February 1978
194
TheJournalofPEDIATRICS
Asymptomatic bacteriuria in schoolgirls VIII. Clinical course during a 3-year follow-up
A 3-year follow-up of 116 schoolgirls with asymptomatic bacteriuria, treated or untreated, is reported. It is concluded that bacteria isolated from girls with a~ymptomatic bacteriuria do not commonly cause symptomatic pyelonephritis and that the risk of developing renal damage as a result of asymptomatic baeteriuria in a schoolgirl with a roentgenographically normal urinary tract seems to be small. It is also suggested that for the majority of these patients therapy is not necessary.
Ulf Lindberg, M.D.,* Ingemar Claesson, M.D., Lars ,~ke Hanson, M.D., and Ulf Jodal, M . D . , G~teborg, S w e d e n
SINC~ the long-term consequences of covert or asymptomatic bacteriuria in children are uncertain and its association with renal infection is unknown, a follow-up of schoolgirls with ABU was started in GOteborg in 1971. The one-year prognosis of ABU, treated or left untreated has been reported1; it was concluded that Escheriehia colt isolated from patients with ABU did not commonly cause symptomatic pye!onephritis, Further, no deterioration of renal concentrating capacity could be demonstrated during the first year of observation in patients who had roentgenographically normal urinary tracts and were not treated for their bacteriuria. The present study is concerned with the clinical course of ABU, treated or untreated, over a period of three years in a group of patients described earlier?. -'
From the Departments of Paediatrics and Paediatric Radiology, East Hospital, and Department of Immunology, Institute of Medical Microbiology, University of GOteborg. Supported by grants from the First of Moy Flower Campaign, the Faculty of Medicine, University of Gbteborg, and the Swedish Medical Research Council (Project No. 215). *Reprint address: Department of Paediatries, East Hospital, S-416 85 GOteborg, Sweden.
Vol. 92, No. 2, pp. 194-199
MATERIAL AND METHODS The patients were 116 schoolgirls who were 7 to 15 years of age when their ABU was detected in a screening program. 2 They were divided into three groups according to roentgenographic observations: 12 patients with parenchymal reduction (11 of 12 also had vesicoureteric reflux), 13 patients with reflux but without parenchymal reduction, and 91 patients with neither parenchymal reduction nor reflux.
See related article, p. 188. Abbreviations used ABU: asymptomatic bacteriuria CRP: C-reactive protein ESR: erythrocyte sedimentation rate MCU: micturition cystourethrography In the first 60 of the 116 ABU patients examined, a bladder washout was performed to establish the level (bladder or renal parenchyma) of the bacteriuria as earlier described3; in 34 of the patients a negative urine culture was obtained the day after the washout, but the remaining 26 continued to have bacteriuria. The 12 patient s with parenchymal reduction and the 13 patients with vesicoureteric reflux were treated with chemotherapeutic agents within six months after detection of bacteriuria. Seven of
0022-3476/78/0292-0194500.60/0 9 1978 The C. V. Mosby Co.
Volume 92 Number ]
A symptornatic bacteriuria
195
Renol length cm
ABU Scarred kidney drained by 9 ureter without reflux ureter with ~eftux grade I [z ureter with reflux grade lI
15no p
a
r
e
n
~
no reflux
parenchyma[ reduction and/or
I
reflux
@
/,
// ///
13/
/
/
/
/
/ /
/
/
11- /1" )
/
/ /
61
/
///
1/,-
t2-
ABU (
~ / /
/I
bacteriuria eliminated during the first 6 months
10-
/ 9.
8" non treatment group
/
/
treatment group
Fig. 1. Plan of study in 116 schoolgirls with asymptomatic bacteriuria.
the 91 patients without parenchymal reduction or reflux were also treated at the time of initial diagnosis; one of them had a bladder diverticulum, and six had enuresis and foul-sine!ling urine. The remainder of the 91 patients were observed for six months without treatment; 61 of them who still had bacteriuria were randomly assigned to treatment (30 patients) and nontreatment groups (31 patients) (Fig. 1). A roentgenographic reinvestigation (intravenous pyelography and micturition cystourethrography) was performed after three years of follow-up in 11 of the 12 patients with scarred kidneys, in 11 o f i h e 13 patients with roentgenographically normal kidneys but with vesicoureteric reflux, a n d i n 14 of 31 patients from the untreated group who had persistent bacteriuriaq the remaining 17 patients in the untreated group had no bacteriuria at the e n d o f the observation period. Two patients, one in the treatmen t group a n d one in the nontreatment group, Who developed symptomatic pyelonephritis, were reinvestigated. One patient with a Scarred kidney and two patients with unscarred kidneys but with Grade I vesicoureteric reflux refused the roentgenographic re-examination.
7"
7
~
~
lb
II
12
LI-L3 cm
Fig. 2. Renal growth during a 3-year period in 13 scarred Iddneys. Mean renal lengths ~ ) and _+ 2SD (---) in relation to L1 to L~ length in normal children. (From ClaEsson 1, and Lindberg U: Radiology 124:179, 1977.)
Diagnostic procedures and criteria. Midstream urine samples were kept at + 4~ until they were semiquantitatively cultured. Growth Of _> 10 ~ bacteria/ml was considered to be significant bacteriuria. To obtain a second sample in patients Mth a suspected asymptomatic recurrence, the patient was instructed to collect morning midstream urine and to culture it with a dipslide (Uricult, Orion Pharmaceutical Co., Helsinki, Finland) at home. The slide was sent by mail to th e laboratory and read after incubation overnight at 37~ Classification of the bacteria and 0 grouping of E. coil were performed as described earlier? The concentrating capacity of the kidneys was estimated by freeze-p0int reduction in two consecutive urine samples obtained at home after fluid deprivation for at least 15 hours; highest osmolality of the two samples was
19 6
Lindberg et al.
The Journal of Pediatrics February 1978
Table I. Recurrence rate during the three years after an apparent initial cure in 78 schoolgirls with asymptomatic bacteriuria* Roentgenographic observations
No. of patients
No recurrence
Asymptomatic recurrence
Symptomatic cystitis
Symptomatic pyelonephritis
Parenchymal reduction (l 1/ 12 with reflux) Reflux without parenchymal reduction No reflux or parenchymal reduction Total
12
6
2
1
3
13
4
7
2
0
53
32
17
1
3
78
42 (54%)
26 (33%)
4 (5%)
6 (8%)
*Each patient who had a recurrence is represented only once.
recorded. The age-related normal values of Winberg" were used as a reference. If the concentrating capacity was < 814 mOsm/1, the test was repeated. Blood samples were obtained and analyzed for erythrocyte sedimentation rate and C-reactive Pr0tein.7 The diagnosis of asymptomatic recurrence, after a preceding examination with negative urine culture, was made if the patient had no obvious symptoms but had had two urine samples with significant bacteriuria and the same type of bacteria in each culture. The criteria for symptomatic cystitis were acute frequency and burning, temperature not exceeding 38.0~ significant bacteriuria, and normal renal concentrating capacity.~ Criteria for pyelonephritis were fever > 38.0~ significant bacteri, uria, and at least two of the following: ESR > 20 mm after one hour, CRP > 10/~g/ml, or renal concentrating capacity < 814 m O s m / l ? A spontaneous remission was diagnosed if two negative urine cultures were found on two successive examinations. MaXimum renal length was estimated and correlated to the distance between the upper surface of the first lumbar vertebra a n d the lower surface of the third lumbar vertebra, according to the method of Ekl6f and Ringertz, ~ on intravenous pyelograms obtained at the time of detection of the bacteriuria, and at the 3-year re-examination. 4 The growth of the kidneys during the observation period was calculated. The degree of vesicoureteric reflux was rated according to the following schema: Grade I-vesicoureteric reflux not reaching the kidney pelvis in a nondilated ureter; Grade II--vesicoureteric reflux into the kidney pelvis but without ureteric dilatation; and Grade III--vesicoureteric reflux into the kidney pelvis with mode-rate dilatation of the pelvis and ureter?. 1o Therapy. Patients with ABU selected for treatment and patients with symptomatic cystitis were given nitrofurantoin, 3 mg/kg/24 hours for ten days. Long-term propHylaxis, over a six-month period, with nitrofurantoin, 1 mg/ kg/24 hr, was given after initial sterilization of urine, to
patients who had recurrences after a second short course of treatment. Patients with symptomatic pyelonephritis were given sulphafurazole, 200 mg/kg/24 hr for ten days. Follow-up. The patients were examined every third or sixth month when urine for semiquantitative culture, blood samples for CRP and, in symptomatic patients, for E s R were obtained. The renal concentrating capacity was tested. Urine for culture was also always obtained within a week after completion of chemotherapy. For statistical evaluation the chi square test was employed. RESULTS
Twelve patients with parenchymal reduction (11 of 12 with reflux). In one patient bacteriuria was eliminated and has not recurred after a bladder washout test. Five patients have not had recurrence after the initial shortterm treatment with nitrofurantoin. Three patients have had attacks of pyelonephritis, one of them twice during pregnancy. One patient has had cystitis, and two have had asymptomatic recurrence (Table I). Long-term prophylaxis, 'because of repeated recurrences, was prescribed for two of the patients. The growth for three years of 13 scarred kidneys from 11 of the 12 patients is shown in Fig. 2. The growth of eight of these 13 kidneys was within normal limits. The renal parenchyma in on e of the kidneys of the patient who had had two attacks of febrile pyelonephritis during pregnancy decreased during the observation period; the growth of the other kidney had accelerated (Fig. 2). There was essentially no growth of the three smallest kidneys ( < - 6 SD). The vesicoureteric reflux had disappeared in three of the 13 ureters; it had changed from Grade II to Grade I in one, from Grade I to Grade II in two, and was unchanged in seven ureters. Thirteen patients with reflux but without parenchymal reduction. One of the 13 patients had bacterinria eliminated by a bladder washout and it has not recurred. Three
Volume 92 Number I
patients have not had recurrences since the initial shortterm treatment with nitrofurantoin. Two patients have had cystitis; seven have had asymptomatic recurrences (Table I). Long-term prophylaxis was prescribed for four of the 13 patients because of repeated recurrences. Two of these four patients are still having recurrences. The growth of 17 unscarred kidneys associated with ureteral reflux in 11 of the 13 patients was normal during the observation period. The reflux disappeared in nine of the 17 ureters; it changed from Grade II to Grade I in five ureters; it was unchanged in three of them. The disappearance'of vesicoureteric reflux or a change from Grade II to I was significantly more common (P < 0.01) in patients with unscarred kidneys than in those with scarred kidneys. Ninety-one patients without parenchymal reduction or reflux. Sixteen of the 91 patients had not had recurrences at the one-year follow-up after an initial bladder washout test that eliminated the bacteriuria. Thirteen of these 16 patients still had sterile urine at the three-year follow-up; one of them had had an asymptomatic recurrence during the third year; two patients were lost to follow-up. Seven of the 91 patients had initially been given nitrofurantoin, six for enuresis and foul-smelling urine and one for a bladder diverticulum. Two of these seven girls had had pyelonephritis, one had cystitis, three had asymptomatic recurrences; and one was lost to follow-up during the observation period. Of the remaining 68 girls who were untreated for six months, two became abacteriuric after they had been given penicillin for otitis and tonsillitis, and four became spontaneously abacteriuric and have not had noted recurrences for three years. One girl was lost to follow-up. There were 61 girls who had bacteriuria and were asymptomatic after the first six months of observation; they were randomly placed into treatment and nontreatment groups. Treatment group: 30 patients. Three patients moved from the area during the observation period. No recurrence has occurred after one short-term treatment in 13 patients (48%), and none after two short-term treatments in five patients. Nine patients (33%) were given long-term prophylaxis with nitrofurantoin because of repeated recurrences. Six of these nine girls continue to have recurrences after three year s of prophylaxis. Two of the patients for whom long-term prophylaxis was prescribed did not follow the prescriptions, and one of them had one attack of pyelonephritis and one episode of cystitis. The roentgenographic reinvestigation of the patient with pyelonephritis showed normal kidney growth without paxenchymal reduction.
A symptomatic bacteriuria
197
Untreated group: 31 patients. One patient moved from the area during the observation period. Five patients became abacteriuric after treatment with penicillin for respiratory tract infection and they have not had recurrences. Nine patients spontaneously became abacteriuric (30%): three during the first year, two during the second year, and four during the third year. None of them have had recurrences. One girl had an attack of symptomatic pyelonephritis after 15 months of observation. E. coli was found in her urine as earlier, but also significant numbers of enterococci. The patient has had asymptomatic recurrences after treatment of the symptomatic infection, and long-term prophylaxis has been prescribed. The roentgenographic reinvestigation revealed a pyelonephritic scar and decreased growth in one of the kidneys. During the second year another patient had dysuria during an attack of measles. She was treated with nitrofurantoin and has not had subsequent recurrences. After three years of observation, 14 girls (47%) were still bacteriuric. In 11 of them an E. coli of the same 0 type or a spontaneously agglutinating E. coli strain was isolated at each examination. In three of the patients there were differences in the E. coli type in two consecutive examinations. The growth of the 28 kidneys in the 14 patients who were still bacteriuric and asymptomatic after three years without treatment was normal; there were no signs of scarring. At the follow-up MCU one patient had a unilateral Grade I reflux. The mean concentrating capacity of the kidneys in the bacteriuric girls after six months and one and three years, respectively, was not different from that at the time of the first identification of ABU: 1,016 • 92 mOsm/1 ( • 1 SD), 1,004 _+ 106 mOsm/1, 1,042 _+ 103 mOsm/1, and 1,039 • 110 mOsm/1, respectively. No increase in serum CRP was found in the girls when they were asymptomafic. No significant difference (P > 0.05) in the number of bacteriuric patients was found in the nontreatment group, 14 of 30 in comparison with the treatment group, 6 of 27 at the end of the observation period. Recurrence rate in 78 patients cured of their bacteriuria. The number of patients who had recurrences of bacteriuria (46%) among 78 girls, i.e., the 116 patients minus 31 girls not treated and seven lost to follow-up, are listed in Table I. These patients became abacteriuric after a bladder washout test or after treatment with penicillin or nitrofurantoin. A recurrence had occurred in 31% of the patients after the first year of observation, in 40% after the second, and, in 46% after the third. The recurrence rate in patients with parenchymal reduction and/or reflux, 15 of 25 (60%), was higher but not significantly different
19 8
Lindberg et al.
(P > 0.05) from that in patients without such radiologic signs, 21 of 53 (40%). DISCUSSION Earlier studies have shown that schoolgirls with ABU have frequent recurrences?. 11-13 Despite this, there is normal renal growth and no increase in the frequency of roentgenographic evidence of vesicoureteric reflux or of pyelonephritis in such patients according to Savage? ~ Only a controlled trial of therapy will show whether treatment with chemotherapy is beneficial or even necessary. The present study demonstrates that chemotherapy reduces the incidence of bacteriuria in a treatment group but not significantly compared to that in untreated girls. Clinical pyelonephritis or illness rarely occurs with or without treatment. These findings are in accord with those presented in the first controlled trial of therapy in covert bacteriuria in childhood by Savage and associates? 4 That ABU probably does not cause progressive renal damage or only rarely does so i n patients with roentgenographically normal urinary tracts is supported by the findings that normal kidney growth was seen in all patients who had been asymptomatic during the observation period. Neither did the bacteria isolated from the untreated ABU patients seem to involve the kidney during the observation period. No decrease in the renal concentrating capacity was observed. Renal scarring and arrested renal growth may occur, however, in schoolgirls who have symptomatic pyelonephritis. In the present study this course of events is exemplified by one patient in the group with parenchymal reduction who aquired further renal scarring and in one girl in the untreated group in whom the parenchymal reduction probably was caused not by the E. coli initially isolated but by enterococci invading the urinary tract. For ethical reasons we decided in the beginning of the study to treat all patients with parenchymal reduction a n d / o r reflux with chemotherapeutic agents. During the follow-up essentially no growth was found in the extremely small scarred kidneys. Otherwise scarred or unscarred kidneys with or without reflux of Grade I or II grew normally. From these results it seems reasonable to believe that a moderate reflux does not restrict renal growth in the absence of bacteriuria. Furthermore, a reduction of the vesicoureteric reflux was often found at the follow-up examination, a feature that is in agreement with the observations that reflux tends to become less severe with time? ~, 16 The disappearance of the vesicoureteric reflux may be related to the fact that all of the involved patients had bacteriuria w h e n the initial M C U was made, whereas they were all nonbacteriuric at the
The Journal of Pediatrics February 1978
time of re-examination. The remission may also be due to maturation of the vesicoureteric j u n c t i o n as described by Hutch. 17 It seems that E. coli strains isolated from schoolgirls with A B U do not c o m m o n l y cause symptomatic pyelonephritis.18. 19 Further, the girls with a roentgenographically normal urinary tract has only a small risk of developing renal damage, hence chemotherapy for the majority of such patients seems unnecessary. REFERENCES
1. Lindberg U: Asymptomatic bacteriuria in schoolgirls. V. The clinical course and response to treatment, Acta Paediatr Scand 64:718, 1975. 2. Lindberg U, Cla~sson I, Hanson LA, and Jodal U: Asymptomatic bacteriuria in schoolgirls. I. Clinical and laboratory findings, Acta Paediatr Scand 64:425, 1975. 3. Lindberg U, Jodal U, Hanson LA, and Kaijser B: Asymptomatic bacteriuria in schoolgirls. IV. Difficulties of level diagnosis and the possible relation to the character of infecting bacteria, Acta Paediatr Scand 64:574, 1975. 4. ClaEsson I, and Lindberg U: Asymptomatic bacteriuria in schoolgirls. VII. A follow-up study of the urinary tract in treated and untreated schoolg!rls with asymptomatic bacteriuria, Radiology 124:179, 1977. 5. Lincoln K, Lidin-Janson G, and Winberg J: Resistant urinary infections resulting from changes in resistance pattern of faecal flora induced by sulphonamide and hospital environment, Br Med J 3:305, 1970. 6. Winberg J: Determination of renal concentrating capacity in infants and children without renal disease, Acta Paediatr Scand 48:318, 1959. 7. Nilsson LA: Comparative testing of precipitation methods for quantitation of C-reactive protein in blood serum, Acta Pathol Microbiol Scand 73:129, 1968. 8. Jodal U, Lindberg U, and Lincoln K: Level diagnosis of symptomatic urinary tract infection in childhood, Acta Paediatr Scand 64:201, 1975. 9. Ekl6f O, and Ringertz H: Kidney size in children--a method of assessment, Acta Radiol 17:617, 1976. 10. Filly R, Friedlund GW, Govan DE, and Fair William R: Development and progression of clubbing and scarring in children with recurrent urinary tract infections, Radiology 113:145, 1974. 11. Kunin CM, Deutscher R, and Paquin A Jr: Urinary tract infections in schoolchildren: An epidemiologic, clinical and laboratory study, Medicine 43:91, 1964. 12. Savage DCL: Natural history of covert bacteriuria in schoolgirls, Kidney Int 4 (Suppl):90, 1975. 13. Verrier-Jones ER, Meller ST, Mc Lachlan MSF, Sussman M, Asscher AW, Mayon-White RT, Ledingham JGG, Smith JC, Fletcher EWL, Smith EH, Jonston HH, and Sleight G: Treatment of bacteriuria in schoolgirls, Kidney Int 4 (Suppl):85, 1975. 14. Savage DCL, Howie G, Adler K, and Wilson MI: Controlled trial of therapy in covert bacteriuria of childhood, Lancet 1:358, 1975. 15. Rolleston GL, Shannon FT, and Utley WLF: Relationship of infantile vesico-ureteric reflux to renal damage, Br Med J 1:460, 1970.
Volume 92 Number 1
16. Winberg J, Larsson H, and Bergstr6m T: Comparison of the natural history of urinary infection in children with and without vesico-ureteric reflux, in Kincaid-Smith P, and Fairley KF, editors: Renal infection and renal scarring, Melbourne, 1971, Mercedes Publishing Service, p 293. 17. Hutch JA: Theory of maturation of the intravesical ureter, J Urol 86:534, 1961. 18. Lindberg U, Hanson L,~, Jodal U, Lidin-Janson G, Lincoln K, and Olling S: Asymptomatic bacteriuria in schoolgirls.
Asymptomatic bacteriuria
1 99
II. Differences in Escherichia coli causing asymptomatic and symptomatic bacteriuria, Acta Paediatr Scand 64:432, 1975. 19. Lidin-Janson G, Hanson LA, Kaijser B, Lincoln K, Lindberg U, Olling S, and Wedel H: Characteristics of Escherichia coli from screening bacteriuria and from asymptomatic and symptomatic reinfections as compared to the faecal reservoir, J Infect Dis (in press).
194
TheJournalofPEDIATRICS
Asymptomatic bacteriuria in schoolgirls VIII. Clinical course during a 3-year follow-up
A 3-year follow-up of 116 schoolgirls with asymptomatic bacteriuria, treated or untreated, is reported. It is concluded that bacteria isolated from girls with a~ymptomatic bacteriuria do not commonly cause symptomatic pyelonephritis and that the risk of developing renal damage as a result of asymptomatic baeteriuria in a schoolgirl with a roentgenographically normal urinary tract seems to be small. It is also suggested that for the majority of these patients therapy is not necessary.
Ulf Lindberg, M.D.,* Ingemar Claesson, M.D., Lars ,~ke Hanson, M.D., and Ulf Jodal, M . D . , G~teborg, S w e d e n
SINC~ the long-term consequences of covert or asymptomatic bacteriuria in children are uncertain and its association with renal infection is unknown, a follow-up of schoolgirls with ABU was started in GOteborg in 1971. The one-year prognosis of ABU, treated or left untreated has been reported1; it was concluded that Escheriehia colt isolated from patients with ABU did not commonly cause symptomatic pye!onephritis, Further, no deterioration of renal concentrating capacity could be demonstrated during the first year of observation in patients who had roentgenographically normal urinary tracts and were not treated for their bacteriuria. The present study is concerned with the clinical course of ABU, treated or untreated, over a period of three years in a group of patients described earlier?. -'
From the Departments of Paediatrics and Paediatric Radiology, East Hospital, and Department of Immunology, Institute of Medical Microbiology, University of GOteborg. Supported by grants from the First of Moy Flower Campaign, the Faculty of Medicine, University of Gbteborg, and the Swedish Medical Research Council (Project No. 215). *Reprint address: Department of Paediatries, East Hospital, S-416 85 GOteborg, Sweden.
Vol. 92, No. 2, pp. 194-199
MATERIAL AND METHODS The patients were 116 schoolgirls who were 7 to 15 years of age when their ABU was detected in a screening program. 2 They were divided into three groups according to roentgenographic observations: 12 patients with parenchymal reduction (11 of 12 also had vesicoureteric reflux), 13 patients with reflux but without parenchymal reduction, and 91 patients with neither parenchymal reduction nor reflux.
See related article, p. 188. Abbreviations used ABU: asymptomatic bacteriuria CRP: C-reactive protein ESR: erythrocyte sedimentation rate MCU: micturition cystourethrography In the first 60 of the 116 ABU patients examined, a bladder washout was performed to establish the level (bladder or renal parenchyma) of the bacteriuria as earlier described3; in 34 of the patients a negative urine culture was obtained the day after the washout, but the remaining 26 continued to have bacteriuria. The 12 patient s with parenchymal reduction and the 13 patients with vesicoureteric reflux were treated with chemotherapeutic agents within six months after detection of bacteriuria. Seven of
0022-3476/78/0292-0194500.60/0 9 1978 The C. V. Mosby Co.
Volume 92 Number ]
A symptornatic bacteriuria
195
Renol length cm
ABU Scarred kidney drained by 9 ureter without reflux ureter with ~eftux grade I [z ureter with reflux grade lI
15no p
a
r
e
n
~
no reflux
parenchyma[ reduction and/or
I
reflux
@
/,
// ///
13/
/
/
/
/
/ /
/
/
11- /1" )
/
/ /
61
/
///
1/,-
t2-
ABU (
~ / /
/I
bacteriuria eliminated during the first 6 months
10-
/ 9.
8" non treatment group
/
/
treatment group
Fig. 1. Plan of study in 116 schoolgirls with asymptomatic bacteriuria.
the 91 patients without parenchymal reduction or reflux were also treated at the time of initial diagnosis; one of them had a bladder diverticulum, and six had enuresis and foul-sine!ling urine. The remainder of the 91 patients were observed for six months without treatment; 61 of them who still had bacteriuria were randomly assigned to treatment (30 patients) and nontreatment groups (31 patients) (Fig. 1). A roentgenographic reinvestigation (intravenous pyelography and micturition cystourethrography) was performed after three years of follow-up in 11 of the 12 patients with scarred kidneys, in 11 o f i h e 13 patients with roentgenographically normal kidneys but with vesicoureteric reflux, a n d i n 14 of 31 patients from the untreated group who had persistent bacteriuriaq the remaining 17 patients in the untreated group had no bacteriuria at the e n d o f the observation period. Two patients, one in the treatmen t group a n d one in the nontreatment group, Who developed symptomatic pyelonephritis, were reinvestigated. One patient with a Scarred kidney and two patients with unscarred kidneys but with Grade I vesicoureteric reflux refused the roentgenographic re-examination.
7"
7
~
~
lb
II
12
LI-L3 cm
Fig. 2. Renal growth during a 3-year period in 13 scarred Iddneys. Mean renal lengths ~ ) and _+ 2SD (---) in relation to L1 to L~ length in normal children. (From ClaEsson 1, and Lindberg U: Radiology 124:179, 1977.)
Diagnostic procedures and criteria. Midstream urine samples were kept at + 4~ until they were semiquantitatively cultured. Growth Of _> 10 ~ bacteria/ml was considered to be significant bacteriuria. To obtain a second sample in patients Mth a suspected asymptomatic recurrence, the patient was instructed to collect morning midstream urine and to culture it with a dipslide (Uricult, Orion Pharmaceutical Co., Helsinki, Finland) at home. The slide was sent by mail to th e laboratory and read after incubation overnight at 37~ Classification of the bacteria and 0 grouping of E. coil were performed as described earlier? The concentrating capacity of the kidneys was estimated by freeze-p0int reduction in two consecutive urine samples obtained at home after fluid deprivation for at least 15 hours; highest osmolality of the two samples was
19 6
Lindberg et al.
The Journal of Pediatrics February 1978
Table I. Recurrence rate during the three years after an apparent initial cure in 78 schoolgirls with asymptomatic bacteriuria* Roentgenographic observations
No. of patients
No recurrence
Asymptomatic recurrence
Symptomatic cystitis
Symptomatic pyelonephritis
Parenchymal reduction (l 1/ 12 with reflux) Reflux without parenchymal reduction No reflux or parenchymal reduction Total
12
6
2
1
3
13
4
7
2
0
53
32
17
1
3
78
42 (54%)
26 (33%)
4 (5%)
6 (8%)
*Each patient who had a recurrence is represented only once.
recorded. The age-related normal values of Winberg" were used as a reference. If the concentrating capacity was < 814 mOsm/1, the test was repeated. Blood samples were obtained and analyzed for erythrocyte sedimentation rate and C-reactive Pr0tein.7 The diagnosis of asymptomatic recurrence, after a preceding examination with negative urine culture, was made if the patient had no obvious symptoms but had had two urine samples with significant bacteriuria and the same type of bacteria in each culture. The criteria for symptomatic cystitis were acute frequency and burning, temperature not exceeding 38.0~ significant bacteriuria, and normal renal concentrating capacity.~ Criteria for pyelonephritis were fever > 38.0~ significant bacteri, uria, and at least two of the following: ESR > 20 mm after one hour, CRP > 10/~g/ml, or renal concentrating capacity < 814 m O s m / l ? A spontaneous remission was diagnosed if two negative urine cultures were found on two successive examinations. MaXimum renal length was estimated and correlated to the distance between the upper surface of the first lumbar vertebra a n d the lower surface of the third lumbar vertebra, according to the method of Ekl6f and Ringertz, ~ on intravenous pyelograms obtained at the time of detection of the bacteriuria, and at the 3-year re-examination. 4 The growth of the kidneys during the observation period was calculated. The degree of vesicoureteric reflux was rated according to the following schema: Grade I-vesicoureteric reflux not reaching the kidney pelvis in a nondilated ureter; Grade II--vesicoureteric reflux into the kidney pelvis but without ureteric dilatation; and Grade III--vesicoureteric reflux into the kidney pelvis with mode-rate dilatation of the pelvis and ureter?. 1o Therapy. Patients with ABU selected for treatment and patients with symptomatic cystitis were given nitrofurantoin, 3 mg/kg/24 hours for ten days. Long-term propHylaxis, over a six-month period, with nitrofurantoin, 1 mg/ kg/24 hr, was given after initial sterilization of urine, to
patients who had recurrences after a second short course of treatment. Patients with symptomatic pyelonephritis were given sulphafurazole, 200 mg/kg/24 hr for ten days. Follow-up. The patients were examined every third or sixth month when urine for semiquantitative culture, blood samples for CRP and, in symptomatic patients, for E s R were obtained. The renal concentrating capacity was tested. Urine for culture was also always obtained within a week after completion of chemotherapy. For statistical evaluation the chi square test was employed. RESULTS
Twelve patients with parenchymal reduction (11 of 12 with reflux). In one patient bacteriuria was eliminated and has not recurred after a bladder washout test. Five patients have not had recurrence after the initial shortterm treatment with nitrofurantoin. Three patients have had attacks of pyelonephritis, one of them twice during pregnancy. One patient has had cystitis, and two have had asymptomatic recurrence (Table I). Long-term prophylaxis, 'because of repeated recurrences, was prescribed for two of the patients. The growth for three years of 13 scarred kidneys from 11 of the 12 patients is shown in Fig. 2. The growth of eight of these 13 kidneys was within normal limits. The renal parenchyma in on e of the kidneys of the patient who had had two attacks of febrile pyelonephritis during pregnancy decreased during the observation period; the growth of the other kidney had accelerated (Fig. 2). There was essentially no growth of the three smallest kidneys ( < - 6 SD). The vesicoureteric reflux had disappeared in three of the 13 ureters; it had changed from Grade II to Grade I in one, from Grade I to Grade II in two, and was unchanged in seven ureters. Thirteen patients with reflux but without parenchymal reduction. One of the 13 patients had bacterinria eliminated by a bladder washout and it has not recurred. Three
Volume 92 Number I
patients have not had recurrences since the initial shortterm treatment with nitrofurantoin. Two patients have had cystitis; seven have had asymptomatic recurrences (Table I). Long-term prophylaxis was prescribed for four of the 13 patients because of repeated recurrences. Two of these four patients are still having recurrences. The growth of 17 unscarred kidneys associated with ureteral reflux in 11 of the 13 patients was normal during the observation period. The reflux disappeared in nine of the 17 ureters; it changed from Grade II to Grade I in five ureters; it was unchanged in three of them. The disappearance'of vesicoureteric reflux or a change from Grade II to I was significantly more common (P < 0.01) in patients with unscarred kidneys than in those with scarred kidneys. Ninety-one patients without parenchymal reduction or reflux. Sixteen of the 91 patients had not had recurrences at the one-year follow-up after an initial bladder washout test that eliminated the bacteriuria. Thirteen of these 16 patients still had sterile urine at the three-year follow-up; one of them had had an asymptomatic recurrence during the third year; two patients were lost to follow-up. Seven of the 91 patients had initially been given nitrofurantoin, six for enuresis and foul-smelling urine and one for a bladder diverticulum. Two of these seven girls had had pyelonephritis, one had cystitis, three had asymptomatic recurrences; and one was lost to follow-up during the observation period. Of the remaining 68 girls who were untreated for six months, two became abacteriuric after they had been given penicillin for otitis and tonsillitis, and four became spontaneously abacteriuric and have not had noted recurrences for three years. One girl was lost to follow-up. There were 61 girls who had bacteriuria and were asymptomatic after the first six months of observation; they were randomly placed into treatment and nontreatment groups. Treatment group: 30 patients. Three patients moved from the area during the observation period. No recurrence has occurred after one short-term treatment in 13 patients (48%), and none after two short-term treatments in five patients. Nine patients (33%) were given long-term prophylaxis with nitrofurantoin because of repeated recurrences. Six of these nine girls continue to have recurrences after three year s of prophylaxis. Two of the patients for whom long-term prophylaxis was prescribed did not follow the prescriptions, and one of them had one attack of pyelonephritis and one episode of cystitis. The roentgenographic reinvestigation of the patient with pyelonephritis showed normal kidney growth without paxenchymal reduction.
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Untreated group: 31 patients. One patient moved from the area during the observation period. Five patients became abacteriuric after treatment with penicillin for respiratory tract infection and they have not had recurrences. Nine patients spontaneously became abacteriuric (30%): three during the first year, two during the second year, and four during the third year. None of them have had recurrences. One girl had an attack of symptomatic pyelonephritis after 15 months of observation. E. coli was found in her urine as earlier, but also significant numbers of enterococci. The patient has had asymptomatic recurrences after treatment of the symptomatic infection, and long-term prophylaxis has been prescribed. The roentgenographic reinvestigation revealed a pyelonephritic scar and decreased growth in one of the kidneys. During the second year another patient had dysuria during an attack of measles. She was treated with nitrofurantoin and has not had subsequent recurrences. After three years of observation, 14 girls (47%) were still bacteriuric. In 11 of them an E. coli of the same 0 type or a spontaneously agglutinating E. coli strain was isolated at each examination. In three of the patients there were differences in the E. coli type in two consecutive examinations. The growth of the 28 kidneys in the 14 patients who were still bacteriuric and asymptomatic after three years without treatment was normal; there were no signs of scarring. At the follow-up MCU one patient had a unilateral Grade I reflux. The mean concentrating capacity of the kidneys in the bacteriuric girls after six months and one and three years, respectively, was not different from that at the time of the first identification of ABU: 1,016 • 92 mOsm/1 ( • 1 SD), 1,004 _+ 106 mOsm/1, 1,042 _+ 103 mOsm/1, and 1,039 • 110 mOsm/1, respectively. No increase in serum CRP was found in the girls when they were asymptomafic. No significant difference (P > 0.05) in the number of bacteriuric patients was found in the nontreatment group, 14 of 30 in comparison with the treatment group, 6 of 27 at the end of the observation period. Recurrence rate in 78 patients cured of their bacteriuria. The number of patients who had recurrences of bacteriuria (46%) among 78 girls, i.e., the 116 patients minus 31 girls not treated and seven lost to follow-up, are listed in Table I. These patients became abacteriuric after a bladder washout test or after treatment with penicillin or nitrofurantoin. A recurrence had occurred in 31% of the patients after the first year of observation, in 40% after the second, and, in 46% after the third. The recurrence rate in patients with parenchymal reduction and/or reflux, 15 of 25 (60%), was higher but not significantly different
19 8
Lindberg et al.
(P > 0.05) from that in patients without such radiologic signs, 21 of 53 (40%). DISCUSSION Earlier studies have shown that schoolgirls with ABU have frequent recurrences?. 11-13 Despite this, there is normal renal growth and no increase in the frequency of roentgenographic evidence of vesicoureteric reflux or of pyelonephritis in such patients according to Savage? ~ Only a controlled trial of therapy will show whether treatment with chemotherapy is beneficial or even necessary. The present study demonstrates that chemotherapy reduces the incidence of bacteriuria in a treatment group but not significantly compared to that in untreated girls. Clinical pyelonephritis or illness rarely occurs with or without treatment. These findings are in accord with those presented in the first controlled trial of therapy in covert bacteriuria in childhood by Savage and associates? 4 That ABU probably does not cause progressive renal damage or only rarely does so i n patients with roentgenographically normal urinary tracts is supported by the findings that normal kidney growth was seen in all patients who had been asymptomatic during the observation period. Neither did the bacteria isolated from the untreated ABU patients seem to involve the kidney during the observation period. No decrease in the renal concentrating capacity was observed. Renal scarring and arrested renal growth may occur, however, in schoolgirls who have symptomatic pyelonephritis. In the present study this course of events is exemplified by one patient in the group with parenchymal reduction who aquired further renal scarring and in one girl in the untreated group in whom the parenchymal reduction probably was caused not by the E. coli initially isolated but by enterococci invading the urinary tract. For ethical reasons we decided in the beginning of the study to treat all patients with parenchymal reduction a n d / o r reflux with chemotherapeutic agents. During the follow-up essentially no growth was found in the extremely small scarred kidneys. Otherwise scarred or unscarred kidneys with or without reflux of Grade I or II grew normally. From these results it seems reasonable to believe that a moderate reflux does not restrict renal growth in the absence of bacteriuria. Furthermore, a reduction of the vesicoureteric reflux was often found at the follow-up examination, a feature that is in agreement with the observations that reflux tends to become less severe with time? ~, 16 The disappearance of the vesicoureteric reflux may be related to the fact that all of the involved patients had bacteriuria w h e n the initial M C U was made, whereas they were all nonbacteriuric at the
The Journal of Pediatrics February 1978
time of re-examination. The remission may also be due to maturation of the vesicoureteric j u n c t i o n as described by Hutch. 17 It seems that E. coli strains isolated from schoolgirls with A B U do not c o m m o n l y cause symptomatic pyelonephritis.18. 19 Further, the girls with a roentgenographically normal urinary tract has only a small risk of developing renal damage, hence chemotherapy for the majority of such patients seems unnecessary. REFERENCES
1. Lindberg U: Asymptomatic bacteriuria in schoolgirls. V. The clinical course and response to treatment, Acta Paediatr Scand 64:718, 1975. 2. Lindberg U, Cla~sson I, Hanson LA, and Jodal U: Asymptomatic bacteriuria in schoolgirls. I. Clinical and laboratory findings, Acta Paediatr Scand 64:425, 1975. 3. Lindberg U, Jodal U, Hanson LA, and Kaijser B: Asymptomatic bacteriuria in schoolgirls. IV. Difficulties of level diagnosis and the possible relation to the character of infecting bacteria, Acta Paediatr Scand 64:574, 1975. 4. ClaEsson I, and Lindberg U: Asymptomatic bacteriuria in schoolgirls. VII. A follow-up study of the urinary tract in treated and untreated schoolg!rls with asymptomatic bacteriuria, Radiology 124:179, 1977. 5. Lincoln K, Lidin-Janson G, and Winberg J: Resistant urinary infections resulting from changes in resistance pattern of faecal flora induced by sulphonamide and hospital environment, Br Med J 3:305, 1970. 6. Winberg J: Determination of renal concentrating capacity in infants and children without renal disease, Acta Paediatr Scand 48:318, 1959. 7. Nilsson LA: Comparative testing of precipitation methods for quantitation of C-reactive protein in blood serum, Acta Pathol Microbiol Scand 73:129, 1968. 8. Jodal U, Lindberg U, and Lincoln K: Level diagnosis of symptomatic urinary tract infection in childhood, Acta Paediatr Scand 64:201, 1975. 9. Ekl6f O, and Ringertz H: Kidney size in children--a method of assessment, Acta Radiol 17:617, 1976. 10. Filly R, Friedlund GW, Govan DE, and Fair William R: Development and progression of clubbing and scarring in children with recurrent urinary tract infections, Radiology 113:145, 1974. 11. Kunin CM, Deutscher R, and Paquin A Jr: Urinary tract infections in schoolchildren: An epidemiologic, clinical and laboratory study, Medicine 43:91, 1964. 12. Savage DCL: Natural history of covert bacteriuria in schoolgirls, Kidney Int 4 (Suppl):90, 1975. 13. Verrier-Jones ER, Meller ST, Mc Lachlan MSF, Sussman M, Asscher AW, Mayon-White RT, Ledingham JGG, Smith JC, Fletcher EWL, Smith EH, Jonston HH, and Sleight G: Treatment of bacteriuria in schoolgirls, Kidney Int 4 (Suppl):85, 1975. 14. Savage DCL, Howie G, Adler K, and Wilson MI: Controlled trial of therapy in covert bacteriuria of childhood, Lancet 1:358, 1975. 15. Rolleston GL, Shannon FT, and Utley WLF: Relationship of infantile vesico-ureteric reflux to renal damage, Br Med J 1:460, 1970.
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16. Winberg J, Larsson H, and Bergstr6m T: Comparison of the natural history of urinary infection in children with and without vesico-ureteric reflux, in Kincaid-Smith P, and Fairley KF, editors: Renal infection and renal scarring, Melbourne, 1971, Mercedes Publishing Service, p 293. 17. Hutch JA: Theory of maturation of the intravesical ureter, J Urol 86:534, 1961. 18. Lindberg U, Hanson L,~, Jodal U, Lidin-Janson G, Lincoln K, and Olling S: Asymptomatic bacteriuria in schoolgirls.
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II. Differences in Escherichia coli causing asymptomatic and symptomatic bacteriuria, Acta Paediatr Scand 64:432, 1975. 19. Lidin-Janson G, Hanson LA, Kaijser B, Lincoln K, Lindberg U, Olling S, and Wedel H: Characteristics of Escherichia coli from screening bacteriuria and from asymptomatic and symptomatic reinfections as compared to the faecal reservoir, J Infect Dis (in press).
