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

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. 2018年9月18日

Incidence of Urinary Tract Infection Among Children Am J Med. 2002;113(1A):5S–13S. 2018年9月18日

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. 2018年9月18日

2018年9月18日

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):675-690, 2001 2018年9月18日 Pediatr Nephrol (2001) :69-72

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

Sequence of recurrent UTI in Pediatric Girls Am J Med. 2002;113(1A):55S–66S. 2018年9月18日

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. 2018年9月18日

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. 2018年9月18日

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%. 2018年9月18日

Diagnosis of Pediatric UTI Am J Med. 2002;113(1A):55S–66S. 2018年9月18日

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

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 2018年9月18日

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;83:1011-5. Pediatrics 1986;78:96-9. Clin Pediatr [Phila] 1993;32:130-4. 2018年9月18日

Etiology of Uncomplicated Versus Complicated UTI Adult women Am J Med. 2002;113(1A):14S–19S. 2018年9月18日

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. 2018年9月18日

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) 143:150-154 2018年9月18日

Reanl parenchymal damage Pathogenesis of UTI colonization Ascending infection inflammation Tissue ischemia and reperfusion Reanl parenchymal damage 2018年9月18日

Inflammation process 2018年9月18日

Ischemia and reperfusion 2018年9月18日

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 (44- 92%). Antibody-coated bacteria, and renal nuclear scanning have been used as indicators of PAN. However, the utility of these tests is still limited. 2018年9月18日

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. 2018年9月18日

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. 2018年9月18日

Dimercaptosuccinic acid (DMSA) renal scan findings in different age groups positive negative 2018年9月18日 Pediatr Nephrol (2002) 17:30–34

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 2018年9月18日

Association of APN with VUR, severity of reflux, and renal scar in all three groups Pediatr Nephrol (2003) 18:362–365 2018年9月18日

APN or scar formation according to presence of low grade or absence of VUR Pediatr Nephrol (2003) 18:362–365 2018年9月18日

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; 221:366-370. 2018年9月18日

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, 1005-1008 2018年9月18日

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. 2018年9月18日 Pediatr Nephrol (1999) 13:219–222

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

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

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% 2018年9月18日

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% 2018年9月18日

Relationship of DMSA inflammatory volume and renal US 11.0±2.4ml 3.0±0.8ml 2018年9月18日

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 2018年9月18日

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 2018年9月18日

Therapeutic Management of Pediatric UTI 2018年9月18日 Am J Med. 2002;113(1A):55S–66S.

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. 2018年9月18日

Risk Factors for Trimethoprim-Sulfamethoxazole (TMP-SMX) Resistance Am J Med. 2002;113(1A):29S–34S. 2018年9月18日

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 2018年9月18日

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. 2018年9月18日

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. 2018年9月18日

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. 2018年9月18日

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) 17:506-510. 2018年9月18日

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