1984;30:1332– 1338. 27.
Ng PC. Diagnostic markers of infection in neonates. Arch Dis Child Fetal
Neotatal Ed 2004; 89: F229-235.
Table 1: Descriptive characteristics of clinical and laboratory parameters on admission in predictive of moderate/severe acute renal lesions. DMSA score
1 and 2 (n=92)
3 and 4 (n=56)
Median (range)
Median (range)
3.0
4.0
(0.5-24.0)
(0.3-24.0)
48.0
72.0
fever (hours)
(3.0-180.0)
(6.0-180.0)
Prolonged fever
6/92(6.52%)
7/56(12.5%)
0.84**
Shivering
4/74(5.4%)
7/43(16.3%)
0.057*
15,300
18,900
0.001*
(2,300-31,700)
(2,600-38,100)
7,134
11,200
(500-26,311)
(119.9-23,638)
44.0
105.0
(0.3-202.0)
(5.0-336.0)
0.40
9.58
(0.10-8.25)
(4.0-28.68)
Age (months)
Total duration of
WBC (/μL)
ANC (/μL)
CRP (mg/L)
PCT (ng/ml)
Prolonged fever: Duration of fever ≥3 days after treatment initiation
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P value
0.991*
0.438*
