Urinary tract infections inchildrenLyda Jadresic

Abstract

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.

Incidence and epidemiology

Reliable measurements of the incidence of UTI in children have

been difficult. Epidemiologically strong studies from Sweden

member of theNICEGuidelineDevelopment Group for ChildhoodUTIwhich

SYMPOSIUM: NEPHROLOGYpublished 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.Urinary tract infection (UTI) is a common bacterial infection that can affect

infants and children. The severity of illness depends on microbial viru-

lence 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.

Inmost children urinary infections are isolated acute infections fromwhich

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 associatedwith systemic symptoms.

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

andperineal flora. Theurinary 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 factorswhich 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 aPAEDIATRICS AND CHILD HEALTH 24:7 289the 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 commu-

nity acquired urinary tract infections. Followingmucosal 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, in-

terferons 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 andmay be explained by this

type of genetically transmitteddefects 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

Key points

C 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.

C Infections with non Escherichia coli UTIs are associated with

increased risk of underlying obstructive structural abnormalities.

C Clinical features inform the decision as to which children need

renal imaging.

C Children with recurrent UTIs should have a basic clinical

assessment of bladder function.

C Genetic differences in innate immunity and uropathogens

virulence factors play a key role in the risk of acute

pyelonephritis. 2013 Elsevier Ltd. All rights reserved.

SYMPOSIUM: NEPHROLOGYhave 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 inci-

dence of UTI. Girls are more likely to have recurrences of UTI.

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) orother 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 dehydra-

tion, 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 rec-

ommended 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.

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 evi-

dence 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 diag-

nosis 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 labora-

tory 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 toPAEDIATRICS AND CHILD HEALTH 24:7 290infections, 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 antibi-

otics 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.

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 pressureThe 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 resis-

tance of E. coli to amoxicillin is currently too high for this anti-

biotic 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. Chil-

dren 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 anti-

biotics 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.

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 beenquestionedbyanumber ofmeta-

analyses; 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, 2013 Elsevier Ltd. All rights reserved.

targeted to the minority of children whose

puts them at risk of underlying pathology

basic outline ofwho requires investigations is

is followed by the full details of the imaging

Children who need some form of renafter a first UTI include:

C Children under 6 months of ageC Children with an atypical presentation:

SYMPOSIUM: NEPHROLOGYhowever 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.

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 risewas 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%ofwomen and 32% inmen. Therefore,

children with UTI are much more at risk of developing hyperten-

sion 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.

Follow up

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 andPAEDIATRICS AND CHILD HEALTH 24:7 291mass

raised creatinine

septicaemia

failure to respond

to treatment with

suitable antibiotics

within 48 hours

infection with non

E. coli organisms

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 in-

vestigations of children with atypical UTI please refer to the NICE

Childhood UTI guidelines.

Children with recurrent infections also need investiga-tion. 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 ul-

trasound, infection with non E. coli organisms, abnormal urine

stream, or is found to have bright and small kidneys on ultra-

sound (renal displasia) or has a degree of renal failure.abdominal or bladderp 2013enal tract imaging are

clinical presentation

as outlined above. A

given below and this

recommendations.

al tract investigation

seriously ill

oor urine flowaddressing 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.

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 radi-

ation load depending on the type of renal imaging algorithm used.

Current recommendations fromNICEon rElsevier Ltd. All rights reserved.

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

ultimately to alternative ways of treating or preventing urine

infections. A

SYMPOSIUM: NEPHROLOGYduring these 3 days.

Recurrent UTI: children with recurrent urine infections should be

referred to a paediatric specialist. This has the purpose of identi-

fying, investigating and managing potential reasons for re-

currences and dealingwith 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 in-

fections. 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

studieswhen 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, onwhom intermittent catheterizationwill need to be

considered in order to prevent infections. In the child who con-

tinues 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 con-

tinues 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 scar-

ring. 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 leadPAEDIATRICS AND CHILD HEALTH 24:7 292FURTHER READING

Carpenter MA, Hoberman A, Mattoo TK, et al. for the RIVUR Trial In-

vestigators. 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 al-

gorithm 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 vesico-

ureteric reflux and bladder function at 16 months. BJU Int 2001; 87:

457e62.

Hannula A, Perhomaa M, Venhola M, Pokka T, Renko M, Uhari M. Long-

term 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. Ambu-

latory 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. 2013 Elsevier Ltd. All rights reserved.

Urinary tract infections in childrenDefinitionCausative organisms and host responseIncidence and epidemiologyClinical presentation and differential diagnosisUrine analysisManagement and treatment of UTIPrevention of UTILong term outcomeFollow upFuture researchFurther reading