1. Urinary tract infection: old concepts and new concepts
NCKU medical center
Department of Pediatric, division of nephrology
Yuan-Yow Chiou
2018年9月18日

2. Urinary Tract Infection Epidemiology: Measurement Concerns
It is difficult to accurately assess the incidence of UTIs, because they are not reportable diseases in the United States. This situation is further complicated by the fact that accurate diagnosis depends on both the presence of symptoms and a positive urine culture, although in most outpatient settings this diagnosis is made without the benefit of culture.
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3. Incidence of Urinary Tract Infection Among Children
Am J Med. 2002;113(1A):5S–13S.
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4. Urinary Tract Infection in Pediatric Patients
Epidemiology:
In the neonatoal period, 1% for full-term infants and 3% for premature infants
In febrile neonate, UTI increases to 4.6% in the presence of fever (for neonates less than 2mo)
The risk of UTI from age to 10y/o to be 3.5% in girls and 1.1% in boys (Sweden)
For febrile children presenting in the 1yo, the incidence of UTI is approximately 5.6%.
After the first year of life, UTI is clearly more common in females.
Therefore, the risk of a UTI in a febrile infant is significant, especially if there is no source of fever or only a presumptive source of fever.
女性有trimodal age distribution:
最高為highest in the first year
次之為2-3 years at the time of toilet training (caused primarily by cystitis because of dysfunctional voiding around the toilet training years)
最後為adolescence when sexual activity begins
Am J Med. 2002;113(1A):55S–66S.
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5. 2018年9月18日

6. Recurrence and follow-up after UTI under age of 1year
Once treated it is common for children to develop additional UTIs. There infections can be caused by a persistent or partially treated UTI. On the other hand, infection may result from a recurrent infection within 6 months or a year of the previous UTI. During the first year, 18% of boys will have a recurrence, as will 26% of girls. The recurrence rate decreases with age.
Pediatric urinary tract infection. EMERGENCY MEDICINE CLINICS OF NORTH AMERICA. 19(3): , 2001
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Pediatr Nephrol (2001) :69-72

7. Recurrence and follow-up after UTI under age of 1year
2018年9月18日
Pediatr Nephrol (2001) :69-72

8. Sequence of recurrent UTI in Pediatric Girls
Am J Med. 2002;113(1A):55S–66S.
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9. Financial Implications of Urinary Tract Infection (UTI)
(1997, National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey)Each year, UTIs account for > 7million office visits and >1million visits to emergency departments, necessitating 100,000 hospitalizations.
Catheter-associated UTIs account for 40% of all nosocomial infections and are important source of septicemia in hospitalized patients.
The ramifications of UTI include significant morbidity and health care utilization, as well as overall costs estimated at >$1 billion/year.
Am J Med. 2002;113(1A):5S–13S.
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10. The approach to the diagnosis and management of Pediatric UTI
Age: neonate~3m/o: catheterized urinalysis or bladder aspiration is part of the standard work-up for fever
Age:2 to 3 m/o~2 to 3 y/o: urine culture with a fever greater than 39C
Older children: may be less complicated
Children on prophylactic antibiotics for reflux or with a history of reflux should have a urinalysis and culture checked with each febrile episode.
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11. Other physicians point out that a urinalysis is 80% sensitive and with a 5% prevalence of UTI, the rate of UTI in a negative urinalysis is about 1.3%.
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12. Diagnosis of Pediatric UTI
Am J Med. 2002;113(1A):55S–66S.
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13. Inherited or Acquired Host Susceptibility Factors
For the risk factors of UTI
The most common risk is VUR, which is present in 31% of children with UTIs.
By DMSA, scarring from recurrent PN occurs in 42% of kidneys, esp. those with high-grade reflux.
Additional risk factors: previous UTI, or a history of UTI or reflux in a parent or sibling.
White children : black children = 2:1
Toilet training period = dysfunctional voiding habits
Constipation or encopress often accompanies voiding dysfunction
Some studies have found that normalizing voiding pattern leads to resolution of VUR
Am J Med. 2002;113(1A):14S–19S.
2018年9月18日

14. APN, VUR, and severity of reflux during acute phase of first febrile UTI in three Age groups
In boys with UTIs, who are less than 1 yo, the rate of VUR is even higher (68%).
The rate decreases as boys become older to 25% in boys age 1-3 yo.
Group I: 1y/o; Group II: 1-5 y/o; Group III: 5y/o
Pediatr Nephrol (2003) 18:362–365
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15. The Foreskin and Urinary Tract Infections
Wiswell and associates:
The incidence of UTI in uncircumcised males (≦6m/o) was 1 to 4 percent.
The incidence in circumcised males was 0.1 to 0.2 percent.
Routine circumcision or selective circumcision?
There was a 3.7-fold increased risk of UTI in uncircumcised boys in the first year of life and 4.5-fold increase in the first month of life. This increased risk for uncircumcised males may persist up until age 5.
Pediatrics 1985;75:901-3.
Pediatrics 1989;83:
Pediatrics 1986;78:96-9.
Clin Pediatr [Phila] 1993;32:130-4.
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16. Etiology of Uncomplicated Versus Complicated UTI
Adult women
Am J Med. 2002;113(1A):14S–19S.
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17. Asymptomatic bacteriuria
Def: growth of bacteria in culture without symptoms of infection or abnormalities on urinalysis.
Tx:
Unnecessary – except….
Neonate and perhaps in children with known urologic abnormalities.
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18. Pathogenesis of UTI
The sequence of events in the untreated animal leads to a loss of approximately 20% of total renal function, with the damage all having begun within 24 h of renal inoculation but continuing for 1-2 weeks after infection.
Treatment of experimental pyelonephritis in the monkey: allopurinol and antibiotics (1989)
J. Urol. (1989) 143:
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19. Reanl parenchymal damage
Pathogenesis of UTI
colonization
Ascending infection
inflammation
Tissue ischemia and reperfusion
Reanl parenchymal damage
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20. Inflammation process
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21. Ischemia and
reperfusion
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22. Complicating that diagnosis of upper tract infection is the fact that there is no gold standard test for pyelonephritis.
Fever as a marker for upper tract infection: sensitivities (53-84%) and specificities ( %).
Antibody-coated bacteria, and renal nuclear scanning have been used as indicators of PAN. However, the utility of these tests is still limited.
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23. a. DMSA renal scan in a 3-year-old girl with an acute febrile UTI (arrowhead). b Followup DMSA renal scan 2 years later (arrowhead).
Typical findings of APN are demonstrated by this DMSA renal scan from a 10-month-old boy with a febrile UTI.
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24. Role of Technetium 99m-dimercaptosuccinic acid (DMSA) scintigraphy in children
The imaging agent of choice for the detection and evaluation of acute pyelonephritis and renal cortical scarring.
Confirmed the primary role of the acute inflammatory response, associated with both reflux and nonreflux pyelonephritis, in the etiology of irreversible renal scarring.
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25. Dimercaptosuccinic acid (DMSA) renal scan findings in different age groups
positive
negative
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Pediatr Nephrol (2002) 17:30–34

26. APN, VUR, and severity of reflux during acute phase of first febrile UTI in three Age groups
Group I: 1y/o; Group II: 1-5 y/o; Group III: 5y/o
Pediatr Nephrol (2003) 18:362–365
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27. Association of APN with VUR, severity of reflux, and renal scar in all three groups
Pediatr Nephrol (2003) 18:362–365
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28. APN or scar formation according to presence of low grade or absence of VUR
Pediatr Nephrol (2003) 18:362–365
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29. Relationship of inflammatory volume and renal scar (sequelae) by DMSA renal SPECT
Radioactivity ratio between abnormal and normal renal tissue (L/N ratio)
45% 1.2
39%1.4
Lesion volume of the sequelae group and the nonsequelae group.
15.0 2.0ml
2.5 1.2ml
Radiology. 2001; 221:
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30. Evolution of differential renal function(DRF) after APN
The purposes of this retrospective study
were (1) to assess the relationship between DRF obtained during acute pyelonephritis and at follow-up,
and (2) to elucidate the value of initial DRF in predicting subsequent renal scars.
We found the correlation between initial and follow-up DRF poor (adjusted
R2 = 0.396). Whether or not renal scars developed determined the follow-up DRF. Vesicoureteral reflux was
significantly more common in children who developed renal scars. In addition, the higher the grade of
vesicoureteral reflux, the lower the follow-up DRF and the improvement in DRF. When using a DRF of
46% as the cut-off value to predict subsequent renal scars, the sensitivity and specificity were 47.8% and
83.3%, respectively. Owing to the low sensitivity, initial DRF is not suitable for predicting the occurrence of
renal scars.
Nuclear Medicine Communications, 2002, 23,
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31. How about of comparison of ultrasound and DMSA changes in APN
APN in echo finding:
consisting of an increased kidney volume, and/or
a thickening of the wall of the renal pelvis, and/or
a focal hyper- or hypoechogenicity, and/or
a diffuse hyperechogenicity in children.
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Pediatr Nephrol (1999) 13:219–222

32. Renal ultrasonography (US) findings in different age groups.
Distribution of renal US findings in normal and positive DMSA renal scans.
normal
abnormal
normal
abnormal
Renal ultrasonography (US) findings in different age groups.
Pediatr Nephrol (2002) 17:30–34
2018年9月18日

33. Distribution of vesicoureteral reflux (VUR) in different age groups
positive
negative
Distribution of vesicoureteral reflux (VUR) in different age groups
No VUR
Low grade
VUR
Distribution of VUR in children with normal and abnormal DMSA renal scans.
High grade
VUR
Pediatr Nephrol (2002) 17:30–34
2018年9月18日

34. Compare the result of initial US and acute DMSA in APN kidney (n=90)
followed DMSA in previous APN
kidney (n=65)
Acute DMSA US
Abnormal
Normal
Cold lesion 32 33 3 22
Followed DMSA US
Abnormal
Normal
Scar 19 13 20
Sensitivity: 49.2%
Specificity:88.0%
Positive predictive value:91.4%
Negative predictive value:40.0%
Sensitivity: 59.4%
Specificity: 60.6%
Positive predictive value: 59.4%
Negative predictive value: 60.6%
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35. Compare the initial positive US with high CRP(>80) and acute DMSA
in previous APN kidney (n=90)
Compare initial positive US with high
CRP and followed DMSA in previous
APN kidney (n=65)
P<0.005
P<0.005
Positive US and high CRP
acute DMSA
Abnormal
Normal
Negative 41 23
Positive 21 1
Positive US and high CRP
Followed DMSA
Abnormal
Normal
Negative 15 26
positive 16 5
Sensitivity: 33.9%
Specificity:95.8%
Positive predictive value:95.5%
Negative predictive value:35.9%
Sensitivity: 51.6%
Specificity: 83.9%
Positive predictive value: 76.2%
Negative predictive value: 63.4%
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36. Relationship of DMSA inflammatory volume
and renal US
11.0±2.4ml
3.0±0.8ml
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37. Role of Tc-99m DMSA scintigraphy in the diagnosis of culture negative pyelonephritis?
●(A prospective study)
15(9%) had negative or equivocal urine culture despite clinical and scintigraphic evidence of APN
-> US: normal in 7 children
VCUG: VUR in 9 children
-> follow up DMSA 6 months later:
8 disappear
4 partial improvement
Pediatr Nephrol (2001) 16:503–506
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38. Other factors to predict APN?
Procalcitonin as a marker of acute pyelonephritis in infants and children
Pediatr Nephrol (2002) 17:409–412
Urinary interleukin-6 and interleukin-8 in children with urinary tract infection
Pediatr Nephrol (2000) 15:236–240
Urinary microalbumin and β2-microglobulin
Acta Paediatrica Sinica (2001) 42:84-89
For the prediction of acute pyelonephritis, the sensitivity and specificity of PCT were 94.1% and 89.7%, respectively; CRP had a sensitivity of 100%, but a specificity of 18.5%. We conclude that serum PCT may be an accurate marker for early diagnosis of acute pyelonephritis.
PCT: a polypeptide, identical to a prohormone of calcitonin, procalcitonin, was initially described as a potential marker of bacterial disease by Assicot et al. Plasma PCT conc. Is low in healthy individuals (<0.5ug/l), but rises to very high values in response to bacterial endotoxin. In the first 2 days of life, the PCT conc. can be physiologically increased to as much as 21 ug/l.
UIL-6 and UIL-8 concentrations were statistically significantly correlated with urine white blood cells (WBC). UIL-8 concentrations were elevated
in patients with E. coli organisms producing hemolysin. UIL-6 and UIL-8 are elevated in children with febrile UTI and decrease in response to antibiotic therapy. Magnitude of UIL-8 response is associated with hemolysin production, a bacterial virulence factor of E. coli. UIL-6 and UIL-8 concentrations are statistically correlated with urine WBC. UIL-6 and UIL-8 may be mediators of inflammation in children with febrile UTI. However, UIL6 and UIL8 concentrations were lower in follow-up urine samples from UTI patients, obtained 48h after the initiation of antibiotic therapy.
DMSA positive patients have elevated urinary 1-microglobulin excretion and DMSA negative have normal level.
European Urology. (1998) 34(6):486-91
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39. Therapeutic Management of Pediatric UTI
2018年9月18日
Am J Med. 2002;113(1A):55S–66S.

40. Urinary Tract Infection Isolates: 1999 National Outpatient Data
Alternative agents that exhibit continued in vitro activity against most uropathogens causing uncomplicated UTI (nitrofurantoin, fluoroquinolones, fosfomycin) or complicated UTI (fluoroquinolones, aminoglycosides, third-generation cephalosporins) are being increasing used.
Am J Med. 2002;113(1A):29S–34S.
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41. Risk Factors for Trimethoprim-Sulfamethoxazole (TMP-SMX) Resistance
Am J Med. 2002;113(1A):29S–34S.
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42. Efficacy of 7 days’ (group A) and 3 days’ (group B) IV antibiotics, both followed by an oral treatment in APN ?
When the patients were stratified according to the delay of treatment, the percentage of patients with sequelae in group A was comparable, whether the delay of treatment was less or more than 1 week. In group B, the percentage of patients with sequelae was significantly higher (P<0.01) when the delay was more than 1 week.
We report a prospective randomized study, in a population of children with high suspicion of APN, to compare the efficacy of two types of treatment: a 7-day intravenous antibiotic treatment, followed by 2 weeks of oral antibiotics, and
a 3-day intravenous antibiotic treatment followed by 18 days of oral antibiotics.
The presence of renal sequelae on technetium-99m dimercaptosuccinic acid (DMSA) scintigraphy, 6 months after the acute episode, was used as endpoint.
Pediatr Nephrol (2001) 16:878–884
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43. Complication and morbidity
Immediate complications: lobar nephronia, abscess formation, urosepsis.
Long-term complications of APN: renal scar formation, ESRD, and hypertension
The risk of scar formation increases with each subsequent infection.
It is estimated that 15% of ESRD in children is caused by the combination of reflux and renal scarring.
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44. Conclusion
There are important medical and financial implications associated with UTIs.
The extent of kidney involvement and the presence of VUR make the possible the identification of different categories of risk of scarring
The sequence of events in the untreated animal leads to a loss of approximately 20% of total renal function, with the damage all having begun within 24 h of renal inoculation but continuing for 1-2 weeks after infection.
Within 10 days the humoral system has been activated and antibody formation leads to opsonization by antibody prior to more effective phagocytosis and eradication of the infection.
It has been thought that recurrent pyelonephritis in children does not lead to further renal scarring, but recent studies by both Berg, in children, and Jacobscon et al., in women who had infection as children, show a decrease in renal function from recurrent disease.
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45. Thank you for your attention!
Although most physicians are not responsible for the work-up after a UTI, the physician may want to educate the parents and stress the importance of follow-up and further work-up.
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46. Prophylactic antibiotics in children at risk for UTI
Lesser grades of VUR and constipation did not significantly increase the risk of UTI.
Significantly increased risk of infection among those with voiding dysfunction and VUR of grade 3 or greater severity.
直至，2001僅5篇randomized control trials among children receiving prophylactic antibiotics – they concluded that there is considerable uncertainty as to whether low-dose antibiotics administration prevents UTI in children.
There is little evidence-based information available to help make a decision as to which children considered at risk for a UTI would benefit from being placed on prophylactic antibiotics.
Pediatric nephrology (2002) 17:
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47. Incidence of Bacteriuria and Urinary Infection in 128 Patients with Spinal Cord Injury According to Method of Urinary Tract Drainage
Lesser grades of VUR and constipation didn’t significantly increase the risk of UTI.
The overall rate of UTI: 2.5 episodes/p’t/year
SCI: incontinence, elevated intravesical pressure, reflux, stones, and neurological obstruction commonly found in the spinal cord injured population, increase the risk of UTI.
UTI still ranks as the second leading cause of death in the SCI patient.
Bladder contraction is accompanied by vesicosphincter dyssynergia instead of sphincer relaxation.
Treatment for asymptomatic bacteriuria in SCI p’ts remains controversial.
Symptomatic UTI: tx with the most specific, narrowest spectrum antibiotics available for the shortest possible time.
Characteristics of the quinolones make them well suited to treating UTI in the SCI patient.
J Urol. 2000;164:1285–1289.
2018年9月18日