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The bacteriologic differentiation between upper and lower urinary tract infection in children
364
March, 1969 T h e ]ournal o[ P E D I A T R I C S
The bacteriologic differentiation between upper and lower urinary tract infection in children Specimens o[ ureteric urine were collected [rom 39 children who had urinary infection with a radiographically normal bladder and upper urinary tract; an essential preliminary was the control o[ the bacterial content of the bladder by copious irrigation. The bacteriologic results indicated that in 25 girls the bacteria were confined to the lower urinary tract, in 8 children the bacteria were originating [rom the upper urinary tract. The bacteriologic results/or the remaining 6 children were interpreted as indicating lower urinary tract injection.
j. Whitaker, F.R.C.S., F.R.C.S.E., and A. S. Hewstone, F.A.I.M.L.T., A.I.M.L.T. (UK) MELBOURNE,
AUSTRALIA
P E R S I S T Ig N T o r recurrent urinary t r a c t infection often occurs in children without any demonstrable radiographic abnormality of the bladder or upper urinary tract. The infecting bacteria in these patients may be confined to the lower urinary tract or may arise from one or both kidneys. The separation of the two conditions by bacteriologic methods has hitherto proved unsatisfactory. Attempts have been made to differentiate between upper and lower infection in other ways, including the assessment of clinical and radiologic features, renal biopsy, and the estimation of the patient's antibody response to the infecting pathogen. However, separation of upper and lower types of infection can only be accomplished in the first in-
From the Department of Surgical Research, Royal Children's Hospital Research Foundation, and the Department o/Bacteriology, Royal Children's Hospital. Vol. 74, No. 3, pp. 364-369
stance on the basis of bacteriologic data; other methods of differentiation must be of only secondary significance unless they are based upon such findings. In attempts to differentiate between upper and lower urinary tract infections, urine specimens have been collected for bacteriologic study from each renal system by the use of ureteric catheters. Difficulties in interpretation of the cultures have resulted because the catheters have been passed through a bladder containing a high concentration of bacteria, some of which may have been carried up from the bladder into the ureters by the catheters, thereby contaminating the ureteric urine so that upper and lower infections could not be distinguished. Stamey 1 introduced a technique to overcome this problem, the principle of which is to control the bacterial content of the bladder by irrigation with water and then
74 tuber 3
Urinary tract injections
pass the ureteric catheters through this controlled medium so that interpretable ureteric specimens may be collected. MATERIAL
AND
METHODS
Thirty-nine children who had persistent or recurrent urinary infections have been studied. These children were known to have a radiographically normal bladder and upper urinary tract, determined by micturition cystourethrography and intravenous pyelography; that is, the pelvicalyceal systems, ureters, and bladder were apparently normal when the urinary infection was first proved. T h e diagnosis of infection was established by the finding of a viable colony count of greater than 100,000 bacteria per milliliter of a single strain, cultured from catheter or midstream specimens within one hour of their collection. The primary investigation has been the collection of ureteric specimens together with control bladder specimens by the application of the Stamey principle of preliminary bladder irrigation. In some of the patients, renal and bladder biopsies were obtained by the use of percutaneous and endoscopic methods, and antibody titers to the infecting pathogen were also estimated. I n this technique the antigen was extracted from cultures of the infecting pathogen and attached to red cells which were then mixed with serial dilutions of the patient's serum. The presence of the homologous bacterial antibody caused agglutination of the modified red blood cells. These findings have formed the basis of a separate paper. 2 Collection of specimens of ureteric urine. The ureteric urine collections were performed at the time of endoscopic examination following the technique described by Stamey, 1 with the following modifications so that the method was suitable for the investigation of children. In all instances the patient was anesthetized and from 900 to 400 ml. of 5 per cent dextrose in distilled water were administered intravenously to ensure an adequate urinary output. For most female patients the No. 18 (Charriere gauge) panendoscope
365
sheath was suitable and was introduced into the bladder and a specimen of urine collected. Preliminary urethral dilatation to size No. 18 was required in some patients. The bladder was irrigated with at least 4 liters of sterile distilled water, and two No. 4 disposable ureteric catheters were introduced via the instrument into the bladder. A control specimen of bladder content was obtained through either the endoscope or the catheters, which were then passed up each ureter for a distance of 10 to 15 cm. The passing of the catheters was performed with the bladder nearly empty in order to reduce the risk of reflux of bladder content occurring through the ureteric orifices splinted by the catheters. In some children who had not had vesicoureteric reflux on micturition cystourethrography, reflux occurred with the ureteric catheters in position if the bladder was filled. The position of the catheters was checked, the bladder emptied further, and the panendoscope fixed in relation to the patient with the tip of the instrument lying on the trigone just inside the bladder neck. This was accomplished by having the sheath pass through a perforated rubber cork which could be moved along the instrument but which still gripped it; with the panendoscope positioned the cork was placed against the external urethral orifice and the viewing end of the instrument was attached to a tape suspended between the lithotomy stirrups. If this fixation is not established, control of the catheters is lost and the validity of the specimens is in doubt. T h e ureteric catheters were then dried and a piece of gauze was arranged around them so that fluid could not run down the outside of the catheters. Dripping from the ends of the catheters commonly occurred spontaneously; if it did not, the injection of 1 ml. of sterile water through the catheter usually initiated the flow of urine. At least 20 drops were allowed to come through the ureteric catheters and then 0.5 to 1 ml. of urine was collected from each. Dripping from the ends of the catheters usually took the form of peristaltic rushes of 3 to 4 drops. Continuous dripping indicated either a very high urinary output
366
Whitaker and H e w s t o n e
or reflux of bladder content about the catheters. As a check on this, indigo carmine was introduced into the bladder; if the drops from the catheter became blue, then reflux was known to be occurring. A final control bladder specimen was obtained after the ureteric collections, and the position of the catheters was checked by endoscopic examination. The No. 14 McCarthy cystourethroscope was used in most male patients and in very young female patients in whom the caliber of the urethra precluded the use of the larger instrument. This meant that only one No. 4 disposable ureterie catheter could be passed at a time. In these patients, after collection of the control specimen of bladder content, one ureter was catheterized and a specimen collected; after collection of a further control bladder specimen, a fresh catheter was passed up the other ureter and a specimen collected. The specimens were collected in sterile screw-capped glass containers and were placed in a refrigerator (4 ~ C.) immediately after their collection and labeling. Culture of ureteric urine specimens. The bacterial concentration of the ureteric specimens and of the bladder fluid after irrigation was found to be of a low order, and therefore it was essential that an adequate volume be cultured to ensure accurate counts. A pour plate method was employed whereby 0.5 ml. or more of the refrigerated bladder and ureteric specimens were mixed with 10 nil. of cooled molten nutrient agar.
The Journal o[ Pediatrics March 1969
After 18 hours incubation at 37 ~ C. the plates were examined and the number of colonies counted.
RESULTS Ureteric urine culture--no growth. The culture of the ureteric urine specimens resulted in no bacterial growth in 25 (all female) of the 39 patients (Table I). In 19 instances the bladder bacterial content was reduced to zero by the irrigation and in the other 6 the control bladder count ranged from 1 to 490 bacteria per milliliter. E. coli was the infecting pathogen in all o f these patients but 2, from whom Paracolon species and Streptococcus faecalis were isolated. It is of interest to note that negative ureterie cultures resulted even though the catheters were passed through bladder bacterial concentrations of up to 490 per milliliter. The failure to cultivate any bacteria from the ureteric specimens of these 25 girls indicated that they were suffering from lower urinary tract infections at the time of the collections. Ureteric urine culture--no significant growth. Five girls had E. coli infections with ureteric urine bacterial counts of a very low order; in 3 of these the bladder bacterial content had been reduced to zero by the irrigation (Table I I ) . Our interpretation is that in these patients the infection was confined to the lower tract and that the positive culture resulted from contamination of the ureteric specimens by bacteria escaping from the wall of the bladder or by external con-
Table I. Ureteric urine culture--no growth No.o[patierits 17 1 1 1 1 1 1 1 1
Bacteriology (bacteria per milliliter) Pathogen 1Controlbladder] Rightureter I Le[tureter E. eoli 0 0 0 Paracolon species 0 0 0 Streptococcus 0 0 0 [aecalis E. coli 1 0 0 E. coli 3 0 0 E. coli 12 0 0 E. coli 15 0 0 E. coli 33 0 0 E. coli 490 0 0
1
Interpretation Lower infection Lower infection Lower infection Lower infection Lower infection Lower infection Lower infection Lower infection Lower infection
Valume 74 NUmber 3
Urinary tract infections
taminants. The contention that the bacteria were confined to the lower tract is supported in 3 of these patients by the complete clearance of bacteria from the bladder by the irrigation. In patients in whom upper tract infection has been proved, some bacteria have usually been cultivated from the postirrigation bladder content, presumably because bacteria pass into the bladder from the ureters in the time interval (approximately 5 minutes) between the termination of the irrigation and the collection of the control bladder specimen (Table I V ) . The other possible explanation of the positive ureteric culture is that very small numbers of bacteria were coming from one or both kidneys. Ureterie urine culture--equivocal growth. T h e bladder bacterial count remained fairly high after the irrigation in 3 girls, and ureteric counts close to these levels were obtained from some of the ureteric urine cultures (Table I I I ) . Bacteriologic differentiation between upper and lower types of infection was difficult in these patients. Consideration of the antibody titers in these patients as measured by indirect bacterial hemagglutination s was of value in
367
reaching a decision regarding upper and lower urinary tract infection. T h e critical antibody level for the differentiation of upper and lower infection appears to be between 1 in 320 and 1 in 640; lower infections have titers of 1 in 320 or less, and upper irffections have titers of 1 in 640 or more. This level was established by the authors 2 in a series of patients in whom the diagnosis was made primarily on the basis of ureteric urine bacteriology. Patient J. H., who had been suffering with an E. coli urinary infection for at least 2 months, had a titer of 1 in 40, indicative of lower infection. Interpretation of the bacterial counts of 18 viable E. coli per milliliter from the control bladder specimen and 2 and 24 per milliliter from the respective ureteric specimens is difficult. These counts could mean that bacteria were arising from the upper tract, or they could result from contamination of the ureteric specimens by bacteria originating in the bladder. The other 2 patients in this group were found to have high antibody titers, indicating upper urinary infections (pyelonephritis). T h e ureteric urine bacterial counts of
Table II. Ureteric urine culture--no significant growth Bacteriology (bacteria per milliliter)
Patient M.L. D.C. J. F. tI. L.C. J. P.
Pathogen E. E. e. E. E.
ICo trolbladderl Right ureter I Left ureter
coli coli coli coli eoli
22 79 0 0
0 1 2 7
0
0
p Interpretation
1 1 0 0
Lower infection Lower infection Lower infection Lower infection Lower infection
Table I I I . Ureteric urine culture--equivocal growth Bacteriology (bacteria per milliliter Patient
Pathogen
Control bladder
Right ureter
J.H. S.W.
E. coli E. coli
18 120
2 90
24 0
1 in 40 1 in 640
M.T.
E. coli
200
6
160
1 in 1280
Left ureter
Antib ody titer
Interpretation
Lower infection Right pyelonephrltis Left pyelonephritis
368
Whitaker and Hewstone
The Journal o/ Pediatrics March 1969
90 and 160 per milliliter, from these 2 patients were probably significant despite the control bladder bacterial counts of 120 and 200 per milliliter, respectively. Even if some of the bladder bacteria were carried up the ureters by the catheters they should be largely washed away by the urine flow which was allowed to pass prior to the collection of specimens. Further evidence that these ureteric urine counts indicate significant upper tract infection is that in some of the patients discussed earlier, who clearly had lower tract infections, the ureteric bacterial counts were either zero or very low in spite of the presence of numbers of bacteria in the control bladder specimen. Finally, if the counts of 90 and 160 bacteria per milliliter were the result of contamination by bacteria escaping from the wall of the bladder, the degree of contamination could be expected to be approximately the same for both ureteric specimens, but in these patients the bacterial counts from the other ureter in each case were much less. Patients S. W. and M. T. therefore appeared to have unilateral upper urinary tract infection. These patients all had radiographically normal upper urinary tracts initially; Patient M. T. was the only one to develop some change, which consisted of a reduction in size of the left kidney over a period of 3 years; it was from this side that the significant uretqric urine bacterial count of 160 per milliliter resulted.
Ureteric urine culture--significant growth. Six patients, including the only boy in the
series, were f o u n d to have ureteric urine bacterial counts which were far in excess of the control bladder count and which indicated unequivocal upper urinary tract infection in one or both systems (Table IV). All of the children in this group had radiographically normal upper urinary tracts at the time of presentation; Patient J. G. was the only one to show a change, the right kidney becoming diminished in size and the calyces distorted and blunted, again over a 3-year period. Pyelonephritis probably limited to the right kidney was indicated in 3 patients (J. G., J. F., and A. J.) in whom only t, 12, and 0 bacteria per milliliter, respectively, were cultivated from the left ureteric specimens. Patient K. K., a boy, was found to yield a culture of greater than 1,000 bacteria per milliliter from the left ureter and 95 per milliliter from the right, with a control bladder count of 216 bacteria per milliliter. Left-sided pyetonephritis is proved on these results, but the count of 95 bacteria per milliliter from the right side is equivocal. Bilateral pyelonephritis was definitely established in the remaining 2 patients. One patient (M. McL.) had significant bacterial counts from both specimens of ureteric urine. The other patient (S. M.) had ureteric urine specimens collected on 2 occasions. From the first collection right-sided infection was established, but no bacteria were cultivated from the left ureteric urine specimen. The second collection, performed
Table IV. Ureterlc urine culture--significant growth Patient' J.G.
Pathogen E. eoli
J.F.
Paracolon species
A. J. K.K.* M. McL. S. M. ( i ) (2)
Bacteriology (bacteria per milliliter) I Control bladder I Right ureter [ Left ureter
Proteus mirabilis E. coli E. coli
50 24 0 216 26
390 530 130 95 ~ 103
1 12 0 ~ 103 260
E. coli Proteus mirabilis
29 3
1,640 > 103
0 300
*The sole male patient.
I
Interpretation
Right pyelonephritis Right pyelonephritis Right pyelonephritis Left pyelonephritis
Bilateral pyelonephritis Right pyelonephritis Bilateral pyelonephritis
Volume 74 Number 3
3 months later, reaffirmed the presence of right-sided infection but also indicated a significant infection on the left side. These results suggest that the left kidney was either not infected or was not actively excreting bacteria at the time of the first collection. Therefore, in this group of 6 children, 2 had bilateral and 3 had probable unilateral pyelonephritis; one was suffering from either unilateral or bilateral disease. DISCUSSION
The occurrence of 25 girls with unequivocal and 6 girls with probable lower urinary tract infection, compared with 7 girls and 1 boy with upper infection, indicates that lower infection is the most common type in those patients in whom micturition cystourethrography and intravenous pyelography have failed to reveal any apparent abnormality of the pelvicalyceal systems, ureters, and bladder. I t is also significant that lower infection occurred in girls alone, suggesting that the incidence of infection is in some way related to the shortness of the female urethra, whereby pathogenic bacteria may have relatively easy access to the bladder. Some of the girls in whom the infection was localized to the lower urinary tract had been observed for some years with persistent or recurrent infections, and yet at the time of investigation there was no suggestion of upper tract involvement. This supports the contention that the ureterovesical valve is usually an effective barrier in preventing the ascent of bacteria into the upper tract. In addition, the passage of the ureteric catheters through the infected bladder content and up into the ureters failed to precipitate any apparent episodes of upper infection. This risk m a y have been eliminated because of the low bacterial concentrations remaining in the bladder after the irrigation, associated with a high urinary output through ureters of normal caliber. Also, antibacterial treatment, usually nitrofurantoin, was instituted within 24 hours of the ureteric catheterization and was continued for at least 3 months.
Urinary tract in/ections
369
Eight of the 39 patients were considered to have upper urinary tract infection or pyelonephritis. The diagnosis was clearly indicated by the ureteric bacteriology in 6 of these; in the other 2 it was suggested by the ureteric bacteriology and confirmed by the finding of an elevated antibody titer. In some of these children the bacteriologic data implicated only one kidney, indicating that at the time of the collection the pyelonephritis was unilateral. This finding has an important bearing on the management of the patient, for if the infection could not be controlled or eventually cured by antibacterial drug treatment, the question of excision of the pyelonephritic kidney should be considered in the hope of effecting a permanent cure. The collection of ureteric urine specimens after b l a d d e r irrigation is a time-consuming procedure. However, in most instances the investigation does enable upper and lower urinary tract infections to be clearly differentiated. Once this is established, the management of the patient can be placed on a more rational basis. T h e bacteriologic differentiation between upper and lower urinary tract irffection also permits the evaluation of other and possibly more simple methods of differentiation, such as the estimation of antibody titers. Lastly, the establishment of an accurate diagnosis of upper or lower urinary tract infection should allow the natural history of the two diseases to be more clearly elucidated. REFERENCES
1. Stamey, T. A., and Pfau, A.: Some functional, pathologic, bacteriologic, and chemotherapeutic characteristics of unilateral pyelonephritls in man. I. Functional and pathologic characteristics, Invest. Urol. 1: 134, 1963. 2. Hewstone, A. S., and Whitaker, J.: The correlation of ureteric urine bacteriology and homologous antibody titre in children with urinary infection. Submitted for publication. 3. Needle, M. tI., Neter, E., Staubitz, W., and Bingham, W. A.: The antibody (haemagglutinin) response of patients with infections of the urinary tract, J. Urol. 74: p. 674, 1955.
March, 1969 T h e ]ournal o[ P E D I A T R I C S
The bacteriologic differentiation between upper and lower urinary tract infection in children Specimens o[ ureteric urine were collected [rom 39 children who had urinary infection with a radiographically normal bladder and upper urinary tract; an essential preliminary was the control o[ the bacterial content of the bladder by copious irrigation. The bacteriologic results indicated that in 25 girls the bacteria were confined to the lower urinary tract, in 8 children the bacteria were originating [rom the upper urinary tract. The bacteriologic results/or the remaining 6 children were interpreted as indicating lower urinary tract injection.
j. Whitaker, F.R.C.S., F.R.C.S.E., and A. S. Hewstone, F.A.I.M.L.T., A.I.M.L.T. (UK) MELBOURNE,
AUSTRALIA
P E R S I S T Ig N T o r recurrent urinary t r a c t infection often occurs in children without any demonstrable radiographic abnormality of the bladder or upper urinary tract. The infecting bacteria in these patients may be confined to the lower urinary tract or may arise from one or both kidneys. The separation of the two conditions by bacteriologic methods has hitherto proved unsatisfactory. Attempts have been made to differentiate between upper and lower infection in other ways, including the assessment of clinical and radiologic features, renal biopsy, and the estimation of the patient's antibody response to the infecting pathogen. However, separation of upper and lower types of infection can only be accomplished in the first in-
From the Department of Surgical Research, Royal Children's Hospital Research Foundation, and the Department o/Bacteriology, Royal Children's Hospital. Vol. 74, No. 3, pp. 364-369
stance on the basis of bacteriologic data; other methods of differentiation must be of only secondary significance unless they are based upon such findings. In attempts to differentiate between upper and lower urinary tract infections, urine specimens have been collected for bacteriologic study from each renal system by the use of ureteric catheters. Difficulties in interpretation of the cultures have resulted because the catheters have been passed through a bladder containing a high concentration of bacteria, some of which may have been carried up from the bladder into the ureters by the catheters, thereby contaminating the ureteric urine so that upper and lower infections could not be distinguished. Stamey 1 introduced a technique to overcome this problem, the principle of which is to control the bacterial content of the bladder by irrigation with water and then
74 tuber 3
Urinary tract injections
pass the ureteric catheters through this controlled medium so that interpretable ureteric specimens may be collected. MATERIAL
AND
METHODS
Thirty-nine children who had persistent or recurrent urinary infections have been studied. These children were known to have a radiographically normal bladder and upper urinary tract, determined by micturition cystourethrography and intravenous pyelography; that is, the pelvicalyceal systems, ureters, and bladder were apparently normal when the urinary infection was first proved. T h e diagnosis of infection was established by the finding of a viable colony count of greater than 100,000 bacteria per milliliter of a single strain, cultured from catheter or midstream specimens within one hour of their collection. The primary investigation has been the collection of ureteric specimens together with control bladder specimens by the application of the Stamey principle of preliminary bladder irrigation. In some of the patients, renal and bladder biopsies were obtained by the use of percutaneous and endoscopic methods, and antibody titers to the infecting pathogen were also estimated. I n this technique the antigen was extracted from cultures of the infecting pathogen and attached to red cells which were then mixed with serial dilutions of the patient's serum. The presence of the homologous bacterial antibody caused agglutination of the modified red blood cells. These findings have formed the basis of a separate paper. 2 Collection of specimens of ureteric urine. The ureteric urine collections were performed at the time of endoscopic examination following the technique described by Stamey, 1 with the following modifications so that the method was suitable for the investigation of children. In all instances the patient was anesthetized and from 900 to 400 ml. of 5 per cent dextrose in distilled water were administered intravenously to ensure an adequate urinary output. For most female patients the No. 18 (Charriere gauge) panendoscope
365
sheath was suitable and was introduced into the bladder and a specimen of urine collected. Preliminary urethral dilatation to size No. 18 was required in some patients. The bladder was irrigated with at least 4 liters of sterile distilled water, and two No. 4 disposable ureteric catheters were introduced via the instrument into the bladder. A control specimen of bladder content was obtained through either the endoscope or the catheters, which were then passed up each ureter for a distance of 10 to 15 cm. The passing of the catheters was performed with the bladder nearly empty in order to reduce the risk of reflux of bladder content occurring through the ureteric orifices splinted by the catheters. In some children who had not had vesicoureteric reflux on micturition cystourethrography, reflux occurred with the ureteric catheters in position if the bladder was filled. The position of the catheters was checked, the bladder emptied further, and the panendoscope fixed in relation to the patient with the tip of the instrument lying on the trigone just inside the bladder neck. This was accomplished by having the sheath pass through a perforated rubber cork which could be moved along the instrument but which still gripped it; with the panendoscope positioned the cork was placed against the external urethral orifice and the viewing end of the instrument was attached to a tape suspended between the lithotomy stirrups. If this fixation is not established, control of the catheters is lost and the validity of the specimens is in doubt. T h e ureteric catheters were then dried and a piece of gauze was arranged around them so that fluid could not run down the outside of the catheters. Dripping from the ends of the catheters commonly occurred spontaneously; if it did not, the injection of 1 ml. of sterile water through the catheter usually initiated the flow of urine. At least 20 drops were allowed to come through the ureteric catheters and then 0.5 to 1 ml. of urine was collected from each. Dripping from the ends of the catheters usually took the form of peristaltic rushes of 3 to 4 drops. Continuous dripping indicated either a very high urinary output
366
Whitaker and H e w s t o n e
or reflux of bladder content about the catheters. As a check on this, indigo carmine was introduced into the bladder; if the drops from the catheter became blue, then reflux was known to be occurring. A final control bladder specimen was obtained after the ureteric collections, and the position of the catheters was checked by endoscopic examination. The No. 14 McCarthy cystourethroscope was used in most male patients and in very young female patients in whom the caliber of the urethra precluded the use of the larger instrument. This meant that only one No. 4 disposable ureterie catheter could be passed at a time. In these patients, after collection of the control specimen of bladder content, one ureter was catheterized and a specimen collected; after collection of a further control bladder specimen, a fresh catheter was passed up the other ureter and a specimen collected. The specimens were collected in sterile screw-capped glass containers and were placed in a refrigerator (4 ~ C.) immediately after their collection and labeling. Culture of ureteric urine specimens. The bacterial concentration of the ureteric specimens and of the bladder fluid after irrigation was found to be of a low order, and therefore it was essential that an adequate volume be cultured to ensure accurate counts. A pour plate method was employed whereby 0.5 ml. or more of the refrigerated bladder and ureteric specimens were mixed with 10 nil. of cooled molten nutrient agar.
The Journal o[ Pediatrics March 1969
After 18 hours incubation at 37 ~ C. the plates were examined and the number of colonies counted.
RESULTS Ureteric urine culture--no growth. The culture of the ureteric urine specimens resulted in no bacterial growth in 25 (all female) of the 39 patients (Table I). In 19 instances the bladder bacterial content was reduced to zero by the irrigation and in the other 6 the control bladder count ranged from 1 to 490 bacteria per milliliter. E. coli was the infecting pathogen in all o f these patients but 2, from whom Paracolon species and Streptococcus faecalis were isolated. It is of interest to note that negative ureterie cultures resulted even though the catheters were passed through bladder bacterial concentrations of up to 490 per milliliter. The failure to cultivate any bacteria from the ureteric specimens of these 25 girls indicated that they were suffering from lower urinary tract infections at the time of the collections. Ureteric urine culture--no significant growth. Five girls had E. coli infections with ureteric urine bacterial counts of a very low order; in 3 of these the bladder bacterial content had been reduced to zero by the irrigation (Table I I ) . Our interpretation is that in these patients the infection was confined to the lower tract and that the positive culture resulted from contamination of the ureteric specimens by bacteria escaping from the wall of the bladder or by external con-
Table I. Ureteric urine culture--no growth No.o[patierits 17 1 1 1 1 1 1 1 1
Bacteriology (bacteria per milliliter) Pathogen 1Controlbladder] Rightureter I Le[tureter E. eoli 0 0 0 Paracolon species 0 0 0 Streptococcus 0 0 0 [aecalis E. coli 1 0 0 E. coli 3 0 0 E. coli 12 0 0 E. coli 15 0 0 E. coli 33 0 0 E. coli 490 0 0
1
Interpretation Lower infection Lower infection Lower infection Lower infection Lower infection Lower infection Lower infection Lower infection Lower infection
Valume 74 NUmber 3
Urinary tract infections
taminants. The contention that the bacteria were confined to the lower tract is supported in 3 of these patients by the complete clearance of bacteria from the bladder by the irrigation. In patients in whom upper tract infection has been proved, some bacteria have usually been cultivated from the postirrigation bladder content, presumably because bacteria pass into the bladder from the ureters in the time interval (approximately 5 minutes) between the termination of the irrigation and the collection of the control bladder specimen (Table I V ) . The other possible explanation of the positive ureteric culture is that very small numbers of bacteria were coming from one or both kidneys. Ureterie urine culture--equivocal growth. T h e bladder bacterial count remained fairly high after the irrigation in 3 girls, and ureteric counts close to these levels were obtained from some of the ureteric urine cultures (Table I I I ) . Bacteriologic differentiation between upper and lower types of infection was difficult in these patients. Consideration of the antibody titers in these patients as measured by indirect bacterial hemagglutination s was of value in
367
reaching a decision regarding upper and lower urinary tract infection. T h e critical antibody level for the differentiation of upper and lower infection appears to be between 1 in 320 and 1 in 640; lower infections have titers of 1 in 320 or less, and upper irffections have titers of 1 in 640 or more. This level was established by the authors 2 in a series of patients in whom the diagnosis was made primarily on the basis of ureteric urine bacteriology. Patient J. H., who had been suffering with an E. coli urinary infection for at least 2 months, had a titer of 1 in 40, indicative of lower infection. Interpretation of the bacterial counts of 18 viable E. coli per milliliter from the control bladder specimen and 2 and 24 per milliliter from the respective ureteric specimens is difficult. These counts could mean that bacteria were arising from the upper tract, or they could result from contamination of the ureteric specimens by bacteria originating in the bladder. The other 2 patients in this group were found to have high antibody titers, indicating upper urinary infections (pyelonephritis). T h e ureteric urine bacterial counts of
Table II. Ureteric urine culture--no significant growth Bacteriology (bacteria per milliliter)
Patient M.L. D.C. J. F. tI. L.C. J. P.
Pathogen E. E. e. E. E.
ICo trolbladderl Right ureter I Left ureter
coli coli coli coli eoli
22 79 0 0
0 1 2 7
0
0
p Interpretation
1 1 0 0
Lower infection Lower infection Lower infection Lower infection Lower infection
Table I I I . Ureteric urine culture--equivocal growth Bacteriology (bacteria per milliliter Patient
Pathogen
Control bladder
Right ureter
J.H. S.W.
E. coli E. coli
18 120
2 90
24 0
1 in 40 1 in 640
M.T.
E. coli
200
6
160
1 in 1280
Left ureter
Antib ody titer
Interpretation
Lower infection Right pyelonephrltis Left pyelonephritis
368
Whitaker and Hewstone
The Journal o/ Pediatrics March 1969
90 and 160 per milliliter, from these 2 patients were probably significant despite the control bladder bacterial counts of 120 and 200 per milliliter, respectively. Even if some of the bladder bacteria were carried up the ureters by the catheters they should be largely washed away by the urine flow which was allowed to pass prior to the collection of specimens. Further evidence that these ureteric urine counts indicate significant upper tract infection is that in some of the patients discussed earlier, who clearly had lower tract infections, the ureteric bacterial counts were either zero or very low in spite of the presence of numbers of bacteria in the control bladder specimen. Finally, if the counts of 90 and 160 bacteria per milliliter were the result of contamination by bacteria escaping from the wall of the bladder, the degree of contamination could be expected to be approximately the same for both ureteric specimens, but in these patients the bacterial counts from the other ureter in each case were much less. Patients S. W. and M. T. therefore appeared to have unilateral upper urinary tract infection. These patients all had radiographically normal upper urinary tracts initially; Patient M. T. was the only one to develop some change, which consisted of a reduction in size of the left kidney over a period of 3 years; it was from this side that the significant uretqric urine bacterial count of 160 per milliliter resulted.
Ureteric urine culture--significant growth. Six patients, including the only boy in the
series, were f o u n d to have ureteric urine bacterial counts which were far in excess of the control bladder count and which indicated unequivocal upper urinary tract infection in one or both systems (Table IV). All of the children in this group had radiographically normal upper urinary tracts at the time of presentation; Patient J. G. was the only one to show a change, the right kidney becoming diminished in size and the calyces distorted and blunted, again over a 3-year period. Pyelonephritis probably limited to the right kidney was indicated in 3 patients (J. G., J. F., and A. J.) in whom only t, 12, and 0 bacteria per milliliter, respectively, were cultivated from the left ureteric specimens. Patient K. K., a boy, was found to yield a culture of greater than 1,000 bacteria per milliliter from the left ureter and 95 per milliliter from the right, with a control bladder count of 216 bacteria per milliliter. Left-sided pyetonephritis is proved on these results, but the count of 95 bacteria per milliliter from the right side is equivocal. Bilateral pyelonephritis was definitely established in the remaining 2 patients. One patient (M. McL.) had significant bacterial counts from both specimens of ureteric urine. The other patient (S. M.) had ureteric urine specimens collected on 2 occasions. From the first collection right-sided infection was established, but no bacteria were cultivated from the left ureteric urine specimen. The second collection, performed
Table IV. Ureterlc urine culture--significant growth Patient' J.G.
Pathogen E. eoli
J.F.
Paracolon species
A. J. K.K.* M. McL. S. M. ( i ) (2)
Bacteriology (bacteria per milliliter) I Control bladder I Right ureter [ Left ureter
Proteus mirabilis E. coli E. coli
50 24 0 216 26
390 530 130 95 ~ 103
1 12 0 ~ 103 260
E. coli Proteus mirabilis
29 3
1,640 > 103
0 300
*The sole male patient.
I
Interpretation
Right pyelonephritis Right pyelonephritis Right pyelonephritis Left pyelonephritis
Bilateral pyelonephritis Right pyelonephritis Bilateral pyelonephritis
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3 months later, reaffirmed the presence of right-sided infection but also indicated a significant infection on the left side. These results suggest that the left kidney was either not infected or was not actively excreting bacteria at the time of the first collection. Therefore, in this group of 6 children, 2 had bilateral and 3 had probable unilateral pyelonephritis; one was suffering from either unilateral or bilateral disease. DISCUSSION
The occurrence of 25 girls with unequivocal and 6 girls with probable lower urinary tract infection, compared with 7 girls and 1 boy with upper infection, indicates that lower infection is the most common type in those patients in whom micturition cystourethrography and intravenous pyelography have failed to reveal any apparent abnormality of the pelvicalyceal systems, ureters, and bladder. I t is also significant that lower infection occurred in girls alone, suggesting that the incidence of infection is in some way related to the shortness of the female urethra, whereby pathogenic bacteria may have relatively easy access to the bladder. Some of the girls in whom the infection was localized to the lower urinary tract had been observed for some years with persistent or recurrent infections, and yet at the time of investigation there was no suggestion of upper tract involvement. This supports the contention that the ureterovesical valve is usually an effective barrier in preventing the ascent of bacteria into the upper tract. In addition, the passage of the ureteric catheters through the infected bladder content and up into the ureters failed to precipitate any apparent episodes of upper infection. This risk m a y have been eliminated because of the low bacterial concentrations remaining in the bladder after the irrigation, associated with a high urinary output through ureters of normal caliber. Also, antibacterial treatment, usually nitrofurantoin, was instituted within 24 hours of the ureteric catheterization and was continued for at least 3 months.
Urinary tract in/ections
369
Eight of the 39 patients were considered to have upper urinary tract infection or pyelonephritis. The diagnosis was clearly indicated by the ureteric bacteriology in 6 of these; in the other 2 it was suggested by the ureteric bacteriology and confirmed by the finding of an elevated antibody titer. In some of these children the bacteriologic data implicated only one kidney, indicating that at the time of the collection the pyelonephritis was unilateral. This finding has an important bearing on the management of the patient, for if the infection could not be controlled or eventually cured by antibacterial drug treatment, the question of excision of the pyelonephritic kidney should be considered in the hope of effecting a permanent cure. The collection of ureteric urine specimens after b l a d d e r irrigation is a time-consuming procedure. However, in most instances the investigation does enable upper and lower urinary tract infections to be clearly differentiated. Once this is established, the management of the patient can be placed on a more rational basis. T h e bacteriologic differentiation between upper and lower urinary tract irffection also permits the evaluation of other and possibly more simple methods of differentiation, such as the estimation of antibody titers. Lastly, the establishment of an accurate diagnosis of upper or lower urinary tract infection should allow the natural history of the two diseases to be more clearly elucidated. REFERENCES
1. Stamey, T. A., and Pfau, A.: Some functional, pathologic, bacteriologic, and chemotherapeutic characteristics of unilateral pyelonephritls in man. I. Functional and pathologic characteristics, Invest. Urol. 1: 134, 1963. 2. Hewstone, A. S., and Whitaker, J.: The correlation of ureteric urine bacteriology and homologous antibody titre in children with urinary infection. Submitted for publication. 3. Needle, M. tI., Neter, E., Staubitz, W., and Bingham, W. A.: The antibody (haemagglutinin) response of patients with infections of the urinary tract, J. Urol. 74: p. 674, 1955.