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Urinary tract infections in children
SYMPOSIUM: NEPHROLOGY
Urinary tract infections in children
Key points C
Lyda Jadresic C
C
Abstract Urinary tract infection (UTI) is a common bacterial infection that can affect infants and children. The severity of illness depends on microbial virulence and host susceptibility. It has a number of different ways to manifest itself clinically ranging from a mild cystitis to a presentation with systemic symptoms such as a nonspecific fever, vomiting, failure to thrive or irritability or with significant dehydration and electrolyte imbalance which can be seen in infants in the first 3 months of life. It is therefore a ubiquitous differential diagnosis in many children presenting both in primary care and in the hospital setting. In most children urinary infections are isolated acute infections from which they recover quickly. In a small minority of children urinary infections can be associated with underlying significant pathology: either they are associated with congenital renal tract malformations such as renal dysplasia and/or hydronephrosis or if they have recurrent infections this may lead to renal scarring, particularly if the infections are associated with systemic symptoms.
C
C
the uroepithelium, one of these is the possession of P fimbriae which increase bacterial adhesion to the mucosa and facilitate its exposure to bacterial toxins. UPEC are cause 70e90% of community acquired urinary tract infections. Following mucosal adhesion the innate immune response is stimulated and various families of Toll like receptors (TLRs) play a key role in the activation of transcription factors, and production of a variety of cytokines, interferons and their regulatory factors. The degree of renal damage has been found to be correlated to high blood and urinary levels of various cytokines, for example Interleukin 6 (IL-6), which induces fever, stimulates hepatocyte production of C reactive protein and acts on the urothelium to produce IgA antibodies. Over the last few years it has become increasingly clear that there is genetic variation in innate immunity, e.g. affecting the expression and function of TLRs, Interferon Regulator Factor 3 (IRF3) and IL-8 receptors, resulting in clinical differences in the host response ranging from being able to tolerate bacteria asymptomatically (asymptomatic bacteriuria) to mounting a severe inflammatory response resulting in acute pyelonephritis. The familial occurrence of recurrent UTI has been known about for some time and may be explained by this type of genetically transmitted defects in single proteins involved in the innate immunity of the uroepithelium to uropathogens. Most children with UTI do not have underlying structural abnormalities and this area of study, which is already seeing major expansion, should provide in the future the tools for identifying children at risk of renal damage as well as enabling the development of specific biological agents to prevent recurrent UTI. Other bacteria are other coliforms such as Klebsiella as well as organisms such as Proteus mirabilis, Pseudomonas, coagulase negative Staphs, Streptococci (e.g. Group B strep, Enterococci), Staphylococcus aureus and occasionally Haemophilus influenzae as well as others. These non E. coli organisms often do not possess the aforementioned virulence factors seen in UPEC and it has been shown that their ability to cause urinary infections depends heavily on the presence of host factors, particularly structural urinary tract abnormalities leading to urinary stasis. Therefore, one of the indications for investigating the urinary tract in children is the type of organism involved in the infection.
Keywords acute pyelonephritis; bladder function; constipation; cystitis; fever; non Escherichia coli urine infection; renal scarring; urine infection; uropathogenic Escherichia coli
Definition The definition of a urinary tract infection consists of bacteriuria in the presence of symptoms. Bacterial growth of more than 105 is regarded as the threshold number for a significant bacterial growth; however, the evidence base for this threshold is weak. There is evidence that infants may have urine infections with lower bacterial counts. Although in most instances there is also pyuria this may sometimes be absent. Asymptomatic bacteriuria needs no treatment or investigation.
Causative organisms and host response The bacteria that cause urinary tract infections originate from gut and perineal flora. The urinary tract is kept sterile by a normal urine flow and the innate (or nonspecific) local immune system. The ability of bacteria to cause urinary infections depends on bacterial virulence factors as well as host factors. Uropathogenic E. coli (UPEC) have specific virulence factors which enable them to attack Lyda Jadresic FRCPCH MD is Consultant Paediatrician at the Gloucestershire Hospital NHS Trust, Gloucester, UK. Conflicts of interest: The author was a member of the NICE Guideline Development Group for Childhood UTI which published the current guideline back in 2007. The author participated in the development of NICE Quality Standards of this guideline and i nits recent Evidence Update. The author had a grant from HQIP to carry out a multisite audit of the NICE UTI guideline both in 1ry and 2ry care centres; no monies will come to the author or her department apart from covering travel expenses to meetings in London and Birmingham.
PAEDIATRICS AND CHILD HEALTH 24:7
Urine for microscopy and culture should not be collected by bag or pad; a clean catch sample should be obtained with the option in hospital of a catheter or suprapubic sample. Infections with non Escherichia coli UTIs are associated with increased risk of underlying obstructive structural abnormalities. Clinical features inform the decision as to which children need renal imaging. Children with recurrent UTIs should have a basic clinical assessment of bladder function. Genetic differences in innate immunity and uropathogens virulence factors play a key role in the risk of acute pyelonephritis.
Incidence and epidemiology Reliable measurements of the incidence of UTI in children have been difficult. Epidemiologically strong studies from Sweden
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SYMPOSIUM: NEPHROLOGY
have reported that around 2% of boys and girls aged less than 2 years have a UTI. Based on evidence extracted from Swedish and UK data, approximately 10% of girls and 3% of boys will have had a UTI before the age 16 years. In infancy, the incidence of UTI in the under 3 months of age is higher in boys most probably reflecting a higher incidence of obstructive congenital urogenital abnormalities in males. After this age, girls have a higher incidence of UTI. Girls are more likely to have recurrences of UTI.
infections, viral or bacterial, other than UTI. In situations when the dipstick is negative for both nitrite and leucocyte esterase but the symptoms point to a UTI, the sample should be sent to the laboratory and the question of empirical treatment with antibiotics prior to the culture results depends on the severity of illness. Febrile children should be assessed according to the NICE fever guideline and careful assessment of very young infants with possible UTI should include a decision about ruling out an associated meningitis in severe ill infants. This is a rare complication.
Clinical presentation and differential diagnosis The clinical presentation can be divided into two types. In a lower tract UTI or cystitis the symptoms are confined to the bladder and consist of dysuria, frequency, incontinence, urgency of micturition and abdominal pain. An upper tract UTI or ‘acute pyelonephritis’ is defined by the presence of fever (38 C) or other systemic symptoms such as loin pain or vomiting and in infants typically failure to thrive or persistent irritability. Babies under 3 months of age can occasionally present with dehydration, hyponatraemia and hyperkalaemia mimicking the findings in congenital adrenal hyperplasia. The symptoms in the very young children particularly infants are nonspecific and it is safer to assume that they are upper tract in nature. The diagnosis needs to be confirmed by obtaining a urine specimen which is sent for culture but this is difficult in children still in nappies. Febrile children should be assessed using the ‘traffic light system’ of the NICE fever guideline and it is recommended that in those with nonspecific fever regardless of the severity of illness should have a urinalysis. Large numbers of young children present with nonspecific symptoms to primary care and the DUTY study hopes to create an algorithm of presenting symptoms and signs to help select which children should have a urine sample taken.
Management and treatment of UTI Infants under 3 months with a suspected diagnosis of UTI should be assessed by paediatricians. The history and examination on all children with confirmed UTI should be recorded and should include the following: temperature hydration history suggesting previous UTI or confirmed previous UTI recurrent fever of uncertain origin antenatally-diagnosed renal abnormality family history of vesicoureteric reflux (VUR) or renal disease constipation dysfunctional voiding including urine flow enlarged bladder abdominal mass evidence of spinal lesion growth blood pressure The vast majority of UTIs in children older than 3 months can be treated orally. Children with cystitis/lower tract symptoms can be treated with a 3 day course of antibiotic. Common and useful antibiotics are trimethoprim, nitrofurantoin (should not be used in AP/upper tract UTI), cephalexin or co-amoxiclav. The resistance of E. coli to amoxicillin is currently too high for this antibiotic to be recommended as a first line antibacterial. The choice of antibiotic should ideally be agreed along joint guidelines with the local microbiology department. This is particularly important to contain the emergence of increasingly resistant bacteria. Children with AP/upper tract infection can be treated with a 7e10 days course of oral antibiotics. Exceptions to the initiation of oral therapy include vomiting, evidence of circulatory shock, or the presence of known potential obstruction such as hydronephrosis. Continuing fever at the end of 48 hours in spite of suitable antibiotics should be investigated with at least a repeat urine culture and an ultrasound of the renal tract as urinary obstruction can be a cause for failure to respond to antibiotics. There is no indication for the routine use of antibiotic prophylaxis.
Urine analysis There is a significant risk of contamination of the urine sample if urine bags are used and this is slightly less when pads are used and changed every 30 minutes. The gold standard is a suprapubic aspiration (SPA) with ultrasound guidance although recent evidence shows that urethral in out catheterization yields reliable results and is better tolerated. These techniques require training and they are not feasible in primary care. Therefore the best and most practical way to try to obtain a noncontaminated sample is by clean catch and this should be possible in the community. Urine dipsticks with reagent strips to look for the presence of nitrite and leucocyte esterase are useful particularly to rule out UTI, they can be useful to rule in UTI but the likelihood ratios are less. They are unreliable in children under 2 years. There is not enough data on how reliability changes as the child gets older and NICE recommends that children under 3 years should have urgent microscopy rather than urine dipstick for the rapid diagnosis of UTI. Antibiotics should be started after sending the sample to the laboratory if the dipstick is nitrite positive or bacteria are seen on microscopy. If the dipstick is leucocyte positive or if there is only pyuria on microscopy, the sample should be sent to the laboratory and the decision to start empirical antibiotic treatment for UTI should be based on the clinical findings and the severity of illness. Isolated pyuria can occur in febrile children due to
PAEDIATRICS AND CHILD HEALTH 24:7
Prevention of UTI There have been many studies on a variety of interventions to try and prevent UTI in children including antibiotic prophylaxis, cranberry juice, probiotics, circumcision, Vitamin A, etc. The role of antibiotic prophylaxis has been questioned by a number of metaanalyses; it may confer a small protective effect in girls with recurrent infections and VUR. Proanthocyanidin-A present in cranberry juice, inhibits bacterial adhesion to uroepithelial cells,
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Ó 2013 Elsevier Ltd. All rights reserved.
SYMPOSIUM: NEPHROLOGY
addressing any issues around bladder function. It is helpful to give general advice regarding healthy life styles. If renal tract investigations are needed these need to be explained. It is helpful to have an advice leaflet to hand out.
however a recent Evidence Update by NICE found that cranberry juice does not appear to prevent UTIs although the evidence was limited. Circumcision significantly lowers the incidence of UTI but it does not have a role in the management of simple UTI. Under specialist paediatric urology guidance it may play a part in the management of a small subgroup of boys with recurrent UTIs or high grade VUR. The presence of dysfunctional bladder and or chronic constipation increases the risk of recurrence of UTI.
The investigation of the renal tract: historically a UTI was associated with concerns about vesicoureteric reflux which is diagnosed with a micturating cystourethrogram (MCUG). Over the last 5e7 years there has been a trend towards less imaging. Recent evidence suggests that VUR may be as common in children with UTI as those without. The NICE 2007 Childhood UTI guideline does not recommend looking for VUR after the first UTI and more recently the 2011 American Association of Paediatrics (AAP)’s UTI guideline has also moved away from the routine use of the cystogram in infants with a first febrile UTI. A DMSA scan is no longer recommended in the AAP guidelines, which favour the use of the renal ultrasound instead. There is a different radiation load depending on the type of renal imaging algorithm used. Current recommendations from NICE on renal tract imaging are targeted to the minority of children whose clinical presentation puts them at risk of underlying pathology as outlined above. A basic outline of who requires investigations is given below and this is followed by the full details of the imaging recommendations. Children who need some form of renal tract investigation after a first UTI include:
Long term outcome The proportion of children found to have renal parenchymal defects if investigated after a first UTI is approximately 5%. Studies have demonstrated that bladder dysfunction can play a key role in UTIs and that VUR can be a secondary effect. It is important, therefore, to make a clinical assessment of bladder function in children with UTIs. Large, long term follow up studies from Sweden on blood pressure in patients known to have scarred kidneys in association with childhood UTI have shown no significant differences compared to normal controls. A nonsignificant rise was seen in the subgroup with bilateral scarring in association with loss of renal mass. The prevalence of hypertension in adults in England is high, affecting an average of 29% of women and 32% in men. Therefore, children with UTI are much more at risk of developing hypertension as a result of life style factors rather than UTIs. It is important when advising patients and their parents/carers (see below) to use the opportunity for recommendations on a healthy life style. Impairment of renal function in association with childhood UTI is very uncommon. In the rare occasion when this occurs it tends to be either a boy with congenital bilateral renal dysplasia or seen very rarely as acquired renal damage in girls from with recurrent febrile UTIs and very often associated bladder dysfunction. Studies show that there needs to be significant reduction in renal mass bilaterally. More long term studies such as the Swedish ones above are needed. In the meantime NICE recommends that once renal scarring is identified that the child has regular blood pressure readings as well as having the urine tested for proteinuria. It is important to add at least a yearly creatinine measurement to those children with bilateral scarring.
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Follow up
Children with an atypical UTI should have and ultrasound of their renal tract during the acute infection as they are more likely to have obstructive structural abnormalities. For further investigations of children with atypical UTI please refer to the NICE Childhood UTI guidelines. Children with recurrent infections also need investigation. NICE defined recurrent UTI as: two UTIs where at least one has been an AP/upper tract infection, or three or more episodes of cystitis/lower tract infection. A micturating cystourethrogram is no longer recommended for all infants with UTI. It should be considered in a young child with a febrile UTI and atypical features such as a history of antenatal hydronephrosis or ureteric or renal dilatation on ultrasound, infection with non E. coli organisms, abnormal urine stream, or is found to have bright and small kidneys on ultrasound (renal displasia) or has a degree of renal failure.
Advice: following a UTI it is vital to give clear advice to parents/ carers and young people about the symptoms of UTI and about the need for prompt recognition and treatment. They and their family doctors need to be made aware or reminded of the nonspecific nature of the symptoms of UTI and particularly that fevers should not be put down to a ‘viral infection’ or teething unless a UTI has been ruled out. It is preferable to treat after a sample has been obtained and be prepared to stop after 48 hours if the cultures come back negative. Equally parents/carers need to know that if their baby fails to thrive, has a vomiting illness or persistent irritability that a UTI could be the reason and to seek medical advice promptly. Parents/carers and young children need to seek medical help again if symptoms do not settle within 48 hours of starting treatment or if the child gets worse. In addition, advice needs to be given regarding prevention such as ensuring a good fluid intake, avoiding constipation and
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Children under 6 months of age Children with an atypical presentation: seriously ill poor urine flow abdominal or bladder mass raised creatinine septicaemia failure to respond to treatment with suitable antibiotics within 48 hours infection with non E. coli organisms
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SYMPOSIUM: NEPHROLOGY
ultimately to alternative ways of treating or preventing urine infections. A
There is a risk of introducing infection at the time of a MCUG and therefore it is recommended that prophylactic antibiotics should be given orally for 3 days with the MCUG taking place on the 2nd day. My personal practice is to use a full therapeutic dose during these 3 days.
FURTHER READING Carpenter MA, Hoberman A, Mattoo TK, et al. for the RIVUR Trial Investigators. The RIVUR trial: profile and baseline clinical associations of children with vesicoureteral reflux. Pediatrics 2013; 132: e34e45. Downing H, Thomas-Jones E, Gal M, et al. The diagnosis of urinary tract infections in young children (DUTY): protocol for a diagnostic and prospective observational study to derive and validate a clinical algorithm for the diagnosis of UTI in children presenting to primary care with an acute illness. BMC Infect Dis 2012; 12: 158. http://www. biomedcentral.com/1471-2334/12/158. Finnell SM, Carroll AE, Downs SM. Technical report e diagnosis and management of an initial UTI in febrile infants and young children (American Association of Paediatrics). Pediatrics 2011; 128: e749e70. Godley ML, Desai D, Yeung CK, Dhillon HK, Duffy PG, Ransley PG. The relationship between early renal status, and the resolution of vesicoureteric reflux and bladder function at 16 months. BJU Int 2001; 87: 457e62. Hannula A, Perhomaa M, Venhola M, Pokka T, Renko M, Uhari M. Longterm follow-up of patients after childhood urinary tract infection. Arch Pediatr Adolesc Med 2012; 166: 1117e22. Hannula A, Venhola M, Renko M, Pokka T, Huttunen NP, Uhari M. Vesicoureteral reflux in children with suspected and proven urinary tract infection. Pediatr Nephrol 2010; 25: 1463e9. Health Survey for England 2008. Trend Tables. The NHS Information Centre for Health and Social Care. Koff SA, Wagner TT, Jayanthi VR. The relationship among dysfunctional elimination syndromes, primary vesicoureteral reflux and urinary tract infections in children. J Urol 1998; 160(3 Pt 2): 1019e22. La Scola C, De Mutiis C, Hewitt IK, et al. Different guidelines for imaging after first UTI in febrile infants: yield, cost, and radiation. Pediatrics 2013; 131: e665e71. NICE guideline: urinary tract infections in children (diagnosis, treatment and long term management) August 2007. NICE. Urinary tract infection in children Evidence Update 48 October 2013. www.nice.org.uk. Sillen U, Brandstrom P, Jodal U, et al. The Swedish reflux trial in children: V. Bladder dysfunction. J Urol 2010; 184: 298e304. Svanborg C. Urinary tract infections in children: microbial virulence versus host susceptibility. Adv Exp Med Biol 2013; 764: 205e10. Toffolo A, Ammenti A, Montini G. Long-term clinical consequences of urinary tract infections during childhood: a review. Acta Paediatr 2012; 101: 1018e31. Wennerstrom M, Hansson S, Hedner T, Himmelmann A, Jodal U. Ambulatory blood pressure 16 to 26 years after the first urinary tract infection in childhood. J Hypertens 2000; 18: 485e91. Wennerstrom M, Hansson S, Jodal U, Sixt R, Stokland E. Renal function 16 to 26 years after the first urinary tract infection. Arch Pediatr Adolesc Med 2000; 154: 339e45. Williams GJ, Craig JC, Carapetis JR. Preventing urinary tract infections in early childhood. Adv Exp Med Biol 2013; 764: 211e8.
Recurrent UTI: children with recurrent urine infections should be referred to a paediatric specialist. This has the purpose of identifying, investigating and managing potential reasons for recurrences and dealing with any sequelae such as scarring. The first step is to identify the clinical features at the time of the infections and distinguish them from either vulvovaginitis or asymptomatic bacteriuria, classify the UTI recurrences into either cystitis or acute pyelonephritis episodes. It is also necessary through direct questioning to seek evidence for any continence abnormalities asking about micturition symptoms when well in between infections. This involves asking questions about the frequency of micturition, urgency, diurnal incontinence, hesitancy, staccato voiding and stress incontinence. Identification of constipation is important as it often is a risk factor for not only UTIs but it also aggravates continence problems. Close liaison with the paediatric continence service for their input is useful not only in managing constipation and continence problems and trying to achieve complete bladder emptying but also in performing uroflowmetry studies when the history suggests the possibility of a dysfunctional bladder. In such children, if the UTIs persist, consideration should be also given to performing an indirect cystogram to look for VUR. There will be the occasional child with recurrent, often febrile UTIs who fails to empty his/her bladder in the absence of outflow obstruction and in spite of a good fluid intake and absence of constipation, on whom intermittent catheterization will need to be considered in order to prevent infections. In the child who continues to have recurrent UTIs in spite of having addressed bladder or constipation problems it is worth considering a period of a few months on low dose antibiotic prophylaxis. Very rarely, in a child known to have VUR with abnormal bladder emptying, who continues to have recurrent febrile UTIs an anti reflux procedure will need to be considered and discussed with a paediatric urologist. Clinic follow up: the three main groups of children requiring follow up are a) children with recurrent UTIs b) children who have a potentially clinically significant abnormal imaging needing paediatric urology referral c) children with renal scarring. In the light of the above studies on long term follow up it is very unlikely that the child with a single focal renal scar but normal individual kidney GFR on the DMSA scan will run into problems with hypertension unless he/she has further UTIs or has other risk factors for hypertension.
Future research Further large scale studies are needed on the role of bladder dysfunction in recurrent UTI and renal damage. Antibacterial resistance is an increasing problem and ongoing research into the genetics of the host response to pathogens is likely to lead
PAEDIATRICS AND CHILD HEALTH 24:7
292
Ó 2013 Elsevier Ltd. All rights reserved.
Urinary tract infections in children
Key points C
Lyda Jadresic C
C
Abstract Urinary tract infection (UTI) is a common bacterial infection that can affect infants and children. The severity of illness depends on microbial virulence and host susceptibility. It has a number of different ways to manifest itself clinically ranging from a mild cystitis to a presentation with systemic symptoms such as a nonspecific fever, vomiting, failure to thrive or irritability or with significant dehydration and electrolyte imbalance which can be seen in infants in the first 3 months of life. It is therefore a ubiquitous differential diagnosis in many children presenting both in primary care and in the hospital setting. In most children urinary infections are isolated acute infections from which they recover quickly. In a small minority of children urinary infections can be associated with underlying significant pathology: either they are associated with congenital renal tract malformations such as renal dysplasia and/or hydronephrosis or if they have recurrent infections this may lead to renal scarring, particularly if the infections are associated with systemic symptoms.
C
C
the uroepithelium, one of these is the possession of P fimbriae which increase bacterial adhesion to the mucosa and facilitate its exposure to bacterial toxins. UPEC are cause 70e90% of community acquired urinary tract infections. Following mucosal adhesion the innate immune response is stimulated and various families of Toll like receptors (TLRs) play a key role in the activation of transcription factors, and production of a variety of cytokines, interferons and their regulatory factors. The degree of renal damage has been found to be correlated to high blood and urinary levels of various cytokines, for example Interleukin 6 (IL-6), which induces fever, stimulates hepatocyte production of C reactive protein and acts on the urothelium to produce IgA antibodies. Over the last few years it has become increasingly clear that there is genetic variation in innate immunity, e.g. affecting the expression and function of TLRs, Interferon Regulator Factor 3 (IRF3) and IL-8 receptors, resulting in clinical differences in the host response ranging from being able to tolerate bacteria asymptomatically (asymptomatic bacteriuria) to mounting a severe inflammatory response resulting in acute pyelonephritis. The familial occurrence of recurrent UTI has been known about for some time and may be explained by this type of genetically transmitted defects in single proteins involved in the innate immunity of the uroepithelium to uropathogens. Most children with UTI do not have underlying structural abnormalities and this area of study, which is already seeing major expansion, should provide in the future the tools for identifying children at risk of renal damage as well as enabling the development of specific biological agents to prevent recurrent UTI. Other bacteria are other coliforms such as Klebsiella as well as organisms such as Proteus mirabilis, Pseudomonas, coagulase negative Staphs, Streptococci (e.g. Group B strep, Enterococci), Staphylococcus aureus and occasionally Haemophilus influenzae as well as others. These non E. coli organisms often do not possess the aforementioned virulence factors seen in UPEC and it has been shown that their ability to cause urinary infections depends heavily on the presence of host factors, particularly structural urinary tract abnormalities leading to urinary stasis. Therefore, one of the indications for investigating the urinary tract in children is the type of organism involved in the infection.
Keywords acute pyelonephritis; bladder function; constipation; cystitis; fever; non Escherichia coli urine infection; renal scarring; urine infection; uropathogenic Escherichia coli
Definition The definition of a urinary tract infection consists of bacteriuria in the presence of symptoms. Bacterial growth of more than 105 is regarded as the threshold number for a significant bacterial growth; however, the evidence base for this threshold is weak. There is evidence that infants may have urine infections with lower bacterial counts. Although in most instances there is also pyuria this may sometimes be absent. Asymptomatic bacteriuria needs no treatment or investigation.
Causative organisms and host response The bacteria that cause urinary tract infections originate from gut and perineal flora. The urinary tract is kept sterile by a normal urine flow and the innate (or nonspecific) local immune system. The ability of bacteria to cause urinary infections depends on bacterial virulence factors as well as host factors. Uropathogenic E. coli (UPEC) have specific virulence factors which enable them to attack Lyda Jadresic FRCPCH MD is Consultant Paediatrician at the Gloucestershire Hospital NHS Trust, Gloucester, UK. Conflicts of interest: The author was a member of the NICE Guideline Development Group for Childhood UTI which published the current guideline back in 2007. The author participated in the development of NICE Quality Standards of this guideline and i nits recent Evidence Update. The author had a grant from HQIP to carry out a multisite audit of the NICE UTI guideline both in 1ry and 2ry care centres; no monies will come to the author or her department apart from covering travel expenses to meetings in London and Birmingham.
PAEDIATRICS AND CHILD HEALTH 24:7
Urine for microscopy and culture should not be collected by bag or pad; a clean catch sample should be obtained with the option in hospital of a catheter or suprapubic sample. Infections with non Escherichia coli UTIs are associated with increased risk of underlying obstructive structural abnormalities. Clinical features inform the decision as to which children need renal imaging. Children with recurrent UTIs should have a basic clinical assessment of bladder function. Genetic differences in innate immunity and uropathogens virulence factors play a key role in the risk of acute pyelonephritis.
Incidence and epidemiology Reliable measurements of the incidence of UTI in children have been difficult. Epidemiologically strong studies from Sweden
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Ó 2013 Elsevier Ltd. All rights reserved.
SYMPOSIUM: NEPHROLOGY
have reported that around 2% of boys and girls aged less than 2 years have a UTI. Based on evidence extracted from Swedish and UK data, approximately 10% of girls and 3% of boys will have had a UTI before the age 16 years. In infancy, the incidence of UTI in the under 3 months of age is higher in boys most probably reflecting a higher incidence of obstructive congenital urogenital abnormalities in males. After this age, girls have a higher incidence of UTI. Girls are more likely to have recurrences of UTI.
infections, viral or bacterial, other than UTI. In situations when the dipstick is negative for both nitrite and leucocyte esterase but the symptoms point to a UTI, the sample should be sent to the laboratory and the question of empirical treatment with antibiotics prior to the culture results depends on the severity of illness. Febrile children should be assessed according to the NICE fever guideline and careful assessment of very young infants with possible UTI should include a decision about ruling out an associated meningitis in severe ill infants. This is a rare complication.
Clinical presentation and differential diagnosis The clinical presentation can be divided into two types. In a lower tract UTI or cystitis the symptoms are confined to the bladder and consist of dysuria, frequency, incontinence, urgency of micturition and abdominal pain. An upper tract UTI or ‘acute pyelonephritis’ is defined by the presence of fever (38 C) or other systemic symptoms such as loin pain or vomiting and in infants typically failure to thrive or persistent irritability. Babies under 3 months of age can occasionally present with dehydration, hyponatraemia and hyperkalaemia mimicking the findings in congenital adrenal hyperplasia. The symptoms in the very young children particularly infants are nonspecific and it is safer to assume that they are upper tract in nature. The diagnosis needs to be confirmed by obtaining a urine specimen which is sent for culture but this is difficult in children still in nappies. Febrile children should be assessed using the ‘traffic light system’ of the NICE fever guideline and it is recommended that in those with nonspecific fever regardless of the severity of illness should have a urinalysis. Large numbers of young children present with nonspecific symptoms to primary care and the DUTY study hopes to create an algorithm of presenting symptoms and signs to help select which children should have a urine sample taken.
Management and treatment of UTI Infants under 3 months with a suspected diagnosis of UTI should be assessed by paediatricians. The history and examination on all children with confirmed UTI should be recorded and should include the following: temperature hydration history suggesting previous UTI or confirmed previous UTI recurrent fever of uncertain origin antenatally-diagnosed renal abnormality family history of vesicoureteric reflux (VUR) or renal disease constipation dysfunctional voiding including urine flow enlarged bladder abdominal mass evidence of spinal lesion growth blood pressure The vast majority of UTIs in children older than 3 months can be treated orally. Children with cystitis/lower tract symptoms can be treated with a 3 day course of antibiotic. Common and useful antibiotics are trimethoprim, nitrofurantoin (should not be used in AP/upper tract UTI), cephalexin or co-amoxiclav. The resistance of E. coli to amoxicillin is currently too high for this antibiotic to be recommended as a first line antibacterial. The choice of antibiotic should ideally be agreed along joint guidelines with the local microbiology department. This is particularly important to contain the emergence of increasingly resistant bacteria. Children with AP/upper tract infection can be treated with a 7e10 days course of oral antibiotics. Exceptions to the initiation of oral therapy include vomiting, evidence of circulatory shock, or the presence of known potential obstruction such as hydronephrosis. Continuing fever at the end of 48 hours in spite of suitable antibiotics should be investigated with at least a repeat urine culture and an ultrasound of the renal tract as urinary obstruction can be a cause for failure to respond to antibiotics. There is no indication for the routine use of antibiotic prophylaxis.
Urine analysis There is a significant risk of contamination of the urine sample if urine bags are used and this is slightly less when pads are used and changed every 30 minutes. The gold standard is a suprapubic aspiration (SPA) with ultrasound guidance although recent evidence shows that urethral in out catheterization yields reliable results and is better tolerated. These techniques require training and they are not feasible in primary care. Therefore the best and most practical way to try to obtain a noncontaminated sample is by clean catch and this should be possible in the community. Urine dipsticks with reagent strips to look for the presence of nitrite and leucocyte esterase are useful particularly to rule out UTI, they can be useful to rule in UTI but the likelihood ratios are less. They are unreliable in children under 2 years. There is not enough data on how reliability changes as the child gets older and NICE recommends that children under 3 years should have urgent microscopy rather than urine dipstick for the rapid diagnosis of UTI. Antibiotics should be started after sending the sample to the laboratory if the dipstick is nitrite positive or bacteria are seen on microscopy. If the dipstick is leucocyte positive or if there is only pyuria on microscopy, the sample should be sent to the laboratory and the decision to start empirical antibiotic treatment for UTI should be based on the clinical findings and the severity of illness. Isolated pyuria can occur in febrile children due to
PAEDIATRICS AND CHILD HEALTH 24:7
Prevention of UTI There have been many studies on a variety of interventions to try and prevent UTI in children including antibiotic prophylaxis, cranberry juice, probiotics, circumcision, Vitamin A, etc. The role of antibiotic prophylaxis has been questioned by a number of metaanalyses; it may confer a small protective effect in girls with recurrent infections and VUR. Proanthocyanidin-A present in cranberry juice, inhibits bacterial adhesion to uroepithelial cells,
290
Ó 2013 Elsevier Ltd. All rights reserved.
SYMPOSIUM: NEPHROLOGY
addressing any issues around bladder function. It is helpful to give general advice regarding healthy life styles. If renal tract investigations are needed these need to be explained. It is helpful to have an advice leaflet to hand out.
however a recent Evidence Update by NICE found that cranberry juice does not appear to prevent UTIs although the evidence was limited. Circumcision significantly lowers the incidence of UTI but it does not have a role in the management of simple UTI. Under specialist paediatric urology guidance it may play a part in the management of a small subgroup of boys with recurrent UTIs or high grade VUR. The presence of dysfunctional bladder and or chronic constipation increases the risk of recurrence of UTI.
The investigation of the renal tract: historically a UTI was associated with concerns about vesicoureteric reflux which is diagnosed with a micturating cystourethrogram (MCUG). Over the last 5e7 years there has been a trend towards less imaging. Recent evidence suggests that VUR may be as common in children with UTI as those without. The NICE 2007 Childhood UTI guideline does not recommend looking for VUR after the first UTI and more recently the 2011 American Association of Paediatrics (AAP)’s UTI guideline has also moved away from the routine use of the cystogram in infants with a first febrile UTI. A DMSA scan is no longer recommended in the AAP guidelines, which favour the use of the renal ultrasound instead. There is a different radiation load depending on the type of renal imaging algorithm used. Current recommendations from NICE on renal tract imaging are targeted to the minority of children whose clinical presentation puts them at risk of underlying pathology as outlined above. A basic outline of who requires investigations is given below and this is followed by the full details of the imaging recommendations. Children who need some form of renal tract investigation after a first UTI include:
Long term outcome The proportion of children found to have renal parenchymal defects if investigated after a first UTI is approximately 5%. Studies have demonstrated that bladder dysfunction can play a key role in UTIs and that VUR can be a secondary effect. It is important, therefore, to make a clinical assessment of bladder function in children with UTIs. Large, long term follow up studies from Sweden on blood pressure in patients known to have scarred kidneys in association with childhood UTI have shown no significant differences compared to normal controls. A nonsignificant rise was seen in the subgroup with bilateral scarring in association with loss of renal mass. The prevalence of hypertension in adults in England is high, affecting an average of 29% of women and 32% in men. Therefore, children with UTI are much more at risk of developing hypertension as a result of life style factors rather than UTIs. It is important when advising patients and their parents/carers (see below) to use the opportunity for recommendations on a healthy life style. Impairment of renal function in association with childhood UTI is very uncommon. In the rare occasion when this occurs it tends to be either a boy with congenital bilateral renal dysplasia or seen very rarely as acquired renal damage in girls from with recurrent febrile UTIs and very often associated bladder dysfunction. Studies show that there needs to be significant reduction in renal mass bilaterally. More long term studies such as the Swedish ones above are needed. In the meantime NICE recommends that once renal scarring is identified that the child has regular blood pressure readings as well as having the urine tested for proteinuria. It is important to add at least a yearly creatinine measurement to those children with bilateral scarring.
C C
Follow up
Children with an atypical UTI should have and ultrasound of their renal tract during the acute infection as they are more likely to have obstructive structural abnormalities. For further investigations of children with atypical UTI please refer to the NICE Childhood UTI guidelines. Children with recurrent infections also need investigation. NICE defined recurrent UTI as: two UTIs where at least one has been an AP/upper tract infection, or three or more episodes of cystitis/lower tract infection. A micturating cystourethrogram is no longer recommended for all infants with UTI. It should be considered in a young child with a febrile UTI and atypical features such as a history of antenatal hydronephrosis or ureteric or renal dilatation on ultrasound, infection with non E. coli organisms, abnormal urine stream, or is found to have bright and small kidneys on ultrasound (renal displasia) or has a degree of renal failure.
Advice: following a UTI it is vital to give clear advice to parents/ carers and young people about the symptoms of UTI and about the need for prompt recognition and treatment. They and their family doctors need to be made aware or reminded of the nonspecific nature of the symptoms of UTI and particularly that fevers should not be put down to a ‘viral infection’ or teething unless a UTI has been ruled out. It is preferable to treat after a sample has been obtained and be prepared to stop after 48 hours if the cultures come back negative. Equally parents/carers need to know that if their baby fails to thrive, has a vomiting illness or persistent irritability that a UTI could be the reason and to seek medical advice promptly. Parents/carers and young children need to seek medical help again if symptoms do not settle within 48 hours of starting treatment or if the child gets worse. In addition, advice needs to be given regarding prevention such as ensuring a good fluid intake, avoiding constipation and
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ultimately to alternative ways of treating or preventing urine infections. A
There is a risk of introducing infection at the time of a MCUG and therefore it is recommended that prophylactic antibiotics should be given orally for 3 days with the MCUG taking place on the 2nd day. My personal practice is to use a full therapeutic dose during these 3 days.
FURTHER READING Carpenter MA, Hoberman A, Mattoo TK, et al. for the RIVUR Trial Investigators. The RIVUR trial: profile and baseline clinical associations of children with vesicoureteral reflux. Pediatrics 2013; 132: e34e45. Downing H, Thomas-Jones E, Gal M, et al. The diagnosis of urinary tract infections in young children (DUTY): protocol for a diagnostic and prospective observational study to derive and validate a clinical algorithm for the diagnosis of UTI in children presenting to primary care with an acute illness. BMC Infect Dis 2012; 12: 158. http://www. biomedcentral.com/1471-2334/12/158. Finnell SM, Carroll AE, Downs SM. Technical report e diagnosis and management of an initial UTI in febrile infants and young children (American Association of Paediatrics). Pediatrics 2011; 128: e749e70. Godley ML, Desai D, Yeung CK, Dhillon HK, Duffy PG, Ransley PG. The relationship between early renal status, and the resolution of vesicoureteric reflux and bladder function at 16 months. BJU Int 2001; 87: 457e62. Hannula A, Perhomaa M, Venhola M, Pokka T, Renko M, Uhari M. Longterm follow-up of patients after childhood urinary tract infection. Arch Pediatr Adolesc Med 2012; 166: 1117e22. Hannula A, Venhola M, Renko M, Pokka T, Huttunen NP, Uhari M. Vesicoureteral reflux in children with suspected and proven urinary tract infection. Pediatr Nephrol 2010; 25: 1463e9. Health Survey for England 2008. Trend Tables. The NHS Information Centre for Health and Social Care. Koff SA, Wagner TT, Jayanthi VR. The relationship among dysfunctional elimination syndromes, primary vesicoureteral reflux and urinary tract infections in children. J Urol 1998; 160(3 Pt 2): 1019e22. La Scola C, De Mutiis C, Hewitt IK, et al. Different guidelines for imaging after first UTI in febrile infants: yield, cost, and radiation. Pediatrics 2013; 131: e665e71. NICE guideline: urinary tract infections in children (diagnosis, treatment and long term management) August 2007. NICE. Urinary tract infection in children Evidence Update 48 October 2013. www.nice.org.uk. Sillen U, Brandstrom P, Jodal U, et al. The Swedish reflux trial in children: V. Bladder dysfunction. J Urol 2010; 184: 298e304. Svanborg C. Urinary tract infections in children: microbial virulence versus host susceptibility. Adv Exp Med Biol 2013; 764: 205e10. Toffolo A, Ammenti A, Montini G. Long-term clinical consequences of urinary tract infections during childhood: a review. Acta Paediatr 2012; 101: 1018e31. Wennerstrom M, Hansson S, Hedner T, Himmelmann A, Jodal U. Ambulatory blood pressure 16 to 26 years after the first urinary tract infection in childhood. J Hypertens 2000; 18: 485e91. Wennerstrom M, Hansson S, Jodal U, Sixt R, Stokland E. Renal function 16 to 26 years after the first urinary tract infection. Arch Pediatr Adolesc Med 2000; 154: 339e45. Williams GJ, Craig JC, Carapetis JR. Preventing urinary tract infections in early childhood. Adv Exp Med Biol 2013; 764: 211e8.
Recurrent UTI: children with recurrent urine infections should be referred to a paediatric specialist. This has the purpose of identifying, investigating and managing potential reasons for recurrences and dealing with any sequelae such as scarring. The first step is to identify the clinical features at the time of the infections and distinguish them from either vulvovaginitis or asymptomatic bacteriuria, classify the UTI recurrences into either cystitis or acute pyelonephritis episodes. It is also necessary through direct questioning to seek evidence for any continence abnormalities asking about micturition symptoms when well in between infections. This involves asking questions about the frequency of micturition, urgency, diurnal incontinence, hesitancy, staccato voiding and stress incontinence. Identification of constipation is important as it often is a risk factor for not only UTIs but it also aggravates continence problems. Close liaison with the paediatric continence service for their input is useful not only in managing constipation and continence problems and trying to achieve complete bladder emptying but also in performing uroflowmetry studies when the history suggests the possibility of a dysfunctional bladder. In such children, if the UTIs persist, consideration should be also given to performing an indirect cystogram to look for VUR. There will be the occasional child with recurrent, often febrile UTIs who fails to empty his/her bladder in the absence of outflow obstruction and in spite of a good fluid intake and absence of constipation, on whom intermittent catheterization will need to be considered in order to prevent infections. In the child who continues to have recurrent UTIs in spite of having addressed bladder or constipation problems it is worth considering a period of a few months on low dose antibiotic prophylaxis. Very rarely, in a child known to have VUR with abnormal bladder emptying, who continues to have recurrent febrile UTIs an anti reflux procedure will need to be considered and discussed with a paediatric urologist. Clinic follow up: the three main groups of children requiring follow up are a) children with recurrent UTIs b) children who have a potentially clinically significant abnormal imaging needing paediatric urology referral c) children with renal scarring. In the light of the above studies on long term follow up it is very unlikely that the child with a single focal renal scar but normal individual kidney GFR on the DMSA scan will run into problems with hypertension unless he/she has further UTIs or has other risk factors for hypertension.
Future research Further large scale studies are needed on the role of bladder dysfunction in recurrent UTI and renal damage. Antibacterial resistance is an increasing problem and ongoing research into the genetics of the host response to pathogens is likely to lead
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