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THE NATURAL HISTORY OF BACTERIURIA IN CHILDHOOD
URINARY TRACT INFECTIONS
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THE NATURAL HISTORY OF BACTERIURIA IN CHILDHOOD Sverker Hansson, MD, PhD, Jeanette Martinell, MD, Eira Stokland, MD, PhD, and Ulf Jodal, MD, PhD
The identification of bacteria 1 century ago soon led to the finding of microorganisms in the urine and to the description of children with urinary tract infection (UTI). An early report by Goppert described different clinical presentations and pointed out that it is a common disease of endemic character? He also described a mortality rate of 20% in infants and small children with febrile UTI. Effective therapy was not available until the introduction of the sulfonamides during the 1930s, but since then the further development of antibiotics and an increased awareness of the high frequency of UTI in children together with improved diagnostic methods have decreased acute mortality to close to zero in industrialized countries. Urinary tract infection is the term used for a mixture of diseases of different causes with growth of bacteria within the urinary tract in common. There is a great variation in the clinical presentation. In some individuals, bacteriuria causes no symptoms and only screening of healthy children can reveal its existence. Symptoms vary from foul smelling urine, dysuria, and loin pain to peaking fever and signs of circulatory shock. Many children have only one episode of UTI; others have repeated infections. Some children develop permanent renal damage that potentially can lead to hypertension, pregnancy complications, and even renal failure. It is a complex pattern dominated by benign episodes of UTI but with a large proportion of potentially serious infections; these children need to be diagnosed, treated, investigated, and followed-up on. Our knowledge of the natural history of UTI in childhood is still incomplete. There are several reasons for this. Most children with UTI are managed at the primary care level, each practitioner handling only a restricted number of chilThe financial support of the Swedish Medical Research Council, the Skandia Life Insurance Company, and the Frimurare-Barnhusdirektionenis greatly appreciated.
From the Department of Pediatrics, Sahlgrenska University Hospital, East Clinics, Goteborg, Sweden
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dren. It is therefore difficult to create population-based registries that are necessary for large epidemiologic studies. Furthermore, the course of UTI often runs over several decades, and to follow patients over such long periods of time is difficult. Finally, there is the continuous change in the management that influences and hopefully improves the long-term prognosis but which also can make comparisons between different time periods difficult. An example of this is the switch from urography to dimercaptosuccinic acid (DMSA) scanning to study renal damage that is going on in many centers.4 During the first half of the 1960s, Jan Winberg et a1 performed pioneering studies on UTI in children in Goteborg. They introduced a standardized protocol for diagnosis, treatment, investigation, and follow-up and encouraged the primary care doctors to refer children suspected to have UTI to the Children’s Hospital. A special UTI clinic was created to provide an instrument for efficient long-term follow-up but also to manage the children whenever a recurrence was suspected. A close cooperation evolved, especially with the departments of pediatric radiology and microbiology and several important papers were published.34,15 The Goteborg Childhood UTI Research Group has been continuously functioning since 1960 and still uses basically the same protocol, although the focus of interest and the members have changed over the years. This article describes the local organization and the protocol for management of children with UTI in Goteborg. Further, it gives selected aspects of the natural history of UTI in childhood focusing on results from the authors’ study group. TERMINOLOGY AND DEFINITIONS
A diagnosis of UTI requires significant bacteriuria. Although lower numbers of bacteria can occur in children with symptomatic UTI, the minimum number accepted in the studies is growth of 100,000 colony forming units in freshly voided urine obtained as a midstream specimen. For urine obtained by bag technique, the authors require two samples with homogeneous growth of at least this magnitude. In urine obtained by suprapubic aspiration, any growth is considered significant. Symptomatic UTI is subdivided into acute pyelonephritis when there is fever of at least 38.5”C, mostly supported by a high C-reactive protein, and acute cystitis when there are acute voiding symptoms but low fever and no signs of renal involvement. Ten percent to 20% of the infections cannot be classified in this way, and for those, the term unspecified UTI is used. A diagnosis of asymptomatic bacteriuria (ABU) requires repeated samples with identical growth in a child who does not report symptoms and who has not been ill for at least 2 weeks. LOCAL ORGANIZATION
The city of Goteborg has had a stable population of about 420,000 inhabitants for many years, of whom 80,000 are children below 16 years of age. There is one Children’s Hospital providing the only round-the-clock emergency service for children in the city. There are 20 district pediatricians employed by the city working at seven outpatient clinics. They have mostly prearranged appointments during regular office hours and a limited capacity to handle acute cases. In the city, there are only three other pediatricians, and home calls are rarely done. Therefore, most children with acute diseases are seen at the emergency
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room of the Children’s Hospital. From surveys of the diagnosis records, the authors know that at the hospital are managed 90% of the children with febrile and 50% of those with nonfebrile UTI in the population. In addition to the pediatric medical care organization, the community also runs child health centers and school health units. These are primarily meant for preventive measures, and different types of screening procedures are included in their routine work. It has been possible to perform studies within SChoo~SIU-lZ, 20-22 and at child health A good cooperation between the health units, the outpatient clinics, and the Children’s Hospital has been ensured by the fact that many pediatricians have part-time positions at several units. The principal features of the protocol that Winberg et a1 used during the 1960s are still maintained, and the isolated bacteria are routinely preserved. Modifications of the protocol, however, have been done according to the technical development and to the increased knowledge about the risk factors in childhood UTI. Thus, DMSA scintigraphy is used for identification of children with renal damage and the number of check-ups to find bacteriuria in children without symptoms has been greatly reduced as a consequence of the finding that ABU is an essentially innocent state (see later discussion).
EPIDEMIOLOGY In the classical studies of Winberg et a1 from the 1960s, the cumulative incidence of symptomatic UTI during the first 10 years of life was 3.0% in girls and 1.1%in boys.34Increased awareness of the diagnosis and more frequent culturing of urine in sick children have increased these figures gradually. Our most recent figures are based on the records of children entering school at the age of 7 years. From a cohort of 3556 school entrants, 7.8% of the girls and 1.6% of the boys were found to have had symptomatic UTI as confirmed by significant bacteriuria.” In half of the children, the UTI had been associated with high fever according to the original case records from hospital or outpatient clinics, and in most of these, a diagnosis of acute pyelonephritis was supported by laboratory tests such as C-reactive protein or sedimentation rate. The incidence of febrile first-time UTI is highest during the first year of life. This is most marked for boys but also evident for girls as seen in Figures 1 and 2, which illustrate the age-related number of children with symptomatic firsttime UTI diagnosed at the emergency room of the authors’ hospital during the years 1992 to 1995. The authors believe that this pattern reflects the true incidence of febrile UTI in the population, whereas the incidence of nonfebrile UTI in children over 1 year of age is underestimated; nonfebrile UTI should occur approximately twice as often in the total population. Symptoms that directly point to the urinary tract are acute voiding problems and back or loin pain. In infants with symptomatic UTI, such localizing symptoms are rare. Even in children more than 2 years of age with febrile UTI, less than half had acute dysuria, 6 of 19 (32%) boys and 42 of 105 (40%) girls (Figure 1 and 2). Loin or back pain was even less common and found in 1 of 19 boys and 28 of 105 (27%) girls. For children more than 2 years of age with nonfebrile UTI, few lacked dysuria, and a clinical diagnosis of acute cystitis was mostly made. IMAGING TECHNIQUES
Because the long-term risks for childhood UTI are related to the impact on renal development and function, the methods to detect renal damage are of
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Figure 1. Boys with symptomatic first-time UTI diagnosed at the Children’s Hospital in Goteborg from 1992 to 1995 according to age at detection: (A) febrile UTI and (6) nonfebrile UTI. White bar = no dysuria; hatched bar = dysuria.
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Figure 2. Girls with symptomatic first-time UTI diagnosed at the Children’s Hospital in Goteborg from 1992 to 1995 according to age at detection: (A)febrile UTI and (B) nonfebrile UTI. White bar = no dysuria; hatched bar = dysuria.
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great importance. The standard technique to define permanent renal damage has for a long-time been urography. The radiologic features of renal scarring were well defined by Hodson in 1959, and our present knowledge of the longterm outcome of childhood UTI is based on this te~hnique.'~ The development of standardized measuring techniques, for example, relating parenchymal thickness to the Ll-L3 vertebrae distance has improved the accuracy of scar detection2 A difficulty, however, is the long time until a scar has developed to be easily seen at urography, often up to 2 years3 The introduction of new techniques has challenged urography as the standard for imaging of the kidneys and presently ultrasonography and DMSA scintigraphy are favored in many centers. The authors' have compared the ability of these different techniques to identify renal scarring and tried to analyse the advantages, the drawbacks and the pitfalls of the respective methods. Ultrasonography Versus Urography
Ultrasonography has replaced intravenous urography as the method of choice for detection of major malformations of the urinary tract. Arguments in favor of ultrasonography are noninvasiveness, absence of radiation, accessibility, and independence of renal function. It has become a standard procedure in the primary evaluation of children with UTI and is especially good for detection of dilatation of the urinary tract. For the identification of pyelonephritic renal scarring, however, ultrasonography is of limited value. In a study of 25 patients aged 2 to 16 years who had recently been examined by urography (and most also by DMSA scintigraphy) because of UTI, 15 had clearcut urographic evidence of renal scarring with parenchymal reduction and caliceal def~rrnity?~ During 1 day, all children were examined by ultrasonography by 10 radiologists, representing the most experienced examiners in the country, with special interest in pediatric renal ultrasonography. With urographic renal scarring as the diagnostic criterion, the sensitivity of ultrasonography was only 54%, with a specificity of 80%. There were wide interobserver variations with sensitivity ranging from 40% to 90%. It was concluded that ultrasonography is not accurate enough to identify kidneys with scarring and that this technique is not suitable for deciding which children are at risk for future complications after UTI. DMSA Scintigraphy Versus Urography
Many centers have abandoned urography for DMSA in the evaluation and follow-up of children with UTI. Difficulties in identifying the renal outline in the urogram, especially when a digitalized system is used, is a major reason as is also the higher sensitivity of the scintigraphy to detect renal damage. A further problem is the difficulty to differentiate between transient scintigraphic uptake defects caused by inflammation and permanent defects caused by scarring. Urography will only detect permanent damage. To compare the two techniques, the authors prospectively followed 175 children aged 0 to 5 years from their first recognized nonobstructive UTLZ8The median age at inclusion was low, only 0.4 years. There were 78 girls and 97 boys. At the time of the infection, all were investigated by DMSA scintigraphy and urography and all but one by voiding cystourethrography. After 1 year,
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DMSA scintigraphy and urography were repeated in 157 children. All the examinations were evaluated blindly.z9 Analysis of the 157 children who had repeat investigations showed that 68 (43%) had abnormal DMSA and 10 (6%) had urographic evidence of renal scarring at the initial examination. At the 1-year follow-up examination, resolution of the abnormal DMSA findings were seen in 30 of the 68 children. Thus, there were 38 (24%) children with persisting scintigraphic abnormality. The renal area involvement at the first investigation was significantly larger in the group with persisting abnormality compared with those who were normalized at the follow-up (p
In principle, the long-term risks for pyelonephritic renal damage have been known for a long time, for example, development of hypertension and
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Table 1. CAPACITY OF IMAGING TECHNIQUES TO DETECT UPPER URINARY TRACT ABNORMALITIES ~~~~~~~~~~~
Dilatation Inflammation Scarring Side distribution of function
Ultrasonography
Urography
DMSA Scintigraphy
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complications during pregnan~y.'~, XI The extent of this risk, however, is inadequately known, depending on factors such as the long follow-up required and the difficulty in attaining continuity of data. To evaluate the long-term aspects, the authors have followed-up on a group of 111 women from their first recognized UTI in childhood through the growth p e r i ~ d . ~ They ~ - ' ~ were selected for continued follow-up into adulthood at the age of 15 to 18 years because of renal scarring as identified by urography in 54 or a proneness to UTI in 57; of the 54 with renal scarring, 36 were prone to UTI. The index infection was symptomatic in 87 and occurred at a mean age of 4.3 years. In 24 the index infection was asymptomatic and detected through a school screening program. The median age at the last follow-up was 27.5 years, and the median follow-up time was 23.1 years. Symptomatic recurrences were seen in 97 women with a median of 7 per individual. The infections became less symptomatic with increasing number and age. In 89 there were between 1 and 14 recurrences without symptoms, and many were subsequently left untreated. Because the true number of asymptomatic episodes is not possible to establish, the UTI pattern in Figure 3 illustrates only the attack rate (number of UTI per woman per observation year) for symptomatic infections according to age. The attack rate was highest during the first year of life and gradually decreased thereafter to reach the lowest in the age group from 11 to 15 years. During the first 5 years of life, febrile UTI was the dominating type of infection; thereafter, nonfebrile UTI was most common. Women with urographic renal scarring, however, continued to have a high proportion of febrile recurrences also after 10 years of life. There was a high proportion of febrile UTI when the children had reflux. After the reflux was absent, the attack rate of symptomatic UTI was still high, but the proportion of febrile infections was lower. The proportion of febrile attacks of UTI was significantly higher in women with reflux compared with those without reflux after elimination of age as a confounding variable (p
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sion of at least 140/90 mm Hg was diagnosed in 3 of the 54 females (5.5%) with renal scarring, 2 before and 1 at the follow-up examination.2hThus, these young women who were continuously followed-up on and were compliant had a wellpreserved renal function, and the incidence of hypertension was low. Further follow-up will show whether some of these women will develop deteriorating renal function. The same group of women has also been studied for complications during 65 pregnancies, and compared with 65 controls, randomly selected and matched for parity, age, smoking habits, and date of delivery.24The incidence of bacteriuria during first pregnancies was significantly greater in women with (9, 47%) and without (6, 27%) renal scarring after childhood UTI than in controls (1, 2%) (p
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more breakthrough infections that were mostly caused by resistant bacteria.h There were 26 girls left untreated during a total of 74 observation years. In no case was there development of symptoms. The duration of ABU had no negative impact on renal growth or glomerular filtration rate.7 Whether bacteriuria will produce symptoms or not is determined by hostparasite relations. For patients with ABU, there seems to be a balance between the host defense and the virulence of the bacteria. The E. coli isolated from patients with ABU were different from those causing symptomatic infections; they were often not typable in serogroups, had an increased sensitivity to the bactericidal effect of serum, and a poor adhering ability?* Because of the difficulties with serotyping, "fingerprinting" of the bacteria was done using multilocus enzyme electrophoresis, a technique allowing identification of the bacterial strain despite the lack of surface antigens. Analysis of a large number of consecutively isolated E . coli bacteria from 54 girls with untreated ABU during a total of 151 patient-years revealed only 24 changes of strain? Eleven of the strain changes were associated with antibacterial treatment for intercurrent infections or occurred in connection with a voiding cystourethrogram. The authors' also observed a successive loss of surface antigens (antigenic drift) during follow-up, probably caused by long-term exposure of E. coli to the host environment in the urinary tract. Thus, untreated ABU was characterized by a stable bacterial flora with a tendency for the bacteria to become less virulent with time. Despite a nontreatment policy, patients with ABU may need antibacterial medication for other infections. The authors studied the effect of penicillin treatment given to patients with ABU for intercurrent infections, mainly tonsillitis and ~ t i t i sPhenoxymethylpenicillin .~ had a dramatic effect on the bacteria in children with ABU. The bacteriuria was cleared, but only 5 of 40 girls treated remained free from recurrences. There were 7 episodes of acute pyelonephritis in 6 patients. It was inferred that each change of strain carries the risk for acquiring a more virulent strain, which can cause acute pyelonephritis. Treatment with erythromycin, on the other hand, was not associated with bacterial clearance and consequently did not increase the risk for recolonization with a more virulent strain. The conclusion from these studies was that not only can ABU be left untreated, but there is also an advantage for the patient to have an asymptomatic growth of low virulent bacteria in the urine. The presence of an established bacterial strain seems to prevent invasion by other bacteria, thus functioning as a kind of biological prophylaxis.16,23 ASYMPTOMATIC BACTERIURIA IN INFANTS Mass screening for bacteriuria in infancy has been discussed as a means of preventing pyelonephritic renal scarring. Studies of bacteriuria in infancy pose problems of reaching a relevant population of adequate size and of difficulties in obtaining uncontaminated urine samples. An unselected group of 3581 infants was screened at three different occasions during the first year of life: at 2 weeks, 3 months, and 10 months of age, respectively?' ABU was confirmed by suprapubic aspiration in 36 (2.5%),of the boys and in 14 (0.9%)of the girls. Bacteriuria in the boys was almost exclusively found during the first 6 months of life, whereas in the girls it was found throughout the first year. Two infants developed pyelonephritis within 2 weeks of the verification of bacteriuria, and the others remained free of symptoms. The bacteriuria cleared spontaneously within a few months in 36 of 45 untreated infants, and it cleared in response to antibiotics given for infections in the respiratory tract in a further 8. Recurrences
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of bacteriuria were observed in 20% of the children, but only one experienced an attack of pyelonephritis. Thus, only 2 of 45 untreated infants with screening bacteriuria developed acute pyelonephritis, whereas the others remained free from symptoms. Within the study population of 3581 infants there were another 22 (1.3%)boys and 20 (1.1%)girls who developed symptomatic UTI during the first year of life. Of those with symptomatic bacteriuria diagnosed after 1 month of age, all had participated in the screening program with normal results before the diagnosis. These findings suggest that infants with primary asymptomatic and symptomatic bacteriuria comprise two subpopulations with only marginal overlapping. Among the infants with screening bacteriuria, radiologic abnormalities were uncommon.” Of the boys, 3 (9%) had vesicoureteric reflux, all without dilatation, and none had renal anomalies. Of the girls, one had a scarred duplex kidney with reflux and another had moderate hydronephrosis. A repeat urography was performed after 3 years in 36 of the 50 children and did not reveal development of renal scarring in any child. Mass screening for bacteriuria in infancy seems to result primarily in the detection of innocent bacteriuric episodes and cannot be recommended. Instead, in infants and small children with high fever without obvious cause or with uncharacteristic symptoms, such as failure to thrive, urine cultures should be considered and performed as part of the general workup of the child. CONCLUSION
It is essential that children with an increased risk for progressive renal deterioration are identified early. Most important is the early detection of those with severe malformations of the urinary tract: obstruction and renal hypoplasia or dysplasia. Many of these children already have a reduced renal function from birth, and superimposed UTI can lead to further loss of function and ultimately chronic renal failure. In addition, a number of risk factors have been described in association with development of pyelonephritic renal scarring, for example, vesicoureteric reflux and number of pyelonephritic attacks.l4 There is no single protocol for children with UTI that can be generally recommended. Each protocol needs to be adapted to local traditions and resources. Our own protocol (Table 2) is based on a high detection rate for Table 2. PROTOCOL FOR INVESTIGATIONS AND FOLLOW-UP OF CHILDREN WITH UTl (GOTEBORG MODEL)* Time After Diagnosis 4-5 days
3-4 weeks
6 months 1 year
Acute Pyelonephritis and All Children <2 Years Old S-creatinine, C-reactive protein Blood pressure Planning for ultrasonography and voiding cystourethrography Information to the family about results and future planning DMSA scintigraphy Last visit (if all investigations have been normal and no recurrence)
*All check-uDs include culture of urine
Acute Cystitis S-Creatinine, C-reactive protein Blood pressure Renal concentrating capacity Last visit
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symptomatic UTI with a dominance of infants a n d that most risk patients are identified early. For girls over the age of 2 years with acute cystitis, the followup is only 3 to 4 weeks. All other children a r e followed u p for a t least 1 year after the UTI. The emphasis a t the control visits is on repeated information to the patient a n d family, including encouragement to return whenever symptoms occur that can be caused by UTI. Repeat radiologic investigations or alternative procedures are primarily performed to detect development o r progress of renal scarring. Long-term follow-up of patients with renal scarring into adulthood is essential with a t least yearly blood pressure measurements. Likewise, the patients should be provided w i t h immediate service a t suspected recurrences or other complications.
ACKNOWLEDGMENTS The authors acknowledge the important contributions of the following members of the Goteborg Childhood UTI Research Group: Marc Bachelard, Einar Hanson, Mikael Hellstrom, Gert Hermansson, Kelm Hjalmis, Bo Jacobsson, Gunilla Lidin-Janson, Peter Larsson, Knut Lincoln, Staffan Mirild, Torsten Sandberg, Ulla Sillen, Rune Sixt, Catharina Svanborg, Martin Wennerstrom, and BjBrn Wettergren.
References 1. Cardiff-Oxford Bacteriuria Study Group: Sequelae of covert bacteriuria in schoolgirls. Lancet 1:889-893, 1978 2. Claesson I, Jacobsson B, Jodal U, et al: Early detection of nephropathy in childhood urinary tract infection. Acta Radio1 Diagnosis 22315-320, 1981 3. Filly R, Friedland GW, Govan DE, et a 1 Development and progression of clubbing and scarring in children with recurrent urinary tract infections. Radiology 113:145-153,1974 4. Goldraich NP, Goldreich IH: Update on dimercaptosuccinic acid renal scanning in children with urinary tract infection. Pediatr Nephrol 9:221-226, 1995 5. Gbppert F: Uber die eitrigen Erkrankungen der Harnwege im Kindesalter. Ergebn Inneren Med Kinderheilkd 2:30-73, 1908 6. Hansson S, Jodal U, Noren L: Treatment vs non-treatment of asymptomatic bacteriuria in girls with renal scarring. In Kass EH, Svanborg Eden C (eds): Host-parasite interactions in urinary tract infections. Chicago, Chicago University Press, 1989, pp 289-291 7. Hansson S, Jodal U, Noren L, et al: Untreated bacteriuria in asymptomatic girls with renal scarring. Pediatrics 84964-968, 1989 8. Hansson S, Caugant D, Jodal U, et al: Untreated asymptomatic bacteriuria in girls. I: Stability of the urinary isolates. BMJ 2982353-855, 1989 9. Hansson S, Jodal U, Lincoln K, et al: Untreated asymptomatic bacteriuria in girls: 11: Effect of phenoxymethylpenicillin and erythromycin given for intercurrent infections. BMJ 298856459, 1989 10. Hellstrom A-L, Hanson E, Hansson S, et al: Micturition habits and incontinence in 7year-old Swedish school entrants. Eur J Pediatr 149:434-437, 1990 11. Hellstrom A, Hanson E, Hansson S, et al: Association between urinary symptoms at 7 years old and previous urinary tract infection. Arch Dis Child 66:232-234, 1991 12. Hellstrom A, Hanson E, Hansson S, et al: Micturition habits and incontinence at age 17: Reinvestigation of a cohort studied at age 7. Br J Urol 76931-234, 1995 13. Hodson CJ: The radiological diaghosis of pyelonephritis. Proc R SOCMed 52:669-672, 1959 14. Jodal U: The natural history of bacteriuria in childhood. Infect Dis Clin North Am 1:713-729, 1987 15. Jodal U, Hellstrom M, M5rild S, et al: Bacteriuria during the first year of life. In Kass
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EH, Svanborg Eden C (eds): Host-parasite interactions in urinary tract infections. Chicago, Chicago University Press, 1989, pp 23-25 16. Kemper KJ, Avner ED: The case against screening urinalyses for asymptomatic bacteriuria in children. Am J Dis Child 146:343-346, 1992 17. Kincaid-Smith P, Becker GJ: Reflux nephropathy in the adult. In Hodson J, KincaidSmith P (eds): Reflux Nephropathy. New York, Masson, 1979, pp 21-28 18. Kunin CM, Deutscher R, Paquin A: Urinary tract infection in school children: An epidemiologic, clinical and laboratory study. Medicine 43:91-130, 1964 19. Kunin CM: A ten-year study of bacteriuria in schoolgirls: Final report of bacteriologic, urologic and epidemiologic findings. J Infect Dis 122:382-393, 1970 20. Lindberg U, Claesson I, Hanson LA, et al: Asymptomatic bacteriuria in schoolgirls. I. Clinical and laboratory findings. Acta Paediatr Scand 64425-431, 1975 21. Lindberg U, Claesson I, Hanson LA, et a1 Asymptomatic bacteriuria in schoolgirls. VIII. Clinical course during a 3-year follow-up. J Pediatr 92194-199, 1978 22. Lindberg U, Hanson L, Jodal U, et a 1 Asymptomatic bacteriuria in schoolgirls. 11. Differences in Escherichia coli causing asymptomatic and symptomatic bacteriuria. Acta Paediatr Scand 64:432436, 1975 23. Linshaw M: Nephrology Forum: Asymptomatic bacteriuria and vesicoureteric reflux in children. Kidney Int 50:312-329, 1996 24. Martinell J, Jodal U, Lidin-Janson G: Pregnancies in women with and without renal scarring after urinary infections in childhood. BMJ 300:840-844, 1990 25. Martinell J, Claesson I, Lidin-Janson G, et al: Urinary infection, reflux and renal scarring in females continuously followed for 13-18 years. Pediatr Nephrol 9:131136, 1995 26. Martinell J, Lidin-Janson G, Jagenburg R, et al: Girls prone to urinary infections followed into adulthood: Indices of renal disease. Pediatr Nephrol 10:139-142, 1996 27. Stokland E, Hellstrom M, Hansson S, et al: Reliability of ultrasonography in identification of reflux nephropathy in children. BMJ 309:235-239, 1994 28. Stokland E, Hellstrom M, Jacobsson B, et a1 Early %"T ' c dimercaptosuccinic acid (DMSA) scintigraphy in first-time symptomatic urinary tract infection. Acta Paediatr 85:430436, 1996 29. Stokland E: Renal imaging in children with urinary tract infection [academic thesis]. Goteborg, 1996 30. Weiss S, Parker F Jr: Pyelonephritis: Its relation to vascular lesions and to arterial hypertension. Medicine 18:221-315, 1939 31. Wettergren B, Jodal U, Jonasson G: Epidemiology of bacteriuria during the first year of life. Acta Paediatr Scand 74:925-933, 1985 32. Wettergren B, Jodal U: Spontaneous clearance of asymptomatic bacteriuria in infants. Acta Paediatr Scand 79:300-304, 1990 33. Wettergren B, Hellstrom M, Stokland E, et al: Six year follow up of infants with bacteriuria on screening. BMJ 301:845-848, 1990 34. Winberg J, Andersen HJ, Bergstrom T, et al: Epidemiology of symptomatic urinary tract infection in childhood. Acta Paediatr Scand 252(suppI):1-20, 1974 35. Winberg J, Bollgren I, Kallenius G, et al: Clinical pyelonephritis and focal renal scarring. A selected review of pathogenesis, prevention, and prognosis. Pediatr Clin North Am 29:801-814. 1982
Address reprint requests to Sverker Hansson, MD Department of Pediatrics East Hospital S-416 85 Goteborg Sweden
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THE NATURAL HISTORY OF BACTERIURIA IN CHILDHOOD Sverker Hansson, MD, PhD, Jeanette Martinell, MD, Eira Stokland, MD, PhD, and Ulf Jodal, MD, PhD
The identification of bacteria 1 century ago soon led to the finding of microorganisms in the urine and to the description of children with urinary tract infection (UTI). An early report by Goppert described different clinical presentations and pointed out that it is a common disease of endemic character? He also described a mortality rate of 20% in infants and small children with febrile UTI. Effective therapy was not available until the introduction of the sulfonamides during the 1930s, but since then the further development of antibiotics and an increased awareness of the high frequency of UTI in children together with improved diagnostic methods have decreased acute mortality to close to zero in industrialized countries. Urinary tract infection is the term used for a mixture of diseases of different causes with growth of bacteria within the urinary tract in common. There is a great variation in the clinical presentation. In some individuals, bacteriuria causes no symptoms and only screening of healthy children can reveal its existence. Symptoms vary from foul smelling urine, dysuria, and loin pain to peaking fever and signs of circulatory shock. Many children have only one episode of UTI; others have repeated infections. Some children develop permanent renal damage that potentially can lead to hypertension, pregnancy complications, and even renal failure. It is a complex pattern dominated by benign episodes of UTI but with a large proportion of potentially serious infections; these children need to be diagnosed, treated, investigated, and followed-up on. Our knowledge of the natural history of UTI in childhood is still incomplete. There are several reasons for this. Most children with UTI are managed at the primary care level, each practitioner handling only a restricted number of chilThe financial support of the Swedish Medical Research Council, the Skandia Life Insurance Company, and the Frimurare-Barnhusdirektionenis greatly appreciated.
From the Department of Pediatrics, Sahlgrenska University Hospital, East Clinics, Goteborg, Sweden
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dren. It is therefore difficult to create population-based registries that are necessary for large epidemiologic studies. Furthermore, the course of UTI often runs over several decades, and to follow patients over such long periods of time is difficult. Finally, there is the continuous change in the management that influences and hopefully improves the long-term prognosis but which also can make comparisons between different time periods difficult. An example of this is the switch from urography to dimercaptosuccinic acid (DMSA) scanning to study renal damage that is going on in many centers.4 During the first half of the 1960s, Jan Winberg et a1 performed pioneering studies on UTI in children in Goteborg. They introduced a standardized protocol for diagnosis, treatment, investigation, and follow-up and encouraged the primary care doctors to refer children suspected to have UTI to the Children’s Hospital. A special UTI clinic was created to provide an instrument for efficient long-term follow-up but also to manage the children whenever a recurrence was suspected. A close cooperation evolved, especially with the departments of pediatric radiology and microbiology and several important papers were published.34,15 The Goteborg Childhood UTI Research Group has been continuously functioning since 1960 and still uses basically the same protocol, although the focus of interest and the members have changed over the years. This article describes the local organization and the protocol for management of children with UTI in Goteborg. Further, it gives selected aspects of the natural history of UTI in childhood focusing on results from the authors’ study group. TERMINOLOGY AND DEFINITIONS
A diagnosis of UTI requires significant bacteriuria. Although lower numbers of bacteria can occur in children with symptomatic UTI, the minimum number accepted in the studies is growth of 100,000 colony forming units in freshly voided urine obtained as a midstream specimen. For urine obtained by bag technique, the authors require two samples with homogeneous growth of at least this magnitude. In urine obtained by suprapubic aspiration, any growth is considered significant. Symptomatic UTI is subdivided into acute pyelonephritis when there is fever of at least 38.5”C, mostly supported by a high C-reactive protein, and acute cystitis when there are acute voiding symptoms but low fever and no signs of renal involvement. Ten percent to 20% of the infections cannot be classified in this way, and for those, the term unspecified UTI is used. A diagnosis of asymptomatic bacteriuria (ABU) requires repeated samples with identical growth in a child who does not report symptoms and who has not been ill for at least 2 weeks. LOCAL ORGANIZATION
The city of Goteborg has had a stable population of about 420,000 inhabitants for many years, of whom 80,000 are children below 16 years of age. There is one Children’s Hospital providing the only round-the-clock emergency service for children in the city. There are 20 district pediatricians employed by the city working at seven outpatient clinics. They have mostly prearranged appointments during regular office hours and a limited capacity to handle acute cases. In the city, there are only three other pediatricians, and home calls are rarely done. Therefore, most children with acute diseases are seen at the emergency
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room of the Children’s Hospital. From surveys of the diagnosis records, the authors know that at the hospital are managed 90% of the children with febrile and 50% of those with nonfebrile UTI in the population. In addition to the pediatric medical care organization, the community also runs child health centers and school health units. These are primarily meant for preventive measures, and different types of screening procedures are included in their routine work. It has been possible to perform studies within SChoo~SIU-lZ, 20-22 and at child health A good cooperation between the health units, the outpatient clinics, and the Children’s Hospital has been ensured by the fact that many pediatricians have part-time positions at several units. The principal features of the protocol that Winberg et a1 used during the 1960s are still maintained, and the isolated bacteria are routinely preserved. Modifications of the protocol, however, have been done according to the technical development and to the increased knowledge about the risk factors in childhood UTI. Thus, DMSA scintigraphy is used for identification of children with renal damage and the number of check-ups to find bacteriuria in children without symptoms has been greatly reduced as a consequence of the finding that ABU is an essentially innocent state (see later discussion).
EPIDEMIOLOGY In the classical studies of Winberg et a1 from the 1960s, the cumulative incidence of symptomatic UTI during the first 10 years of life was 3.0% in girls and 1.1%in boys.34Increased awareness of the diagnosis and more frequent culturing of urine in sick children have increased these figures gradually. Our most recent figures are based on the records of children entering school at the age of 7 years. From a cohort of 3556 school entrants, 7.8% of the girls and 1.6% of the boys were found to have had symptomatic UTI as confirmed by significant bacteriuria.” In half of the children, the UTI had been associated with high fever according to the original case records from hospital or outpatient clinics, and in most of these, a diagnosis of acute pyelonephritis was supported by laboratory tests such as C-reactive protein or sedimentation rate. The incidence of febrile first-time UTI is highest during the first year of life. This is most marked for boys but also evident for girls as seen in Figures 1 and 2, which illustrate the age-related number of children with symptomatic firsttime UTI diagnosed at the emergency room of the authors’ hospital during the years 1992 to 1995. The authors believe that this pattern reflects the true incidence of febrile UTI in the population, whereas the incidence of nonfebrile UTI in children over 1 year of age is underestimated; nonfebrile UTI should occur approximately twice as often in the total population. Symptoms that directly point to the urinary tract are acute voiding problems and back or loin pain. In infants with symptomatic UTI, such localizing symptoms are rare. Even in children more than 2 years of age with febrile UTI, less than half had acute dysuria, 6 of 19 (32%) boys and 42 of 105 (40%) girls (Figure 1 and 2). Loin or back pain was even less common and found in 1 of 19 boys and 28 of 105 (27%) girls. For children more than 2 years of age with nonfebrile UTI, few lacked dysuria, and a clinical diagnosis of acute cystitis was mostly made. IMAGING TECHNIQUES
Because the long-term risks for childhood UTI are related to the impact on renal development and function, the methods to detect renal damage are of
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Boys febrile UTI n=178
150 T
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Figure 1. Boys with symptomatic first-time UTI diagnosed at the Children’s Hospital in Goteborg from 1992 to 1995 according to age at detection: (A) febrile UTI and (6) nonfebrile UTI. White bar = no dysuria; hatched bar = dysuria.
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Girls febrile UTI n = 299
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Figure 2. Girls with symptomatic first-time UTI diagnosed at the Children’s Hospital in Goteborg from 1992 to 1995 according to age at detection: (A)febrile UTI and (B) nonfebrile UTI. White bar = no dysuria; hatched bar = dysuria.
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great importance. The standard technique to define permanent renal damage has for a long-time been urography. The radiologic features of renal scarring were well defined by Hodson in 1959, and our present knowledge of the longterm outcome of childhood UTI is based on this te~hnique.'~ The development of standardized measuring techniques, for example, relating parenchymal thickness to the Ll-L3 vertebrae distance has improved the accuracy of scar detection2 A difficulty, however, is the long time until a scar has developed to be easily seen at urography, often up to 2 years3 The introduction of new techniques has challenged urography as the standard for imaging of the kidneys and presently ultrasonography and DMSA scintigraphy are favored in many centers. The authors' have compared the ability of these different techniques to identify renal scarring and tried to analyse the advantages, the drawbacks and the pitfalls of the respective methods. Ultrasonography Versus Urography
Ultrasonography has replaced intravenous urography as the method of choice for detection of major malformations of the urinary tract. Arguments in favor of ultrasonography are noninvasiveness, absence of radiation, accessibility, and independence of renal function. It has become a standard procedure in the primary evaluation of children with UTI and is especially good for detection of dilatation of the urinary tract. For the identification of pyelonephritic renal scarring, however, ultrasonography is of limited value. In a study of 25 patients aged 2 to 16 years who had recently been examined by urography (and most also by DMSA scintigraphy) because of UTI, 15 had clearcut urographic evidence of renal scarring with parenchymal reduction and caliceal def~rrnity?~ During 1 day, all children were examined by ultrasonography by 10 radiologists, representing the most experienced examiners in the country, with special interest in pediatric renal ultrasonography. With urographic renal scarring as the diagnostic criterion, the sensitivity of ultrasonography was only 54%, with a specificity of 80%. There were wide interobserver variations with sensitivity ranging from 40% to 90%. It was concluded that ultrasonography is not accurate enough to identify kidneys with scarring and that this technique is not suitable for deciding which children are at risk for future complications after UTI. DMSA Scintigraphy Versus Urography
Many centers have abandoned urography for DMSA in the evaluation and follow-up of children with UTI. Difficulties in identifying the renal outline in the urogram, especially when a digitalized system is used, is a major reason as is also the higher sensitivity of the scintigraphy to detect renal damage. A further problem is the difficulty to differentiate between transient scintigraphic uptake defects caused by inflammation and permanent defects caused by scarring. Urography will only detect permanent damage. To compare the two techniques, the authors prospectively followed 175 children aged 0 to 5 years from their first recognized nonobstructive UTLZ8The median age at inclusion was low, only 0.4 years. There were 78 girls and 97 boys. At the time of the infection, all were investigated by DMSA scintigraphy and urography and all but one by voiding cystourethrography. After 1 year,
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DMSA scintigraphy and urography were repeated in 157 children. All the examinations were evaluated blindly.z9 Analysis of the 157 children who had repeat investigations showed that 68 (43%) had abnormal DMSA and 10 (6%) had urographic evidence of renal scarring at the initial examination. At the 1-year follow-up examination, resolution of the abnormal DMSA findings were seen in 30 of the 68 children. Thus, there were 38 (24%) children with persisting scintigraphic abnormality. The renal area involvement at the first investigation was significantly larger in the group with persisting abnormality compared with those who were normalized at the follow-up (p
In principle, the long-term risks for pyelonephritic renal damage have been known for a long time, for example, development of hypertension and
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Table 1. CAPACITY OF IMAGING TECHNIQUES TO DETECT UPPER URINARY TRACT ABNORMALITIES ~~~~~~~~~~~
Dilatation Inflammation Scarring Side distribution of function
Ultrasonography
Urography
DMSA Scintigraphy
+++ + +
+ +- + ++ ++
+++ +++ +++
-
-
complications during pregnan~y.'~, XI The extent of this risk, however, is inadequately known, depending on factors such as the long follow-up required and the difficulty in attaining continuity of data. To evaluate the long-term aspects, the authors have followed-up on a group of 111 women from their first recognized UTI in childhood through the growth p e r i ~ d . ~ They ~ - ' ~ were selected for continued follow-up into adulthood at the age of 15 to 18 years because of renal scarring as identified by urography in 54 or a proneness to UTI in 57; of the 54 with renal scarring, 36 were prone to UTI. The index infection was symptomatic in 87 and occurred at a mean age of 4.3 years. In 24 the index infection was asymptomatic and detected through a school screening program. The median age at the last follow-up was 27.5 years, and the median follow-up time was 23.1 years. Symptomatic recurrences were seen in 97 women with a median of 7 per individual. The infections became less symptomatic with increasing number and age. In 89 there were between 1 and 14 recurrences without symptoms, and many were subsequently left untreated. Because the true number of asymptomatic episodes is not possible to establish, the UTI pattern in Figure 3 illustrates only the attack rate (number of UTI per woman per observation year) for symptomatic infections according to age. The attack rate was highest during the first year of life and gradually decreased thereafter to reach the lowest in the age group from 11 to 15 years. During the first 5 years of life, febrile UTI was the dominating type of infection; thereafter, nonfebrile UTI was most common. Women with urographic renal scarring, however, continued to have a high proportion of febrile recurrences also after 10 years of life. There was a high proportion of febrile UTI when the children had reflux. After the reflux was absent, the attack rate of symptomatic UTI was still high, but the proportion of febrile infections was lower. The proportion of febrile attacks of UTI was significantly higher in women with reflux compared with those without reflux after elimination of age as a confounding variable (p
m
a"
t
i-:r i
c
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I
s
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sion of at least 140/90 mm Hg was diagnosed in 3 of the 54 females (5.5%) with renal scarring, 2 before and 1 at the follow-up examination.2hThus, these young women who were continuously followed-up on and were compliant had a wellpreserved renal function, and the incidence of hypertension was low. Further follow-up will show whether some of these women will develop deteriorating renal function. The same group of women has also been studied for complications during 65 pregnancies, and compared with 65 controls, randomly selected and matched for parity, age, smoking habits, and date of delivery.24The incidence of bacteriuria during first pregnancies was significantly greater in women with (9, 47%) and without (6, 27%) renal scarring after childhood UTI than in controls (1, 2%) (p
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more breakthrough infections that were mostly caused by resistant bacteria.h There were 26 girls left untreated during a total of 74 observation years. In no case was there development of symptoms. The duration of ABU had no negative impact on renal growth or glomerular filtration rate.7 Whether bacteriuria will produce symptoms or not is determined by hostparasite relations. For patients with ABU, there seems to be a balance between the host defense and the virulence of the bacteria. The E. coli isolated from patients with ABU were different from those causing symptomatic infections; they were often not typable in serogroups, had an increased sensitivity to the bactericidal effect of serum, and a poor adhering ability?* Because of the difficulties with serotyping, "fingerprinting" of the bacteria was done using multilocus enzyme electrophoresis, a technique allowing identification of the bacterial strain despite the lack of surface antigens. Analysis of a large number of consecutively isolated E . coli bacteria from 54 girls with untreated ABU during a total of 151 patient-years revealed only 24 changes of strain? Eleven of the strain changes were associated with antibacterial treatment for intercurrent infections or occurred in connection with a voiding cystourethrogram. The authors' also observed a successive loss of surface antigens (antigenic drift) during follow-up, probably caused by long-term exposure of E. coli to the host environment in the urinary tract. Thus, untreated ABU was characterized by a stable bacterial flora with a tendency for the bacteria to become less virulent with time. Despite a nontreatment policy, patients with ABU may need antibacterial medication for other infections. The authors studied the effect of penicillin treatment given to patients with ABU for intercurrent infections, mainly tonsillitis and ~ t i t i sPhenoxymethylpenicillin .~ had a dramatic effect on the bacteria in children with ABU. The bacteriuria was cleared, but only 5 of 40 girls treated remained free from recurrences. There were 7 episodes of acute pyelonephritis in 6 patients. It was inferred that each change of strain carries the risk for acquiring a more virulent strain, which can cause acute pyelonephritis. Treatment with erythromycin, on the other hand, was not associated with bacterial clearance and consequently did not increase the risk for recolonization with a more virulent strain. The conclusion from these studies was that not only can ABU be left untreated, but there is also an advantage for the patient to have an asymptomatic growth of low virulent bacteria in the urine. The presence of an established bacterial strain seems to prevent invasion by other bacteria, thus functioning as a kind of biological prophylaxis.16,23 ASYMPTOMATIC BACTERIURIA IN INFANTS Mass screening for bacteriuria in infancy has been discussed as a means of preventing pyelonephritic renal scarring. Studies of bacteriuria in infancy pose problems of reaching a relevant population of adequate size and of difficulties in obtaining uncontaminated urine samples. An unselected group of 3581 infants was screened at three different occasions during the first year of life: at 2 weeks, 3 months, and 10 months of age, respectively?' ABU was confirmed by suprapubic aspiration in 36 (2.5%),of the boys and in 14 (0.9%)of the girls. Bacteriuria in the boys was almost exclusively found during the first 6 months of life, whereas in the girls it was found throughout the first year. Two infants developed pyelonephritis within 2 weeks of the verification of bacteriuria, and the others remained free of symptoms. The bacteriuria cleared spontaneously within a few months in 36 of 45 untreated infants, and it cleared in response to antibiotics given for infections in the respiratory tract in a further 8. Recurrences
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of bacteriuria were observed in 20% of the children, but only one experienced an attack of pyelonephritis. Thus, only 2 of 45 untreated infants with screening bacteriuria developed acute pyelonephritis, whereas the others remained free from symptoms. Within the study population of 3581 infants there were another 22 (1.3%)boys and 20 (1.1%)girls who developed symptomatic UTI during the first year of life. Of those with symptomatic bacteriuria diagnosed after 1 month of age, all had participated in the screening program with normal results before the diagnosis. These findings suggest that infants with primary asymptomatic and symptomatic bacteriuria comprise two subpopulations with only marginal overlapping. Among the infants with screening bacteriuria, radiologic abnormalities were uncommon.” Of the boys, 3 (9%) had vesicoureteric reflux, all without dilatation, and none had renal anomalies. Of the girls, one had a scarred duplex kidney with reflux and another had moderate hydronephrosis. A repeat urography was performed after 3 years in 36 of the 50 children and did not reveal development of renal scarring in any child. Mass screening for bacteriuria in infancy seems to result primarily in the detection of innocent bacteriuric episodes and cannot be recommended. Instead, in infants and small children with high fever without obvious cause or with uncharacteristic symptoms, such as failure to thrive, urine cultures should be considered and performed as part of the general workup of the child. CONCLUSION
It is essential that children with an increased risk for progressive renal deterioration are identified early. Most important is the early detection of those with severe malformations of the urinary tract: obstruction and renal hypoplasia or dysplasia. Many of these children already have a reduced renal function from birth, and superimposed UTI can lead to further loss of function and ultimately chronic renal failure. In addition, a number of risk factors have been described in association with development of pyelonephritic renal scarring, for example, vesicoureteric reflux and number of pyelonephritic attacks.l4 There is no single protocol for children with UTI that can be generally recommended. Each protocol needs to be adapted to local traditions and resources. Our own protocol (Table 2) is based on a high detection rate for Table 2. PROTOCOL FOR INVESTIGATIONS AND FOLLOW-UP OF CHILDREN WITH UTl (GOTEBORG MODEL)* Time After Diagnosis 4-5 days
3-4 weeks
6 months 1 year
Acute Pyelonephritis and All Children <2 Years Old S-creatinine, C-reactive protein Blood pressure Planning for ultrasonography and voiding cystourethrography Information to the family about results and future planning DMSA scintigraphy Last visit (if all investigations have been normal and no recurrence)
*All check-uDs include culture of urine
Acute Cystitis S-Creatinine, C-reactive protein Blood pressure Renal concentrating capacity Last visit
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symptomatic UTI with a dominance of infants a n d that most risk patients are identified early. For girls over the age of 2 years with acute cystitis, the followup is only 3 to 4 weeks. All other children a r e followed u p for a t least 1 year after the UTI. The emphasis a t the control visits is on repeated information to the patient a n d family, including encouragement to return whenever symptoms occur that can be caused by UTI. Repeat radiologic investigations or alternative procedures are primarily performed to detect development o r progress of renal scarring. Long-term follow-up of patients with renal scarring into adulthood is essential with a t least yearly blood pressure measurements. Likewise, the patients should be provided w i t h immediate service a t suspected recurrences or other complications.
ACKNOWLEDGMENTS The authors acknowledge the important contributions of the following members of the Goteborg Childhood UTI Research Group: Marc Bachelard, Einar Hanson, Mikael Hellstrom, Gert Hermansson, Kelm Hjalmis, Bo Jacobsson, Gunilla Lidin-Janson, Peter Larsson, Knut Lincoln, Staffan Mirild, Torsten Sandberg, Ulla Sillen, Rune Sixt, Catharina Svanborg, Martin Wennerstrom, and BjBrn Wettergren.
References 1. Cardiff-Oxford Bacteriuria Study Group: Sequelae of covert bacteriuria in schoolgirls. Lancet 1:889-893, 1978 2. Claesson I, Jacobsson B, Jodal U, et al: Early detection of nephropathy in childhood urinary tract infection. Acta Radio1 Diagnosis 22315-320, 1981 3. Filly R, Friedland GW, Govan DE, et a 1 Development and progression of clubbing and scarring in children with recurrent urinary tract infections. Radiology 113:145-153,1974 4. Goldraich NP, Goldreich IH: Update on dimercaptosuccinic acid renal scanning in children with urinary tract infection. Pediatr Nephrol 9:221-226, 1995 5. Gbppert F: Uber die eitrigen Erkrankungen der Harnwege im Kindesalter. Ergebn Inneren Med Kinderheilkd 2:30-73, 1908 6. Hansson S, Jodal U, Noren L: Treatment vs non-treatment of asymptomatic bacteriuria in girls with renal scarring. In Kass EH, Svanborg Eden C (eds): Host-parasite interactions in urinary tract infections. Chicago, Chicago University Press, 1989, pp 289-291 7. Hansson S, Jodal U, Noren L, et al: Untreated bacteriuria in asymptomatic girls with renal scarring. Pediatrics 84964-968, 1989 8. Hansson S, Caugant D, Jodal U, et al: Untreated asymptomatic bacteriuria in girls. I: Stability of the urinary isolates. BMJ 2982353-855, 1989 9. Hansson S, Jodal U, Lincoln K, et al: Untreated asymptomatic bacteriuria in girls: 11: Effect of phenoxymethylpenicillin and erythromycin given for intercurrent infections. BMJ 298856459, 1989 10. Hellstrom A-L, Hanson E, Hansson S, et al: Micturition habits and incontinence in 7year-old Swedish school entrants. Eur J Pediatr 149:434-437, 1990 11. Hellstrom A, Hanson E, Hansson S, et al: Association between urinary symptoms at 7 years old and previous urinary tract infection. Arch Dis Child 66:232-234, 1991 12. Hellstrom A, Hanson E, Hansson S, et al: Micturition habits and incontinence at age 17: Reinvestigation of a cohort studied at age 7. Br J Urol 76931-234, 1995 13. Hodson CJ: The radiological diaghosis of pyelonephritis. Proc R SOCMed 52:669-672, 1959 14. Jodal U: The natural history of bacteriuria in childhood. Infect Dis Clin North Am 1:713-729, 1987 15. Jodal U, Hellstrom M, M5rild S, et al: Bacteriuria during the first year of life. In Kass
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EH, Svanborg Eden C (eds): Host-parasite interactions in urinary tract infections. Chicago, Chicago University Press, 1989, pp 23-25 16. Kemper KJ, Avner ED: The case against screening urinalyses for asymptomatic bacteriuria in children. Am J Dis Child 146:343-346, 1992 17. Kincaid-Smith P, Becker GJ: Reflux nephropathy in the adult. In Hodson J, KincaidSmith P (eds): Reflux Nephropathy. New York, Masson, 1979, pp 21-28 18. Kunin CM, Deutscher R, Paquin A: Urinary tract infection in school children: An epidemiologic, clinical and laboratory study. Medicine 43:91-130, 1964 19. Kunin CM: A ten-year study of bacteriuria in schoolgirls: Final report of bacteriologic, urologic and epidemiologic findings. J Infect Dis 122:382-393, 1970 20. Lindberg U, Claesson I, Hanson LA, et al: Asymptomatic bacteriuria in schoolgirls. I. Clinical and laboratory findings. Acta Paediatr Scand 64425-431, 1975 21. Lindberg U, Claesson I, Hanson LA, et a1 Asymptomatic bacteriuria in schoolgirls. VIII. Clinical course during a 3-year follow-up. J Pediatr 92194-199, 1978 22. Lindberg U, Hanson L, Jodal U, et a 1 Asymptomatic bacteriuria in schoolgirls. 11. Differences in Escherichia coli causing asymptomatic and symptomatic bacteriuria. Acta Paediatr Scand 64:432436, 1975 23. Linshaw M: Nephrology Forum: Asymptomatic bacteriuria and vesicoureteric reflux in children. Kidney Int 50:312-329, 1996 24. Martinell J, Jodal U, Lidin-Janson G: Pregnancies in women with and without renal scarring after urinary infections in childhood. BMJ 300:840-844, 1990 25. Martinell J, Claesson I, Lidin-Janson G, et al: Urinary infection, reflux and renal scarring in females continuously followed for 13-18 years. Pediatr Nephrol 9:131136, 1995 26. Martinell J, Lidin-Janson G, Jagenburg R, et al: Girls prone to urinary infections followed into adulthood: Indices of renal disease. Pediatr Nephrol 10:139-142, 1996 27. Stokland E, Hellstrom M, Hansson S, et al: Reliability of ultrasonography in identification of reflux nephropathy in children. BMJ 309:235-239, 1994 28. Stokland E, Hellstrom M, Jacobsson B, et a1 Early %"T ' c dimercaptosuccinic acid (DMSA) scintigraphy in first-time symptomatic urinary tract infection. Acta Paediatr 85:430436, 1996 29. Stokland E: Renal imaging in children with urinary tract infection [academic thesis]. Goteborg, 1996 30. Weiss S, Parker F Jr: Pyelonephritis: Its relation to vascular lesions and to arterial hypertension. Medicine 18:221-315, 1939 31. Wettergren B, Jodal U, Jonasson G: Epidemiology of bacteriuria during the first year of life. Acta Paediatr Scand 74:925-933, 1985 32. Wettergren B, Jodal U: Spontaneous clearance of asymptomatic bacteriuria in infants. Acta Paediatr Scand 79:300-304, 1990 33. Wettergren B, Hellstrom M, Stokland E, et al: Six year follow up of infants with bacteriuria on screening. BMJ 301:845-848, 1990 34. Winberg J, Andersen HJ, Bergstrom T, et al: Epidemiology of symptomatic urinary tract infection in childhood. Acta Paediatr Scand 252(suppI):1-20, 1974 35. Winberg J, Bollgren I, Kallenius G, et al: Clinical pyelonephritis and focal renal scarring. A selected review of pathogenesis, prevention, and prognosis. Pediatr Clin North Am 29:801-814. 1982
Address reprint requests to Sverker Hansson, MD Department of Pediatrics East Hospital S-416 85 Goteborg Sweden