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Infectious Diseases in Clinical Practice:
doi: 10.1097/IPC.0b013e318157d272
Original Articles

DMSA Scintigraphy in Febrile Urinary Tract Infections Could Be Omitted in Children With Low Procalcitonin Levels

Karavanaki, Kyriaki MD, PhD*; Angelos Haliotis, Fotis MD†; Sourani, Maria MD†; Kariyiannis, Catherine BSc‡; Hantzi, Eugenia BSc‡; Zachariadou, Levandia MD§; Avlonitis, Spyros MD†; Papassotiriou, Ioannis PhD‡; Stefanidis, Constantinos J. MD, PhD∥

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*Department of Pediatrics, University of Athens, "P. and A. Kyriakou" Children's Hospital, Athens, Greece; †Second Department of Pediatrics, ‡Clinical Biochemistry Department, and §Clinical Microbiology Department, "Aghia Sophia" Children's Hospital and ∥Department of Nephrology, "P. and A. Kyriakou" Children's Hospital, Athens, Greece.

Address correspondence and reprint requests to Kyriaki Karavanaki, MD, PhD, Department of Pediatrics, University of Athens, "P. and A. Kyriakou" Children's Hospital, Thivon and Levadias St, Goudi, 11527 Athens, Greece. E-mail: kakarav2@yahoo.gr.

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Abstract

Purpose: The objective was to assess procalcitonin (PCT) as a marker of renal involvement in children with urinary tract infections (UTI).

Methods: The study included 60 children with UTI, aged (median) 0.6 years (range, 0.1-9.5 years), admitted to a pediatric hospital. White blood cell count, C-reactive protein (CRP), and PCT levels were measured on admission and on the third treatment day, whereas renal involvement was assessed with dimercaptosuccinic acid (DMSA) scintigraphy within 7 days after admission and after 6 months.

Results: During febrile UTI, PCT, and CRP levels increased in parallel with the severity of renal lesions in acute DMSA. During repeat DMSA, PCT levels were increased in the group with partially versus totally reversible renal lesions (5.3 μg/L vs 3.0 μg/L; P = 0.005). Procalcitonin and CRP had increased sensitivity (94% and 100%, respectively) and negative predictive values (97% and 100%, respectively), whereas PCT had higher specificity than CRP (100% vs 55%).

Conclusions: Procalcitonin is a sensitive marker of the development, severity, and persistence of renal lesions in childhood UTI. Because of the high negative predictive values of PCT, we suggest that, in case of low PCT levels, the possibility of renal involvement is low, and DMSA could be omitted.

Febrile urinary tract infection (UTI) is frequently diagnosed among infants with unexplained fever.1 Acute pyelonephritis (APN) in children with febrile UTI is defined as the presence of renal lesions during acute phase dimercaptosuccinic acid (DMSA) scintigraphy.2,3 The distinction between APN and UTI without renal lesions (lower UTI) is difficult because the clinical findings (anorexia, vomiting, lethargy, and absence of fever), especially in children younger than 2 years, and the used inflammatory markers are nonspecific.2

Dimercaptosuccinic acid scintigraphy during the acute phase of infection is important for the detection of renal involvement.4-6 However, it has many disadvantages (ie, increased cost, low availability on an urgent basis, and exposure to radiation).5,6 Moreover, it may not differentiate old scarring from acute renal involvement, unless follow-up scanning is performed.2 For these reasons, it would be necessary to identify the cases of childhood UTI, in whom DMSA could be omitted. C-reactive protein (CRP), in comparison with other inflammatory markers,4 has a better predictive value for the development of renal involvement, but its low specificity decreases its clinical usefulness.7,8

Procalcitonin (PCT) is a 116-amino acid propeptide of calcitonin. Its levels increase within 3 hours after the onset of infection in response to interleukin 6 and tumor necrosis factor α; they reach peak values within 6 to 12 hours and remain high for 48 hours.9 Procalcitonin has been considered as a reliable marker of serious bacterial infections (ie, bacterial meningitis10 and septic shock11) and can differentiate them from viral, chronic infections, and autoimmune diseases.12 Its levels are very low in healthy individuals (<0.05 μg/L).13 In recent studies, PCT levels are correlated with the severity of renal lesions in children with APN.7,8,14-17

The aim of the present study was to assess the role of PCT as a marker of severity and persistence of renal involvement in childhood UTI and also to assess its role in the identification of cases, in which DMSA could be omitted.

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MATERIALS AND METHODS

The present study included all children, aged 1 month to 9.5 years, who, because of a first episode of febrile or afebrile UTI, were admitted to a pediatric ward of a pediatric hospital, during a 12-month period. Patients with unexplained fever or fever accompanied with symptoms suggestive of UTI (abdominal pain and dysuria) or with various symptoms other than fever (lethargy, vomiting, diarrhea, anorexia, failure to thrive, etc) were included in the study. Patients were not included in the study in the presence of the following: (a) a previous episode of UTI (because the DMSA lesions could have preexisted); (b) known abnormalities or malformation of the urinary tract; (c) symptoms and signs of other coincidental infections, including respiratory tract infections; and (d) if they had received antibiotics during the previous week (unless the identified microorganism was resistant).

The diagnosis of UTI was based on clinical symptoms and a positive urine culture (>105 colony forming units/mL for midstream clean-catch collection, >104 for catheterization, and >103 for suprapubic collection).18

The antibiotic treatment was administered intravenously and subsequently orally, or exclusively orally, according to the recommendations of the American Academy of Pediatrics.19 The total treatment duration was 7 days for UTIs without fever and 10 days for febrile UTIs, and it was followed by chemoprophylaxis with low doses of antibiotics for all children with vesicoureteral reflux (VUR).19

White blood cell count (WBC), absolute neutrophil count (ANC), CRP, erythrocyte sedimentation rate (ESR), and PCT levels were measured on admission and on the third day of treatment. All patients underwent renal ultrasonography within the first 5 days of admission and cystourethrography for the detection of VUR was performed at the end of treatment of the UTI.

The renal involvement was assessed with DMSA scintigraphy,4 within the first 7 days of infection by investigators who were blinded to the inflammatory markers and to the clinical condition of the children. The protocol for DMSA scintigraphy was previously described by Benador et al20 and the lesions were graded as follows: (0, absence of lesion; 1, very mild [defect covering <5% surface area]; 2, mild [defect covering 5%-10% surface area]; 3, moderate [defect covering 10%-30% surface area] 4, severe renal parenchymal lesions [defect covering >30% surface area]).20 Dimercaptosuccinic acid scintigraphy was repeated 6 months later in case of an abnormal result to determine whether the renal lesions were permanent. During this 6-month period, all children were checked with a urine culture every month and also during every episode of unexplained fever. None of the patients experienced a relapse of UTI.

White blood cell count was determined using a whole blood autoanalyzer (CellTac α; Nihon Kohden Corporation, Tokyo, Japan). The concentrations of CRP in serum were measured by particle-enhanced immunonephelometric assay (BN ProSpec nephelometer; Dade Behring, Liederbach, Germany). Serum PCT levels (Brahms Diagnostica, Berlin, Germany) were measured by chemiluminescence on the LIAISON random access analyzer (DiaSorin, Saluggia, Italy). Previous studies have used, for PCT, the cutoff values of 0.5 μg/L,3,8,15,16 0.8 μg/L,3 and 1.0 μg/L.3,14 For CRP, the cutoff point of 20 mg/L was used by most studies,8,14-16 whereas 50 mg/L was used in the study of Pecile et al.3 In our study, we used the cutoff points for PCT (0.5, 0.8, and 1.0 μg/L) and the ones of 20 mg/L and 50 mg/L for CRP, respectively.

Ethical committee approval was obtained, and an informed consent was given by the parents of children with UTI.

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Statistical Methods

Because variables were not normally distributed, nonparametric statistics were used. Mann-Whitney U test was used for comparisons between 2 groups of children, in terms of different parameters (CRP, PCT, ESR, and WBC). Kruskal-Wallis 1-way analysis of variance (ANOVA) was used for comparisons among multiple groups (with the following: (a) absence of, (b) mild, and (c) moderate or severe renal lesions). χ2 test was used for the comparison of sex distributions among multiple groups of children. Spearman correlations were used to assess the relationship of PCT with the conventional inflammatory markers. Sensitivity, specificity, and positive (PPVs) and negative predictive values (NPVs) were estimated for PCT and CRP as predictors of renal lesions in the acute and repeat DMSA.

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RESULTS

The study included 58 children with UTI, aged (median) 0.6 years (range, 0.1-9.5 years), admitted to a pediatric hospital. The sex distribution was 27 boys and 34 girls. The most frequently identified pathogen was Escherichia coli (n = 86% [52/60]). Approximately 82.8% (48/58) of the patients did not have VUR, whereas 17.2% (10/58) had VUR grades 2 to 5. Renal ultrasound was normal in 80.7% of the cases.

Most patients (73.3% [44/60]) had febrile UTI. Among the 16 afebrile children, 15 had negative acute DMSA, and in 1 child, DMSA was denied. However, among the 44 febrile ones, in 6 cases, parents did not give permission for the DMSA; thus, they were excluded from the analysis. These patients were infants with mild symptoms and low inflammatory indices. Thus, among the remaining 38 children with febrile UTI, 18 (47.36%) had positive acute DMSA, and 20 had negative acute DMSA. Repeat DMSA was obtained in all 18 patients with positive acute DMSA. It is noteworthy that, in all 18 patients with an acute DMSA with severity scores of 1 to 4, lesions either disappeared 6 months later or improved; therefore, the lesions in acute DMSA could be considered as true lesions of APN and not preexisting scars.

Among the children younger than 2 years with febrile UTI, 17of 30 children had negative acute DMSA, and 13 (43.4%) of 30 had positive acute DMSA. Among the latter children, during repeat DMSA, lesions subsided in 6 of 13 children, whereas lesions were reduced in 7 of 13 children (DMSA score 1 or 2).

Initially, the patients were divided into the following 3 subgroups: group 1, afebrile UTI; group 2, febrile UTI with normal acute DMSA; and group 3, febrile UTI with abnormal acute DMSA. A progressive significant increase of the inflammatory markers was observed among the 3 subgroups, with the lowest values in the afebrile group and the highest ones in the febrile with abnormal acute DMSA (Table 1).

Table 1
Table 1
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When analyzing the subgroups with different degrees of severity of renal scars (as ranked by acute phase DMSA), PCT, CRP, ANC, and ESR levels increased in parallel with the severity of renal lesions, with the exception of WBC (Table 2).

Table 2
Table 2
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Furthermore, the data were analyzed according to the presence of totally reversible (group 1, n = 8) or partially reversible lesions (group 2, n = 10) in repeat DMSA. Erythrocyte sedimentation rate (60.0 mm/h vs 121.0 mm/h; P = 0.001) and PCT (3.08 μg/L vs 5.3 μg/L; P = 0.05) were significantly lower in the group with totally reversible renal lesions, whereas the rest of the inflammatory markers were not different between the 2 groups (median WBC, 17,200 × 103/μL vs 19,300 × 103/μL [P = 0.498]; ANC, 11,868 × 103/μL vs 11,472 × 103/μL [P = 0.673]; CRP, 50.4 mg/L vs 119.5 mg/L [P = 0.356]). No difference in the age and sex distribution was observed between the 2 groups, respectively (median age, 0.75 years [range, 0.3-6.5 years] vs 0.75 years [range, 0.08-4.0 years] [P = nonstatistically significant {NS}]; boys/girls, 4/5 vs 4/6, χ2 = 0.05 [P = NS]).

The PCT levels were significantly correlated with CRP (r = 0.45; P = 0.001), ESR (r = 0.39; P = 0.001), WBC (r = 0.36; P = 0.001), and ANC (r = 0.31; P = 0.05).

For the prediction of the development of renal lesions, the sensitivities and specificities of PCT and CRP on admission were estimated (Table 3), according to the findings in acute phase DMSA. The used cutoff values for PCT were 0.5, 0.8, and 1.0 μg/L, and those for CRP were 20 and 50 mg/L, respectively. The best performance of PCT was observed for the cutoff value of 1.0 μg/L, whereas the one for CRP was observed for the cutoff value of 20 mg/L. According to the latter cutoff values, both PCT and CRP had increased sensitivity for the prediction of renal lesions (94% and 100%, respectively) and increased NPVs (97% and 100%, respectively), whereas the specificity and PPV of PCT were higher than the ones of CRP. When using the cutoff value of 50 mg/L for CRP, its specificity was improved, whereas its sensitivity (73.3%) and NPV (86.6%) were reduced.

Table 3
Table 3
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The PCT and CRP levels, according to the severity of renal lesions as ranked by acute phase DMSA results, are demonstrated in Figures 1 and 2, respectively. In Figure 1, the mean PCT values increase in parallel with the severity of renal lesions. Inversely (Fig. 2), the CRP levels broadly overlap among the groups with different degrees of severity of renal lesions; thus, in some cases with severe renal lesions (DMSA score 4), CRP levels are low (25 mg/L), whereas in others with mild DMSA lesions (score 1), CRP levels are high (200 mg/L). This is not observed in terms of PCT levels (Fig. 1), and it reflects the low specificity and PPV of CRP in comparison with PCT.

Figure 1
Figure 1
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Figure 2
Figure 2
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DISCUSSION

The early diagnosis of renal involvement in UTI is very important because renal parenchymal involvement may be responsible for the development of permanent renal damage (scars), which may lead to arterial hypertension and chronic renal failure.21 Moreover, with the early diagnosis and appropriate treatment of UTI, the risk of renal scarring is reduced.22 The present study presents data on the value of PCT as an early inflammatory marker of the development, severity, and reversibility of renal lesions in children with febrile UTI. Because DMSA scintigraphy is invasive and expensive, our study also presents data on the use of PCT for the selection of cases, in which DMSA could be omitted.

The frequency of parenchymal lesions during acute DMSA in children after a first episode of febrile UTI in our study was 47.36%. Similar frequencies were reported by Pecile et al3 (53%) and Gurgose et al15 (44.7%), whereas others reported higher (71% and 79%7,23) or lower frequencies (30%).8 In all the above studies, as in our study, lesions in the repeat DMSA partially or totally subsided; thus, they were true lesions of APN. It is noteworthy that in the studies with the higher frequency of APN by Benador et al7 and Turlinckx et al,23 the mean age of the children was higher than that of those with the lower frequency of APN (3,8 and the present study). It has been previously shown24 that the risk for renal scars does not diminish, but inversely, it increases with age, as the frequency of positive acute DMSA was 40% in the group of children younger than 1 year and 86% in those aged 1 to 5 years. Thus, the different age distribution of the study populations could explain the different frequencies of APN in children after a first episode of febrile UTI among the above studies.

Procalcitonin and CRP in our study were significantly increased in the group with parenchymal involvement in acute DMSA; thus, they can differentiate APN from lower UTI. Moreover, both PCT and CRP increased in parallel with the severity of renal lesions. However, PCT (and not CRP) could differentiate the group with totally from partially reversible lesions during repeat DMSA. Similar findings were reported by Pecile et al.3 Thus, PCT is a reliable marker of the presence and severity of APN and is also a predictor of the reversibility of renal lesions.

The sensitivities and NPVs (NPV: PCT, 97%; CRP, 100%) of both PCT and CRP in our study were high, offering the best performance at the cutoff value of 1.0 μg/L and 20 mg/L, respectively. Moreover, for the above cutoff values, the specificity and PPVs of PCT were higher than the ones of CRP (PPV: PCT, 100%; CRP, 54%). These findings are in agreement with the ones previously reported.3,7,8 Ng25 reported that a good marker of APN should preferably have sensitivity and NPV approaching 100% and specificity and PPV greater than 85%. According to these criteria, PCT has been proved 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.

Apart from infection,3,7 PCT and CRP levels are also increased during tissue damage.26 In patients with trauma, PCT levels have been correlated with the extent of tissue injury, depicted by the lactate dehydrogenase activity.27 Moreover, increased PCT levels have been reported in patients with burn-related inflammation without evidence of acute infection.28 This observation explains why PCT in our study was increased according to the severity of renal scarring and also could differentiate between totally and partially reversible renal lesions.

The use of acute phase DMSA in young febrile children with a first episode of UTI is not generally accepted because no preventive or therapeutic interventions are beneficial in these patients, whereas the accumulation of radiation during repeat DMSAs is not negligible.2,29 Thus, in cases of febrile UTI, some centers recommend cystourethrography and renal ultrasonography; they also suggest that DMSA should be performed 6 months after the last UTI in all patients with VUR and in those patients without VUR who are at high risk for the development of renal scars (ie, with at least 2 febrile UTIs or 1 febrile UTI and delayed antibiotic treatment).30

Because of the high NPVs of PCT, our findings suggest that, in young children with a first episode of febrile UTI, DMSA during acute phase or after 6 months could be omitted when PCT levels on admission are low (<1.0 μg/L). In consideration of the disadvantages of the DMSA scanning, these findings are of great clinical importance because they may contribute to the avoidance of unnecessary DMSA studies in children with low levels of the above inflammatory markers.

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