Ramifications of requiring pyuria for the diagnosis of urinary tract infection

Classical teaching suggests that urinary tract infections (UTIs) should always be accompanied by a measurable inflammatory response. The presence of inflammation, which can be measured by assessing pyuria, is therefore critical to the accurate diagnosis of UTIs. This may be particularly important when large proportions of children being considered for the diagnosis of UTI have either contaminated samples or asymptomatic bacteriuria (ABU) that is coincident with their presenting symptoms. Accordingly, requiring pyuria for the diagnosis of UTI might help avoid unnecessary antibiotic use in children with contaminated samples or ABU.

This reasoning led to a paradigm shift in the way UTIs are diagnosed in children in the United States. Before the publication of the UTI Guidelines by the American Academy of Pediatrics in 2011,¹ urine culture was considered the reference standard for the diagnosis of UTI and pyuria was considered a screening test clinicians that aided clinicians in the diagnostic process. Therefore, children with a positive urine culture without pyuria were considered as having ABU, contamination or a true UTI with a falsely negative test for pyuria. In contrast, after publication of the 2011 Guideline (now retired), many practitioners and many centres started requiring evidence of pyuria in addition to a positive urine culture criteria to diagnose UTI. Thus, after the guideline, all children with a positive urine culture without pyuria were to be considered as having either ABU or a contaminated sample.

While the reasoning above appears logical, it hinges upon the presumption that inflammation is perfectly measured using current tests for pyuria. There are indications from several directions that the above presumption is false. First, the paper by Lasry et al.² published in Acta Paediatrica found that 9% of febrile children with UTI accompanied by bacteraemia or meningitis with the same organisms did not have pyuria on their dipstick test. Overall, 21% (25/118, Table S2) of children in the study that were judged to have a febrile UTI by a blinded clinician (based on a positive urine culture with pure growth if a single organism in a sample obtained via catheterisation or suprapubic aspiration, no other source for fever and elevated serum inflammatory markers) had a negative leucocyte esterase test (ignoring the one febrile child whose dipstick was positive by virtue of a nitrite test alone). Second, this finding is generally consistent with a large body of studies conducted in other cohorts. In a large meta-analysis that included 95 studies, Williams reported a sensitivity (CI) of 79% (73%-84%) for the leucocyte esterase test.³ Of note, this meta-analysis also reported a similar sensitivity (CI) for the white blood cells count on microscopy (74%, CI 67%-80%). Third, studies that have compared current tests with newer tests like urinary neutrophil gelatinase lipocalin (NGAL), another inflammatory marker released by leucocytes and/or renal cells, suggest that the problem lies largely with the suboptimal accuracy of tests currently available and not with the methods used in previous diagnostic accuracy studies.⁴ In one study of 260 children with suspected UTI, 14 of the 35 children with a positive culture did not have evidence of pyuria using tests currently available.⁵ Notably, all except one of these children had elevated urine NGAL. Fourth, the proportion of children with a positive culture who do not have measurable pyuria (using current tests) is much higher than could be explained by either ABU or contamination. Together, these data suggest that the sensitivity of the leucocyte esterase test (and other widely available tests for pyuria) is too low for it to be required for the diagnosis of UTI.

But is this just of interest to academics with little consequence for child health? Extrapolating the findings above to the US population of children under 2 years of age suggests otherwise (Table 1). Using census and claims data (see Table 1), a prevalence of UTI of 10% and a sensitivity of 85% (the midway point between 79% and 91%), we estimate that requiring pyuria for the diagnosis of UTI likely leads to 13 822 missed UTIs annually. While some might argue that none of these children require treatment (as they do not have measurable inflammation), at least some of the children have no measurable inflammation because current tests are insensitive to detect it.

TABLE 1.

National implications of requiring pyuria for the diagnosis of uti in symptomatic children younger than 2 years undergoing bladder catheterisation for suspected urinary tract infection.

Number of children with a positive urine culture in 2022a	Number of children with a UTI in 2022b	Number of UTIs diagnosed if pyuria required for the diagnosis of UTIc	Number (%) of UTIs missedd
167 254	156 048	142 166	13 882

^aObtained using best available annual rates of children with a positive urine culture (23/1000)⁶ and the number of children <2 years of age in the 2022 census (7 271 930).⁷ Using a prevalence of 10% for positive urine cultures, approximately 1 672 540 children were evaluated to arrive at 167 254 with a positive urine culture.

^bAssumed that 0.21% of children tested would have asymptomatic bacteriuria without pyuria,⁸ and that 0.46% of children might have contamination. The latter was based on two studies by Pryles^9,10; none of the 92 children undergoing bladder catheterisation in these two studies had growth of a single uropathogen at counts >10 000 CFU/mL. One boy with severe phimosis had growth of two organisms on culture from the first few drops of urine exiting the catheter (and no growth from the remainder of the urine). If this boy is considered to have significant bacteriuria, then the rate of contamination would be 0.46% assuming that, of the infants being evaluated for UTI, 28% are males. Thus, of the 2 448 563 children evaluated, 0.67% (0.21% + 0.46%, 11 206 children) likely had ABU or contamination leaving 156 048 children with true UTI.

^cObtained by multiplying sensitivity of the leucocyte esterase test (85%, see text above) and number of children with a positive urine culture.

^dObtained by subtracting the number of UTIs diagnosed if pyuria required for the diagnosis of UTI from the number with UTI.

We must reconsider requiring current imperfect tests for pyuria for the diagnosis of UTI when other tests measuring inflammation clearly outperform it. Continued adherence to the 2011 guideline's requirement for pyuria for the diagnosis of UTI will likely lead to many children with true UTIs being missed.

Abbreviations:

ABU

asymptomatic bacteriuria

UTI

urinary tract infection

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