0022-534 7/92/1485-1650$03.00/0 THE JOURNAL OF UROLOGY Copyright© 1992 by AMERICAN UROLOGICAL ASSOCIATION, INC.
Vol. 148, 1650-1652, November 1992
Printed in U.S.A.
INFECTION PATTERN IN CHILDREN WITH VESICOURETERAL REFLUX RANDOMLY ALLOCATED TO OPERATION OR LONG-TERM ANTIBACTERIAL PROPHYLAXIS ULF JODAL, OLLI KOSKIMIES, EINAR HANSON, GOSTA LOHR, HERMANN OLBING, JEAN SMELLIE AND TYTTI TAMMINEN-MOBIUS ON BEHALF OF THE INTERNATIONAL REFLUX STUDY IN CHILDREN ABSTRACT - - --A-tet~---hllmen--with-gr--aae-I-I-I-te-l¥vesi-G0-ur-e-te!'al-r-eflu.¼+i-nter-n.atienal-G-l-ass-i-f-i-rati-en-)-and- -a history of documented urinary tract infection was randomized into medical (155 patients) or surgical (151 patients) treatment arms in the European portion of the International Reflux Study in Children. Children treated medically were maintained on prophylactic antibacterials as long as the reflux persisted, while those treated surgically were covered prophylactically until followup studies at 6 months postoperatively demonstrated the reflux to be corrected. Standard definitions for bacteriuria were used, and the distinction was made clinically among acute pyelonephritis, cystitis and asymptomatic bacteriuria, supported in many instances by additional laboratory testing. Urine was cultured after 3 months and whenever suspicious symptoms occurred. Urinary tract infections developed during the first 5-year followup period in 59 patients (38%) in the medical group and in 59 (39%) in the surgical group but the incidence of pyelonephritis was higher in the medical group (21%) than in the surgical group (10%) (p <0.01). Pyelonephritis often followed catheterization or cystoscopy but asymptomatic bacteriuria was uncommon after these procedures in either group. Recurrent infections were related to age, sex and treatment center. They were common in boys and girls entering under 1 year of age but were less common in girls and rare in boys entering after 1 year of age. Recurrences were lowest among the Finnish children and highest in the German and Belgian children. Vesicoureteral reflux is most commonly detected during evaluation initiated because of a urinary tract infection but it also may be diagnosed by cystography performed because of suspicion of hereditary reflux or because of dilatation of the renal pelvis found on antenatal ultrasound. For the International Reflux Study in Children it was an entry criterion that all patients have at least 1 previous urinary tract infection. We describe the pattern of urinary tract infection in 151 children treated surgically and 155 children treated medically before and after entry into the European branch of the study. PATIENTS AND METHODS
The details of the selection process and the entry characteristics of the patients included in the study are provided Participating hospitals and principal investigators: University Children's Hospital, Bonn, Germany: Rudolf Mallmann. University Children's Hospital, Universite Libre de Bruxelles, Belgium: Michelle Hall. University Children's Hospital, Essen, Germany (Coordinating Center): Hermann Olbing (Chairman), Tytti Tamminen-Mobius (Coordinator) and Wolfgang Rascher. University Children's Hospital, Gothenburg, Sweden: Kelm Hjii.lmas and Ulf Jodal. Department of Urology, University of Hamburg, Germany: Rainer Busch. University Children's Hospital, Helsinki, Finland: Olli Koskimies. University Children's Hospital, Oulu, Finland: Juhani Seppanen. Karolinska lnstitutet, St. Goran's and Sachska Children's Hospitals, Stockholm, Sweden: Anita Aperia. Data processing and statistical analysis: Institute for Medical Data Processing and Biomathemathics, University Essen, Germany: Hildegard Lax-Gro/3 and Herbert Hirche. Scientific advisors: Klaus-Dieter Ebel (pediatric radiology), Jan van Goo! (pediatric urodynamics), Kalle V. Parkkulainen (pediatric surgery), Jean M. Smellie (pediatrics) and Jan Winberg (pediatrics) Supported by the VW-Foundation (Grants AZ 35 807, AZ I/37 504) until 1985 and thereafter by the Bundesministerium fiir Forschung und Technologie (Grant 07068343).
elsewhere. 1 All children entered into the study demonstrated international grade III or IV reflux2 on 2 successive voiding cystourethrograms. · The date of the second investigation was used as the time of entry into the study. No patient had any other major urinary tract anomaly, such as obstruction or complete duplication of a ureter, or neurogenic or other overt bladder dysfunction, and none had previous urinary tract surgery, elevated serum creatinine or evident inability to follow the study protocol. After stratification for age, sex, grade of vesicoureteral reflux, renal scarring, interval since last urinary tract infection and location of local hospital, the children were randomly allocated to surgical or medical treatment. Two-thirds of the children were already on long-term low dose antibacterial prophylaxis when recruited to the study; in all others it was started immediately at recruitment. In the surgical group the prophylaxis was continued until 6 months after the ureteral reimplantation and in the medical group until resolution of reflux had been confirmed on 2 successive cystograms performed by conventional radiological or isotope techniques. The drugs used for prophylaxis were nitrofurantoin (1 to 2 mg./kg. daily) or trimethoprim (1 to 2 mg./kg. daily) with or without sulfonamide given as a single evening dose. In addition to antibacterial prophylaxis, instructions were given about regular emptying of the bladder and the importance of regular bowel habits. To detect recurrences during followup, urine cultures were performed regularly at a local health center or by a home dipslide. When such a culture indicated bacteriuria, an additional examination was performed at the local hospital or at a local practitioner's office. The parents were encouraged to have additional followup if the child had acute symptoms compatible with urinary tract infection, such as unexplained fever or
INFECTION PATTERN IN CHILDREN WITH VESICOURETERAL REFLUX
voiding disturbances. Treatment was given for 10 days to all children with recurrences including those with asymptomatic infections. The criteria for bacteriuria were any growth in urine obtained by suprapubic aspiration or at least 100,000 colony-forming units of a single species per ml. in a midstream specimen. For a diagnosis of acute pyelonephritis bacteriuria and fever of at least 38.5C, loin or back pain, or general fatigue were required which could not otherwise be explained. The diagnosis was supported by a c-reactive protein level of 30 mg./1. or a sedimentation rate of more than 25 mm. per hour whenever it was possible to be obtained. Other symptomatic urinary tract infections were classified as nonpyelonephritic episodes. Bacteriuria detected at a regular followup of a child not reporting symptoms was referred to as an asymptomatic episode. RESULTS
Of the 233 girls 86 (37%) and of the 73 boys 49 (67%) were less than 1 year old at the time of the first documented urinary tract infection (table 1). Of the 306 children 276 (90%) had been diagnosed as having acute pyelonephritis and 209 (68%) had had at least 2 episodes of pyelonephritis before entry into the study. During the first 5-year followup period 59 of the 151 surgical TABLE
1. Age at the first documented urinary tract infection Age (yrs.)
Girls: Less than 1 1-2.9 3-4.9 5-6.9 7 or older Missing data Totals Boys: Less than 1 1-2.9 3-4.9 5-6.9 7 or older Missing data Totals
46 34 24 8 3 0 115
40 43 21 9 4 1 118
21 8 2 2 3 0
28 2 2 2 3 0
Children with recurrent urinary tract infection during the first 5-year followup period
Character of recurrence:* Pyelonephritic Nonpyelonephritic Asymptomatic No recurrence Missing data Character of episodes: Pyelonephritic Nonpyelonephritic Asymptomatic Total No. episodes
Surgical (151 pts.)
Medical (155 pts.)
15t 28t 16 88 4
33t 13t 13 91 5
18 59 91 168
50 30 47 .127
• Each child is represented by the most serious type of infection. t p <0.01. TABLE
3. Incidence of urinary tract infection recurrences per patient month during the first 5-year period Age at Entry (yrs.)
Less than 1 1-2.9 3-4.9 5-6.9 7 or older
0.023 0.013 0.009 0.010 0.009
0.038 0.002 0.001 0 0
Recurrence rate according to center Symptomatic Recurrences/ Pt.Mo.
Finland Sweden Germany/Belgium
0.005 0.008 0.020
(39%) and 59 of the 155 medical (38%) patients had at least 1 recurrent urinary tract infection. Of the 151 children in the surgical group 43 (28%) and of the 155 in the medical group 46 (30%) had symptomatic infections. Thus, the number of children with urinary tract infections was reduced but there was still a relatively high proportion with recurrences although there was no difference between the treatment groups (table 2). There was, however, an evident difference in the character of the recurrences. Of the surgical patients 15 (10%) experienced acute pyelonephritis compared to 33 (21 %) of the medical patients (p <0.01). In contrast, the number of children having nonpyelonephritic infections was higher among the children in the surgical group making the totals with symptomatic episodes similar in the 2 groups. This pattern was evident also when the total number of recurrent episodes in the 2 groups was com pared (table 2). To study whether catheterization of the bladder or other invasive procedures of the urinary tract induced urinary tract infection the 14 days following such instrumentations were analyzed separately. In the surgical group there was a total of 1,036 instrumentations after which there were 14 episodes of bacteriuria (1.4%), 3 of which were attacks of acute pyelonephritis. The corresponding figure for the medical group was 1,178 instrumentations after which there were 16 episodes of bacteriuria (1.4%), 9 of which were pyelonephritic attacks. Although the risk for bacteriuria following instrumentation was relatively low, it should be noted that 12 of the 68 pyelonephritic episodes (18%) occurred within 14 days of a followup visit to the hospital. Breaking down the figures according to age at entry into the study revealed differences between the sexes (table 3). The incidence of urinary tract infection recurrences was highest in boys less than age 1 year but it was practically zero in those older than age 1. The incidence of recurrences was also highest in the girls less than age 1 year at entry but the difference was less marked and the recurrence rate was relatively high in all age groups. Analysis of the recurrence rate at the different local centers revealed unexpected differences. The lowest frequency was seen at the Finnish and the highest at the German/Belgium centers with the Swedish having an intermediate position (table 4). The reasons are as yet unknown but possible explanations are differences in compliance and local bacterial resistance to the drugs used for prophylaxis. COMMENTS
The diagnosis of acute pyelonephritis was mainly clinical but the same diagnostic criteria were applied to both treatment groups. Hematological studies to confirm the diagnosis were done in 44% of the episodes of clinical pyelonephritis in each treatment group. Positive results for c-reactive protein and/or sedimentation rate were obtained in each instance. In infancy, when the symptomatology is less specific, corroborating hematological studies were more likely to be done. Since the groups were stratified for age, this applied equally to medical and surgical treatment groups. There was a striking reduction in the rate of episodes of acute pyelonephritis overall, probably largely due to antibacterial prophylaxis. The reduction was seen in both treatment groups but the figures were significantly better for the surgical group, which can be attributed to the antireflux operation.
JODAL AND ASSOCIATES
However, it is evident that the overall rate of symptomatic urinary tract infections was not reduced by surgery. The differences in recurrence rates among the centers indicate that better results may be reached by careful consideration of the details of the management. These include carefully repeated explanations to the family to improve understanding and compliance, selection of the most appropriate drug for long-term prophylaxis based on the resistance pattern of the common gram-negative bacteria in the area and special attention to details including additional antibiotic coverage for prophylaxis at the time of invasive procedures. The low risk of recurrences in the boys entered into the study after age 1 year implies that long-term prophylaxis may not be necessary in this group; instead attention should perhaps be
focused on the prepuce in boys with reflux causing dilatation of the upper urinary tract and circumcision considered to facilitate the elimination of the preputial bacterial reservoir. REFERENCES
1. Weiss, R., Tamminen-Miibius, T., Koskimies, 0., Olbing, H., Smellie, J. M., Hirche, H. and Lax-Gross, H.: Characteristics at entry of children with severe primary vesicoureteral reflux recruited for a multicenter, international therapeutic trial comparing medical and surgical management. J. Urol., part 2, 148: 1644, 1992. 2. International Reflux Study Committee: Medical versus surgical treatment of primary vesicoureteral reflux: a prospective international reflux study in children. J. Urol., 125: 277, 1981.