URINARY TRACT INFECTIONS IN CHILDREN

1. URINARY TRACT INFECTIONS IN CHILDREN Assist. prof. dr. Magdalena Stârcea IVth Pediatric Clinic

2. Background: Urinary tract infections (UTIs) are common in the pediatric age group. Early recognition and prompt treatment of UTIs are important to prevent progression of infection to pyelonephritis or urosepsis and to avoid late sequelae such as renal scarring or renal failure. • Infants and young children with UTI may present with few specific symptoms. Older pediatric patients are more likely to have symptoms and findings attributable to an infection of the urinary tract. • Differentiating cystitis from pyelonephritis in the pediatric patient is notalways possible, although small children who appear ill or who present with fever should be presumed to have pyelonephritis if they have evidence of UTI.

3. TERMINOLOGY. CLASSIFICATION I. Urinary tract infection - is the common term for a heterogeneous group of conditions involving pathogenic bacterial colonization of the urinary tract at any level of the urinary meatus renal cortex , followed by the elimination of germs in the urine. Colonization may be transient or permanent .II . Asymptomatic bacteriuria: significant bacteriuria detected by screening in apparently healthy population . It is commonly seen in girls of school age.

4. III . Bacteriuria is pathognomonic feature of urinary infection , a term used for the presence of bacteria in urine obtained optimally by bladder catheterization or suprapubic aspiration puncture . • significant bacteriuria is defined as Kass > 105CFU / ml ( CFU = colony forming units ) in urine obtained by the methods of peripheral collecting (urinary stream) • Johnson describes more complex benchmarks with practical applications for assessing significant bacteriuria : bacteriuria than 10 ² CFU / ml in children catheterized bladder , or any amount of colonies urine specimens collected by suprapubic aspiration . IV . Symptomatic UTI is defined as significant bacteriuria associated with suggestive symptoms (dysuria, urinary urgency, urinary frequency, with or without fever and back pain) . It can manifest as: Pyelonephritis- bacterial infection of the renal parenchyma and intrarenal urinary way and is accompanied by significant bacteriuria, bacteremia, pyuria, hematuria sometimes . Cystitis : inflammation of the bladder, manifested by dysuria , urinary frequency, urinary urgency. Fever is not present .

5. V. Chronic pyelonephritis is a pathological condition which involvesrenal scarring. If pyelonephritis associated with vesicoureteral reflux (especially intrarenal reflux ), the term used is reflux nephropathy. Acute inflammatory changes are found in high UTI and disappear on average 6 months after acute infectious episode . VI. Response to treatmentRecovery is characterized by the loss of bacteriuria following treatment. Relapse : characterized by persistent bacteriuria (same bacterial species) after adequate treatment of the infection; is commonly associated with a structural abnormality of the urinary tract or stones . Reinfection: characterized by successive episodes of symptomatic and asymptomatic episodes of urinary tract infection. This episodes are caused by different bacterial species or serotypes and reflects a defect in the local defense mechanisms .  Persistent infection : characterized by the presence of significant bacteriuria during and after treatment.

6. EPIDEMIOLOGY: • UTI has males predominance in the first trimester of life (up to 3 months). Uncircumcised males have a higher incidence than circumcised males. Uncircumcised male infants have a higher incidence of UTI than female infants. • Except neonatal period, UTIs are more frequent in females than males at all ages. • International studies show the highest incidence peak of the first episode of uper UTI between 0 and 2 years. The peak incidence of the first lower episode of UTI (boys and girls ) is between 2-4 years. • Asymptomatic bacteriuria is more common in girls of school age. • Nosocomial urinary infection occurs only in the case of investigating urinary malformation in children substrates . • After Nelson (18th edition , 2007) the cumulative incidence is 2.5 % for both sexes. ITU occurs 3-5 % of girls and 1% of boys • The American Academy of Pediatrics (Bergman DA , Baltz RD, 2009) recognizes a febrile urinary tract infection incidence of 6.5 % to girls and 3.3 % for boys .

7. ETIOLOGY: • Escherichia coli causes 75-90 % of UTI in children. • Other common bacterial etiology of UTI are Klebsiella pn . , Proteus (30% of boys cystitis ), Staphylococcus saprophyticus (urinary infections in adolescents of both sexes and in the neonate). • In the neonatal period, especially in premature urinary infections are determining by hematologycal way, and etiology are dominated by E. coli, Salmonella , Enterobacter , Klebsiella. • In patients with congenital abnormalitiesof renal or urinary tract function may occur urinary infection caused by bacterial low virulent in normal conditions (Pseudomonas aeruginosa , Staphylococcus aureus or epidermis, Hemophilus influenzae , Group B sterptococi , adenovirus ) . • Acute cystitis may be caused by adenoviruses , especially male school , manifested by fever, dysuria and terminal hematuria . • In adolescents isolated urethritis manifested with dysuria is generated by microorganisms such as Chlamydia trachomatis , Neisseria gonorheae , Mycoplasma genitalium , or herpes simplex virus.

8. PATHOGENESIS - UTI is an interaction between → host factors → invading microorganism • Way of infection a)descending   - Common in the new born   - Unusual for onother age   - Older children are involvevirulent microorganisms such: S.aureus, P. aeruginosa, Serratia, KB b) ascending (colonization retrograde from the urethral orifice) - Germ involved found in bowel flora - Serotypes with virulence special for urothelium- Favored by malformation

9. Host factors: • Anatomical abnormalities Physiologically - adhesion and proliferation of germs is prevented by washing process during urination (local defense mechanism ). Urinary abnormalities may interfere with defense mechanisms  Patients with ITU - 40-50% defectsdetectable radiographically - 30 % have RVU Other malformations : - obstruction at different levels of urinary- ureterocel                             - urinary stones , predispose to stasis/infection.                             - foreign bodies (catheters) facilitate infection • Uroepithelial adherencein patients with recurrent UTIs without malformation, urinary cells have a high density of receptors on their surface → persistence + proliferation of germs. Mechanisms of adhesion is unclear, are involved: • some blood groupantigens presenton cells and secreted from the cell surface • deficit of Se IgA or lysozyme                                  

10. Bacterial factors: Virulence elements: - Bacterial outer membrane is made of - proteins, lipids , lipopolysaccharides . - Bacterial endotoxin (AgO, LPS structure) → responsible for systemicreaction (fever, shock ) - Bacterial capsule is composed of LPS acid (K antigen with important role in bacterial virulence) - Adhesion of E. coli to uroetheliu - essential for persistence in the urinary tract, a phenomenon mediated by receptors (pili or fimbriae) - Virulence of E. coli is signed by associating other bacterial factors:     - Production of hemolysin     - Production of aerobactină

11. CLINICAL PRESENTATIONUrinary tract infection in children has a wide spectrum of manifestations, ranging from asymptomatic bacteriuria or subtle manifestations, of revision (enuresis , urgency of micturition ) to the clinical picture of toxic-septic shock (in newborn and premature. 1. Neonate: nonspecific symptoms such as weight loss, vomiting, flatulence, thermal instability, frequently hypothermia, poor feeding, respiratory distress, prolonged jaundice, Failure to thrive. May be complicated by sepsis with positive blood cultures and secondary dissemination. 2.Perioada infancy : clinical picture is nonspecific- septic type fever, poor feeding, vomiting - irritability, parenteral diarrhea, flatulence, jaundice - strong-smelling urine

12. 3. Preschoolers and schoolers :- Signs of cystitis ( dysuria, urinary frequency, urinary urgency)- Nocturnal enuresis or diurnal (recently installed)- Signs of acute pyelonephritis (fever, vomiting, back pain or flank pain, macroscopic hematuria) - Strong-smelling urine Acute renal failure is rarely reported in association with first acute pyelonephritis. If there happend betrays amalformation. Some infections with Proteus can generate stones (Proteus cleaves ureainto ammonia and CO2, with alkalinization of urine andprecipitation of salts, with formation of calculi) .

13. DIAGNOSIS :Objectives: - Confirm the UTI  - Identification of malformations  - The location of infection

14. Urine analysisa) urine analysis :- Leucocyturia ( > 10WBC/ ) Attention to other situations with leucocyturia without UTI :- dehydration- vaginitis- urethral irritation, stones - tubular acidosis- interstitial nephritis, GN, polycystic kidney diseaseb ) screening tests :- Nitrite test : bacterial nitrate reductase converts urinary nitrates into nitrites. False negative test is if the bacteria does not have nitrate reductase or in case with polyuria - Urinary density may be decreased in chronic pyelonephritis- Proteinuria is found in small quantities- Microscopic hematuria occurs frequently (sometimes macroscopic)

15. c ) urine culture Method for collecting urine is dependent the age : - Older children, teens - from medium urinary jet, after rigorous local toilet. This is the method most frequently used, but the chance of bacterial contamination of the urine sample is great. - Infants and toddlers - by peripheralcollecting vessels after thorough cleaning of the perineal area and pasting container. It has a high risk of contamination, time being near the rectum , but it is no invasive . - In infants- by catheterisation - uncontaminated urine sample - In newborns and infants - suprapubic puncture is most simple, quick and safe method of urine collection .

16. Microbiological Diagnosis Criteria  classical interpretation is the Kasscriteria: significant bacteriuria - over than 105UFC/ml in urine obtained by peripheral method  Johnson describes more complex benchmarks with practical applications for assessing significant bacteriuria : • Bacteriuria than 10 ² CFU / ml in children with catheterized bladder, or • Any colonies from urine specimens collected by suprapubic aspiration, or • Over 105CFU/ml in urine collected by means of peripheral

17. B. Blood analyses - CBC - inflammatory anemia, leukocytosis with netrophils - Acute phase reactants: ESR, Fg; PCR (positive in pyelonephritis )- Nitrogen retention may occur in newborn, smallinfants and in cases that have a pre-existing malformation substrate- Positive blood cultures (in neonates, infants, dystrophic, immunocompromised) Recently, techniques described for immunological diagnosis of renal involvement in urinary tract infection. β2microglobulin, IL 6, procalcitonin, Tamm Horsfall protein, LDHenzyme complex seems to have a important role in the differentiation of lower and upper urinary tract infection and to determinate the severity of pathological lesions of UTIs.

18. C. Imaging evaluation Purpose: - discovery malformations  - discovery renal scars          - evaluation of renal function Imaging evaluation is considered mandatory to: - All children less than 5 years with recurrent UTIs - UTI in infants - All boys with recurrent UTIs, regardless of age - All cases of recurrent UTIs a) Ultrasonography- noninvasive- Reveals dimensions renal system changes pioelocaliceal , stones- Practice regardless of the patient's condition and GFR

20. b ) Voiding cystourethrogram (VCUG) detects urethral and bladder anatomy, UPV andvesicoureteral reflux (VUR). - The only way (usual) for the diagnosis of VUR- Useful in the diagnosis of posterior urethral valve (elective - endoscopy bladder that can be practiced valve resection too)- After at least 3 weeks after the sterilization of urine c ) Intravenous urography (IVU) view size of kidneys, renal scarring , pielocaliceal system and function, stones- Is contraindicated in renal failure d ) Exploring radionuclide* Tc99 DTPA - provides data on renal function * Tc99 DMSA – for renal scarring

24. Imaging investigations algorithm is :• ultrasound - first line• minimum radioisotope examination at 10-14 days for diagnosisrenal scarring of acute infection • at 6 months DMSA for chronic renal scarring • voiding cystourethrogram within 3-6 weeks after infection sterilization

25. TREATMENT:The therapeutic measures depend on the localisation of the infection, the age of the patient. Acute pyelonephritis: • hospitalization, especially in infants andsmall children • iv antibiotics: I. cephalosporins (IIth/ IIIth generation)- Cefamandole 50-150 mg / kg / day- Ceftazidime 50-100 mg / kg / day- Cefuroxime 50-100 mg / kg / day- Ceftriaxone 50-100 mg / kg / day II . aminoglycoside ( netilmicin ) 5 mg / kg / day! Attention to renal toxicity Favorable evolution occurs in 48-72 hours. Urine culture control is performed in 48 - 72hours.

26. After 3-5 days you can switch to oral therapy if:- Toxic signs disappeared- Clinical improvement occurred- Germ is sensitive to oral antibiotics The duration of the treatment = 10-14 days In case of lack of response may suspicion :- resistance to antibiotics- urinary tract obstruction- presence of complications (renal abscess) Acute cystitis- oral therapy: - Trimethoprim 5-8 mg / kg / day - Amoxicilin+clavulanic acid (40 mg / kg / day) - Nitrofurantoin 5-7 mg / kg / day - Quinolones in adolescents The control urine cultures performed 48 hours Duration of treatment = 5-7 days

27. UTI in newborn- emergency hospitalization (risk of sepsis)- iv antibiotic therapy starts quickly after hospitalisations andcontinued until the blood and urine normalization - antibiotic dosage is based on gestational age in preterm newborns and glomerular filtration rate for newborn - after clinic normalization malformation willfund evaluate - in the absence of malformations or complications AB stops after 10-14 days UTI recurrence prevention - Recurrence occurs in 40-50 % of cases even in the absence of malformations. - Prophylactic therapy is applied in single dose at bedtime , 1/ 4 to 1 /3 of the loading dose . * Nitrofurantoin 1-2 mg / kg / day * Trimethoprim 2 mg / kg / day* Second generation cephalosporins(Cefaclor 5-10mg/kg/zi)

28. Prophylactic therapy is applicable to:- Recurrent UTI- UTI with malformation- UTI + urinary stones- UTI + neurogenic/unstable bladder Asymptomatic bacteriuria- In 40-50 % of cases sterilized without treatment- There is no deterioration of renal function Hygienic-dietary regime in UTI: - Rich fluid regime- Regular urination - Emptying of the bladder - Combating constipation

29. References: 1. O. Brumariu, Mihaela Munteanu, Infecția tractului urinar, în Hematologie și nefrologie pediatrică, elemente practice de diagnostic și tratament, editura Junimea, Iași, 2008, cap. 10, pag. 283 – 293. 2. Brumariu O, Munteanu M, Gavrilovici C, Infecţia tractului urinar, în Ciofu E, Ciofu C, Pediatria - tratat, ediţia I, Bucureşti, 2001, cap. 11, pag. 711- 718. 3. Nelson textbook of pediatrics - 18 ed. Behrman RE, Kliegman RM, Jenson HB: Urinary Tract Infections, cap. 538, pag. 2223 – 2227, Saunders Elsevier, 2007. 4. Rubin HR, Cotran RS, Tolkof – Rubin N.E. Urinary Tract Infection, Pyelonephritis, and Reflux Nephropathy, BRENNER & RECTOR’S THE KIDNEY, ediția 9, Saunders Elsevier, 2012; cap. 34:1203 – 1238. 5. Rees L., Brogan P., Bockenhauer D., Webb N., Urinary Tract Infections, în Pediatric Nephrology, Oxford Specialist Handbooks in Pediatrics, second edition, cap. 4, pag. 75 - 90. 6. Stârcea (Buhuș) Iuliana, Infecția de tract urinar la copil. Probleme de diagnostic și tratament, teză de doctorat, Iași, 2011. 7. Stârcea Magdalena, Mihaela Munteanu, Gabriela Coman, Cristiana Dragomir, O. Brumariu: Infecția urinară la copil. Aspecte ale diagnosticului bacteriologic, Rev. Med. Chir, Iași, 2008; 112(4):932-937. 8. Svanborg C., Godaly G., Urinary tract infections revisited, Kidney International (2007) 71, 721–723.