The importance of UA in diagnosing UTIs in infants under 2 months

A 28-day-old uncircumcised male infant presents to the emergency department with fever of 38.9° C, decreased feeding, and irritability. The physical examination is normal with the exception of the irritability and your assessment of mild dehydration. The infant undergoes a sepsis work-up. The CBC is remarkable for a WBC of 16,500/mm³ with 44% neutrophils, 52% lymphocytes, and 4% monocytes. Platelet count is normal. Cerebrospinal fluid (CSF) shows no white or red blood cells with normal glucose and protein. The urinalysis (UA) has a positive 1+ leukocyte esterase (LE) with 10 WBC per high-power field (HPF), but negative nitrite and 1+ bacteria microscopically. The child is admitted to the hospital for empiric antibiotics pending blood, urine, and CSF cultures. What are the chances that a urinary tract infection (UTI) is the origin of the febrile presentation?

UTIs are currently the most common serious bacterial infection (SBI) in < 2-year-old febrile children without an apparent source of fever (Pediatrics 2011;128:595-610). Since 2000, the prevalence of UTIs in all febrile infants and young children without an apparent source is unchanged, being approximately 5%. The rate of UTIs in fever-without-apparent-source presentations at < 90 days of age is higher, ranging from 6%-15% in different studies.

Meanwhile bacteremia, sepsis, meningitis, and other previously common SBIs, mostly caused by Haemophilus influenzae type b (Hib) or pneumococcus, have decreased. We recognize these reductions as effects of universal implementation of Hib (mid-1990s) and pneumococcal (2000 and 2010) conjugate vaccines.

Given the case above, other pertinent facts are that uncircumcised males have more UTIs in the first months of life (J. Pediatr. 1996;128:23-7) and approximately 5% of young infants with UTIs also are concurrently bacteremic (Pediatrics 1999;104:79-86;J. Pediatr. 1994;124:513-9)

The elephant in the room is the fact that we also need to be cognizant of asymptomatic bacteriuria (AB). AB is colonization of the lower urinary tract without infection. Patients with AB may meet culture criteria for UTI (whether we consider > 50,000 or > 100,000 colony-forming units/mL), but there is no evidence of true infection, that is no inflammation or mucosal injury. So children with AB are not at risk for renal injury or later renal damage and do not require antibiotic treatment.

But when AB patients develop fever, for example with an enterovirus infection, their urine cultures (together with the fever) can do a good imitation of a UTI, unless we focus on the UA results. It not only remains critical to detect true UTIs in infants < 90 days old, such as the one in our case above, but also to distinguish UTI from AB.

The 1999 American Academy of Pediatrics’ UTI guidelines (Pediatrics 1999;103:843-52) included UA results as suggestive of UTI. They stated that a positive LE or nitrite test or > 5 WBC/HPF in a spun urine, or bacteria visualized in unspun gram-stained specimen suggest, but cannot be diagnostic of a UTI. Recommendation five in the guidelines states that UTI diagnosis required 100,000 CFU/mL in culture of sterilely obtained catheterized urine as the threshold criterion (strength of evidence: strong). However, AB was not fully considered because, in part, data defining AB was incomplete in 1999.

The 1999 guidelines also stated, “The urinalysis … can be valuable in selecting individuals for prompt initiation of treatment while waiting for the results of the urine culture.” So, UA was considered adjunctive. UA’s main function was to allow empiric therapy of sufficiently ill children, given positive results for LE, nitrites, or microscopic visualization of > 5 WBC/HPF or bacteria in the spun urine.

In the 2011 AAP guidelines for UTI, things have changed (Pediatrics 2011;128:595-610). The third action statement tells us that both the UA and culture taken together are necessary for UTI diagnosis. To paraphrase: The diagnosis of UTI requires urinalysis results suggesting infection (pyuria or microscopic bacteriuria) plus > 50,000 CFU/mL of a uropathogen in urine from catheterization or suprapubic aspiration. But remember that these guidelines do not apply specifically to the youngest of infants, that is < 2 months old.

Both of these criteria were changes from the 1999 UTI guidelines. Previously pyuria or microscopic bacteriuria were not considered necessary to diagnose UTI, and >100,000 CFU/mL rather than > 50,000 CFU/mL of a single pathogen species was the critical diagnostic result for catheterized urine. For suprapubic aspiration urine samples, > 10,000 CFU/HPF were considered adequate for UTI diagnoses in 1999.

Now, a recent study of children < 90 days of age (including those < 2 months of age) reports that pyuria (> 3 WBC/HPF) plus > 50,000 CFU/mL are the keys to diagnosing UTI (Pediatrics 2015;135:965-71). One caveat is that the study population was febrile infants < 90 days old with concurrent bacteremia (bacteremic UTI). Bacteremic UTI was studied to reduce as much as possible the chance that AB patients might be inadvertently included in the study. One other conclusion of this new study is that microscopic bacteriuria did not add significantly to the either sensitivity or specificity.

These data in an overall younger population than that covered by the 2011 guidelines adds evidence that pyuria (but not microscopic bacteriuria) is critical to diagnosing UTI. Pyuria plus positive culture has been a combination for the pediatric infectious diseases practitioner’s toolkit for decades. Likewise, it seems to me that primary care pediatric clinicians also often decide whether to undertake the expense of culture based on UA results. For example, a completely normal UA may obviate need for culture except in selected unusual cases.

Requiring UA evidence of inflammation to diagnose UTI (per the 2011 guidelines and the recommendations of the authors of the recent 2015 study) makes sense because most UTIs in otherwise healthy children are caused by gram-negative organisms (> 90% from Escherichia coli) (J. Pediatr. 1994;124:513-9). Why are UA results so important?

A positive nitrite test strongly suggests UTI because nitrites in the urine indicate viable gram-negative organisms also are present in the urine. Nitrates in the urine are converted to nitrites by metabolic activity of gram-negative pathogens. For WBCs or LE in the urine, their presence indicates inflammation in the urinary tract, Consider that lipopolysaccharide (LPS), also known as gram-negative endotoxin, is a major component of the cell membrane of > 90% of uropathogens like E. coli. Moreover, LPS elicits about the strongest innate immune response via toll-like receptor 4 (TLR4) from monocytes/macrophages, inducing a large pro-inflammatory and chemotactic response – interleukin-6, interleukin-8, tetrahydrofuran-alpha. Remember that LPS is also a major cause of fever and of shock during gram-negative sepsis.

So a UTI diagnosis based on a “positive” culture without evidence of metabolic products of gram negatives (nitrites) or without inflammation (no pyuria or negative LE) should be questioned. The combination of > 50,000 CFU/mL with no detectable LE or < 3-5 WBC/HPF in a febrile child is most likely evidence for AB in a child with the fever caused by some non-UTI process.

In contrast, selected SBIs may occur when the culture is “positive” without inflammation or nitrites. The first of three examples is a renal parenchymal abscess, where bacteria enter the urine sporadically in only small numbers, and do not actually infect the urinary tract mucosa. The scenario of no inflammation but “positive” culture also may occur when a large bacteremic load causes results in organisms filtering through the kidney into the urine, again without urinary mucosal infection, such as Staphylococcus aureus, group A streptococcus, or group B streptococcus bacteremia/sepsis. The third scenario with a “positive” culture and no pyuria can be with organisms that have blunted abilities to induce inflammation, such as enterococcus. Enterococcal cell components have weak inflammatory and chemotactic capability. So a urinary mucosal infection in the collecting system or bladder may occur without much if any pyuria. In fact, the patients from the recent study with insufficient evidence of pyuria/inflammation were those who had either gram-positive organisms or considerably less than 50,000 CFU/mL of gram-negative organisms.

The sensitivity and specificity of the LE or pyuria was higher in the recent study (Pediatrics 2015;135:965-71) than any prior study. The authors comment that they had not expected such a high sensitivity of 97.6% (94.5-99.2) for LE in confirmed bacteremic UTI, nor did they expect the high specificity of 93.9% (87.9-97.5). The presence of microscopic pyuria defined as > 3 WBC/HPF was nearly as sensitive, 96%, and specific, 91.3%. Disappointingly, positive nitrite testing was only 39.5% sensitive, but it was 100% specific. This likely reflects the short time that urine resides in the bladder of infants < 90 days of age, so there is insufficient time for the pathogens to metabolically convert the nitrates to nitrites.

So how would the UA help with our example case? There is microscopic bacteriuria, pyuria, and positive LE, but negative nitrites. Using the suggestions of the authors of the recent report (Pediatrics 2015;135:965-71) and those of another report on the utility of UA results (Acta Paediatr. 2010;99:581-4), the UA in our case indicates that we should be highly suspicious of a UTI in this child < 2 months old for whom the 2011 guidelines do not directly apply. But remember that these impressive sensitivity and specificity values relate to bacteremic UTI. Whether they apply to nonbacteremic UTI is not known. Likewise, the authors caution that their study design did not allow calculation of positive or negative predictive values – aspects that would clarify things even further.

So we still cannot be more than highly suspicious. Without a positive predictive value, we do not know the odds of this case having a UTI with mathematical precision. The authors do point out that only one of their subjects had a completely normal UA and actually had a bacteremic UTI. If you guessed that it was a gram-positive pathogen, you win the prize. So it seems reasonable to predict that a normal UA has a high specificity for not being a UTI (87.8%), but a positive UA remains only highly suggestive. It is still not clear if a negative UA statistically justifies not submitting the culture of the sterilely obtained urine because we still don’t have a negative predictive value.

Bottom line: The 2011 UTI guidelines provide good advice on diagnosing UTIs.

1. We have more data that evidence of inflammation is essential for diagnosing gram-negative UTIs.

2. We also have more evidence that 50,000 CFU/mL is a good threshold for diagnosing UTIs.

3. It appears that microscopic bacteriuria did not add significantly to the either sensitivity or specificity.

4. And we now have more evidence that these criteria also apply to infants < 2 months of age.

To close the loop on our case, the child’s CSF and blood cultures were negative, but the urine culture revealed > 100,000 CFU/mL of E. coli susceptible to second- and third-generation cephalosporins, ciprofloxacin, and nitrofurantoin, but resistant to trimethoprim-sulfamethoxazole.

Have a great summer and watch for UTIs in your young patients < 90 days old and fever without apparent focus.

Dr. Harrison is professor of pediatrics and pediatric infectious diseases at Children’s Mercy Hospitals and Clinics, Kansas City, Mo. He said he had no relevant financial disclosures. E-mail Dr. Harrison at pdnews@frontlinemedcom.com. 

A 28-day-old uncircumcised male infant presents to the emergency department with fever of 38.9° C, decreased feeding, and irritability. The physical examination is normal with the exception of the irritability and your assessment of mild dehydration. The infant undergoes a sepsis work-up. The CBC is remarkable for a WBC of 16,500/mm³ with 44% neutrophils, 52% lymphocytes, and 4% monocytes. Platelet count is normal. Cerebrospinal fluid (CSF) shows no white or red blood cells with normal glucose and protein. The urinalysis (UA) has a positive 1+ leukocyte esterase (LE) with 10 WBC per high-power field (HPF), but negative nitrite and 1+ bacteria microscopically. The child is admitted to the hospital for empiric antibiotics pending blood, urine, and CSF cultures. What are the chances that a urinary tract infection (UTI) is the origin of the febrile presentation?

UTIs are currently the most common serious bacterial infection (SBI) in < 2-year-old febrile children without an apparent source of fever (Pediatrics 2011;128:595-610). Since 2000, the prevalence of UTIs in all febrile infants and young children without an apparent source is unchanged, being approximately 5%. The rate of UTIs in fever-without-apparent-source presentations at < 90 days of age is higher, ranging from 6%-15% in different studies.

Meanwhile bacteremia, sepsis, meningitis, and other previously common SBIs, mostly caused by Haemophilus influenzae type b (Hib) or pneumococcus, have decreased. We recognize these reductions as effects of universal implementation of Hib (mid-1990s) and pneumococcal (2000 and 2010) conjugate vaccines.

Given the case above, other pertinent facts are that uncircumcised males have more UTIs in the first months of life (J. Pediatr. 1996;128:23-7) and approximately 5% of young infants with UTIs also are concurrently bacteremic (Pediatrics 1999;104:79-86;J. Pediatr. 1994;124:513-9)

The elephant in the room is the fact that we also need to be cognizant of asymptomatic bacteriuria (AB). AB is colonization of the lower urinary tract without infection. Patients with AB may meet culture criteria for UTI (whether we consider > 50,000 or > 100,000 colony-forming units/mL), but there is no evidence of true infection, that is no inflammation or mucosal injury. So children with AB are not at risk for renal injury or later renal damage and do not require antibiotic treatment.

But when AB patients develop fever, for example with an enterovirus infection, their urine cultures (together with the fever) can do a good imitation of a UTI, unless we focus on the UA results. It not only remains critical to detect true UTIs in infants < 90 days old, such as the one in our case above, but also to distinguish UTI from AB.

The 1999 American Academy of Pediatrics’ UTI guidelines (Pediatrics 1999;103:843-52) included UA results as suggestive of UTI. They stated that a positive LE or nitrite test or > 5 WBC/HPF in a spun urine, or bacteria visualized in unspun gram-stained specimen suggest, but cannot be diagnostic of a UTI. Recommendation five in the guidelines states that UTI diagnosis required 100,000 CFU/mL in culture of sterilely obtained catheterized urine as the threshold criterion (strength of evidence: strong). However, AB was not fully considered because, in part, data defining AB was incomplete in 1999.

The 1999 guidelines also stated, “The urinalysis … can be valuable in selecting individuals for prompt initiation of treatment while waiting for the results of the urine culture.” So, UA was considered adjunctive. UA’s main function was to allow empiric therapy of sufficiently ill children, given positive results for LE, nitrites, or microscopic visualization of > 5 WBC/HPF or bacteria in the spun urine.

In the 2011 AAP guidelines for UTI, things have changed (Pediatrics 2011;128:595-610). The third action statement tells us that both the UA and culture taken together are necessary for UTI diagnosis. To paraphrase: The diagnosis of UTI requires urinalysis results suggesting infection (pyuria or microscopic bacteriuria) plus > 50,000 CFU/mL of a uropathogen in urine from catheterization or suprapubic aspiration. But remember that these guidelines do not apply specifically to the youngest of infants, that is < 2 months old.

Both of these criteria were changes from the 1999 UTI guidelines. Previously pyuria or microscopic bacteriuria were not considered necessary to diagnose UTI, and >100,000 CFU/mL rather than > 50,000 CFU/mL of a single pathogen species was the critical diagnostic result for catheterized urine. For suprapubic aspiration urine samples, > 10,000 CFU/HPF were considered adequate for UTI diagnoses in 1999.

Now, a recent study of children < 90 days of age (including those < 2 months of age) reports that pyuria (> 3 WBC/HPF) plus > 50,000 CFU/mL are the keys to diagnosing UTI (Pediatrics 2015;135:965-71). One caveat is that the study population was febrile infants < 90 days old with concurrent bacteremia (bacteremic UTI). Bacteremic UTI was studied to reduce as much as possible the chance that AB patients might be inadvertently included in the study. One other conclusion of this new study is that microscopic bacteriuria did not add significantly to the either sensitivity or specificity.

These data in an overall younger population than that covered by the 2011 guidelines adds evidence that pyuria (but not microscopic bacteriuria) is critical to diagnosing UTI. Pyuria plus positive culture has been a combination for the pediatric infectious diseases practitioner’s toolkit for decades. Likewise, it seems to me that primary care pediatric clinicians also often decide whether to undertake the expense of culture based on UA results. For example, a completely normal UA may obviate need for culture except in selected unusual cases.

Requiring UA evidence of inflammation to diagnose UTI (per the 2011 guidelines and the recommendations of the authors of the recent 2015 study) makes sense because most UTIs in otherwise healthy children are caused by gram-negative organisms (> 90% from Escherichia coli) (J. Pediatr. 1994;124:513-9). Why are UA results so important?

A positive nitrite test strongly suggests UTI because nitrites in the urine indicate viable gram-negative organisms also are present in the urine. Nitrates in the urine are converted to nitrites by metabolic activity of gram-negative pathogens. For WBCs or LE in the urine, their presence indicates inflammation in the urinary tract, Consider that lipopolysaccharide (LPS), also known as gram-negative endotoxin, is a major component of the cell membrane of > 90% of uropathogens like E. coli. Moreover, LPS elicits about the strongest innate immune response via toll-like receptor 4 (TLR4) from monocytes/macrophages, inducing a large pro-inflammatory and chemotactic response – interleukin-6, interleukin-8, tetrahydrofuran-alpha. Remember that LPS is also a major cause of fever and of shock during gram-negative sepsis.

So a UTI diagnosis based on a “positive” culture without evidence of metabolic products of gram negatives (nitrites) or without inflammation (no pyuria or negative LE) should be questioned. The combination of > 50,000 CFU/mL with no detectable LE or < 3-5 WBC/HPF in a febrile child is most likely evidence for AB in a child with the fever caused by some non-UTI process.

In contrast, selected SBIs may occur when the culture is “positive” without inflammation or nitrites. The first of three examples is a renal parenchymal abscess, where bacteria enter the urine sporadically in only small numbers, and do not actually infect the urinary tract mucosa. The scenario of no inflammation but “positive” culture also may occur when a large bacteremic load causes results in organisms filtering through the kidney into the urine, again without urinary mucosal infection, such as Staphylococcus aureus, group A streptococcus, or group B streptococcus bacteremia/sepsis. The third scenario with a “positive” culture and no pyuria can be with organisms that have blunted abilities to induce inflammation, such as enterococcus. Enterococcal cell components have weak inflammatory and chemotactic capability. So a urinary mucosal infection in the collecting system or bladder may occur without much if any pyuria. In fact, the patients from the recent study with insufficient evidence of pyuria/inflammation were those who had either gram-positive organisms or considerably less than 50,000 CFU/mL of gram-negative organisms.

The sensitivity and specificity of the LE or pyuria was higher in the recent study (Pediatrics 2015;135:965-71) than any prior study. The authors comment that they had not expected such a high sensitivity of 97.6% (94.5-99.2) for LE in confirmed bacteremic UTI, nor did they expect the high specificity of 93.9% (87.9-97.5). The presence of microscopic pyuria defined as > 3 WBC/HPF was nearly as sensitive, 96%, and specific, 91.3%. Disappointingly, positive nitrite testing was only 39.5% sensitive, but it was 100% specific. This likely reflects the short time that urine resides in the bladder of infants < 90 days of age, so there is insufficient time for the pathogens to metabolically convert the nitrates to nitrites.

So how would the UA help with our example case? There is microscopic bacteriuria, pyuria, and positive LE, but negative nitrites. Using the suggestions of the authors of the recent report (Pediatrics 2015;135:965-71) and those of another report on the utility of UA results (Acta Paediatr. 2010;99:581-4), the UA in our case indicates that we should be highly suspicious of a UTI in this child < 2 months old for whom the 2011 guidelines do not directly apply. But remember that these impressive sensitivity and specificity values relate to bacteremic UTI. Whether they apply to nonbacteremic UTI is not known. Likewise, the authors caution that their study design did not allow calculation of positive or negative predictive values – aspects that would clarify things even further.

So we still cannot be more than highly suspicious. Without a positive predictive value, we do not know the odds of this case having a UTI with mathematical precision. The authors do point out that only one of their subjects had a completely normal UA and actually had a bacteremic UTI. If you guessed that it was a gram-positive pathogen, you win the prize. So it seems reasonable to predict that a normal UA has a high specificity for not being a UTI (87.8%), but a positive UA remains only highly suggestive. It is still not clear if a negative UA statistically justifies not submitting the culture of the sterilely obtained urine because we still don’t have a negative predictive value.

Bottom line: The 2011 UTI guidelines provide good advice on diagnosing UTIs.

1. We have more data that evidence of inflammation is essential for diagnosing gram-negative UTIs.

2. We also have more evidence that 50,000 CFU/mL is a good threshold for diagnosing UTIs.

3. It appears that microscopic bacteriuria did not add significantly to the either sensitivity or specificity.

4. And we now have more evidence that these criteria also apply to infants < 2 months of age.

To close the loop on our case, the child’s CSF and blood cultures were negative, but the urine culture revealed > 100,000 CFU/mL of E. coli susceptible to second- and third-generation cephalosporins, ciprofloxacin, and nitrofurantoin, but resistant to trimethoprim-sulfamethoxazole.

Have a great summer and watch for UTIs in your young patients < 90 days old and fever without apparent focus.

Dr. Harrison is professor of pediatrics and pediatric infectious diseases at Children’s Mercy Hospitals and Clinics, Kansas City, Mo. He said he had no relevant financial disclosures. E-mail Dr. Harrison at pdnews@frontlinemedcom.com. 

A 28-day-old uncircumcised male infant presents to the emergency department with fever of 38.9° C, decreased feeding, and irritability. The physical examination is normal with the exception of the irritability and your assessment of mild dehydration. The infant undergoes a sepsis work-up. The CBC is remarkable for a WBC of 16,500/mm³ with 44% neutrophils, 52% lymphocytes, and 4% monocytes. Platelet count is normal. Cerebrospinal fluid (CSF) shows no white or red blood cells with normal glucose and protein. The urinalysis (UA) has a positive 1+ leukocyte esterase (LE) with 10 WBC per high-power field (HPF), but negative nitrite and 1+ bacteria microscopically. The child is admitted to the hospital for empiric antibiotics pending blood, urine, and CSF cultures. What are the chances that a urinary tract infection (UTI) is the origin of the febrile presentation?

UTIs are currently the most common serious bacterial infection (SBI) in < 2-year-old febrile children without an apparent source of fever (Pediatrics 2011;128:595-610). Since 2000, the prevalence of UTIs in all febrile infants and young children without an apparent source is unchanged, being approximately 5%. The rate of UTIs in fever-without-apparent-source presentations at < 90 days of age is higher, ranging from 6%-15% in different studies.

Meanwhile bacteremia, sepsis, meningitis, and other previously common SBIs, mostly caused by Haemophilus influenzae type b (Hib) or pneumococcus, have decreased. We recognize these reductions as effects of universal implementation of Hib (mid-1990s) and pneumococcal (2000 and 2010) conjugate vaccines.

Given the case above, other pertinent facts are that uncircumcised males have more UTIs in the first months of life (J. Pediatr. 1996;128:23-7) and approximately 5% of young infants with UTIs also are concurrently bacteremic (Pediatrics 1999;104:79-86;J. Pediatr. 1994;124:513-9)

The elephant in the room is the fact that we also need to be cognizant of asymptomatic bacteriuria (AB). AB is colonization of the lower urinary tract without infection. Patients with AB may meet culture criteria for UTI (whether we consider > 50,000 or > 100,000 colony-forming units/mL), but there is no evidence of true infection, that is no inflammation or mucosal injury. So children with AB are not at risk for renal injury or later renal damage and do not require antibiotic treatment.

But when AB patients develop fever, for example with an enterovirus infection, their urine cultures (together with the fever) can do a good imitation of a UTI, unless we focus on the UA results. It not only remains critical to detect true UTIs in infants < 90 days old, such as the one in our case above, but also to distinguish UTI from AB.

The 1999 American Academy of Pediatrics’ UTI guidelines (Pediatrics 1999;103:843-52) included UA results as suggestive of UTI. They stated that a positive LE or nitrite test or > 5 WBC/HPF in a spun urine, or bacteria visualized in unspun gram-stained specimen suggest, but cannot be diagnostic of a UTI. Recommendation five in the guidelines states that UTI diagnosis required 100,000 CFU/mL in culture of sterilely obtained catheterized urine as the threshold criterion (strength of evidence: strong). However, AB was not fully considered because, in part, data defining AB was incomplete in 1999.

The 1999 guidelines also stated, “The urinalysis … can be valuable in selecting individuals for prompt initiation of treatment while waiting for the results of the urine culture.” So, UA was considered adjunctive. UA’s main function was to allow empiric therapy of sufficiently ill children, given positive results for LE, nitrites, or microscopic visualization of > 5 WBC/HPF or bacteria in the spun urine.

In the 2011 AAP guidelines for UTI, things have changed (Pediatrics 2011;128:595-610). The third action statement tells us that both the UA and culture taken together are necessary for UTI diagnosis. To paraphrase: The diagnosis of UTI requires urinalysis results suggesting infection (pyuria or microscopic bacteriuria) plus > 50,000 CFU/mL of a uropathogen in urine from catheterization or suprapubic aspiration. But remember that these guidelines do not apply specifically to the youngest of infants, that is < 2 months old.

Both of these criteria were changes from the 1999 UTI guidelines. Previously pyuria or microscopic bacteriuria were not considered necessary to diagnose UTI, and >100,000 CFU/mL rather than > 50,000 CFU/mL of a single pathogen species was the critical diagnostic result for catheterized urine. For suprapubic aspiration urine samples, > 10,000 CFU/HPF were considered adequate for UTI diagnoses in 1999.

Now, a recent study of children < 90 days of age (including those < 2 months of age) reports that pyuria (> 3 WBC/HPF) plus > 50,000 CFU/mL are the keys to diagnosing UTI (Pediatrics 2015;135:965-71). One caveat is that the study population was febrile infants < 90 days old with concurrent bacteremia (bacteremic UTI). Bacteremic UTI was studied to reduce as much as possible the chance that AB patients might be inadvertently included in the study. One other conclusion of this new study is that microscopic bacteriuria did not add significantly to the either sensitivity or specificity.

These data in an overall younger population than that covered by the 2011 guidelines adds evidence that pyuria (but not microscopic bacteriuria) is critical to diagnosing UTI. Pyuria plus positive culture has been a combination for the pediatric infectious diseases practitioner’s toolkit for decades. Likewise, it seems to me that primary care pediatric clinicians also often decide whether to undertake the expense of culture based on UA results. For example, a completely normal UA may obviate need for culture except in selected unusual cases.

Requiring UA evidence of inflammation to diagnose UTI (per the 2011 guidelines and the recommendations of the authors of the recent 2015 study) makes sense because most UTIs in otherwise healthy children are caused by gram-negative organisms (> 90% from Escherichia coli) (J. Pediatr. 1994;124:513-9). Why are UA results so important?

A positive nitrite test strongly suggests UTI because nitrites in the urine indicate viable gram-negative organisms also are present in the urine. Nitrates in the urine are converted to nitrites by metabolic activity of gram-negative pathogens. For WBCs or LE in the urine, their presence indicates inflammation in the urinary tract, Consider that lipopolysaccharide (LPS), also known as gram-negative endotoxin, is a major component of the cell membrane of > 90% of uropathogens like E. coli. Moreover, LPS elicits about the strongest innate immune response via toll-like receptor 4 (TLR4) from monocytes/macrophages, inducing a large pro-inflammatory and chemotactic response – interleukin-6, interleukin-8, tetrahydrofuran-alpha. Remember that LPS is also a major cause of fever and of shock during gram-negative sepsis.

So a UTI diagnosis based on a “positive” culture without evidence of metabolic products of gram negatives (nitrites) or without inflammation (no pyuria or negative LE) should be questioned. The combination of > 50,000 CFU/mL with no detectable LE or < 3-5 WBC/HPF in a febrile child is most likely evidence for AB in a child with the fever caused by some non-UTI process.

In contrast, selected SBIs may occur when the culture is “positive” without inflammation or nitrites. The first of three examples is a renal parenchymal abscess, where bacteria enter the urine sporadically in only small numbers, and do not actually infect the urinary tract mucosa. The scenario of no inflammation but “positive” culture also may occur when a large bacteremic load causes results in organisms filtering through the kidney into the urine, again without urinary mucosal infection, such as Staphylococcus aureus, group A streptococcus, or group B streptococcus bacteremia/sepsis. The third scenario with a “positive” culture and no pyuria can be with organisms that have blunted abilities to induce inflammation, such as enterococcus. Enterococcal cell components have weak inflammatory and chemotactic capability. So a urinary mucosal infection in the collecting system or bladder may occur without much if any pyuria. In fact, the patients from the recent study with insufficient evidence of pyuria/inflammation were those who had either gram-positive organisms or considerably less than 50,000 CFU/mL of gram-negative organisms.

The sensitivity and specificity of the LE or pyuria was higher in the recent study (Pediatrics 2015;135:965-71) than any prior study. The authors comment that they had not expected such a high sensitivity of 97.6% (94.5-99.2) for LE in confirmed bacteremic UTI, nor did they expect the high specificity of 93.9% (87.9-97.5). The presence of microscopic pyuria defined as > 3 WBC/HPF was nearly as sensitive, 96%, and specific, 91.3%. Disappointingly, positive nitrite testing was only 39.5% sensitive, but it was 100% specific. This likely reflects the short time that urine resides in the bladder of infants < 90 days of age, so there is insufficient time for the pathogens to metabolically convert the nitrates to nitrites.

So how would the UA help with our example case? There is microscopic bacteriuria, pyuria, and positive LE, but negative nitrites. Using the suggestions of the authors of the recent report (Pediatrics 2015;135:965-71) and those of another report on the utility of UA results (Acta Paediatr. 2010;99:581-4), the UA in our case indicates that we should be highly suspicious of a UTI in this child < 2 months old for whom the 2011 guidelines do not directly apply. But remember that these impressive sensitivity and specificity values relate to bacteremic UTI. Whether they apply to nonbacteremic UTI is not known. Likewise, the authors caution that their study design did not allow calculation of positive or negative predictive values – aspects that would clarify things even further.

So we still cannot be more than highly suspicious. Without a positive predictive value, we do not know the odds of this case having a UTI with mathematical precision. The authors do point out that only one of their subjects had a completely normal UA and actually had a bacteremic UTI. If you guessed that it was a gram-positive pathogen, you win the prize. So it seems reasonable to predict that a normal UA has a high specificity for not being a UTI (87.8%), but a positive UA remains only highly suggestive. It is still not clear if a negative UA statistically justifies not submitting the culture of the sterilely obtained urine because we still don’t have a negative predictive value.

Bottom line: The 2011 UTI guidelines provide good advice on diagnosing UTIs.

1. We have more data that evidence of inflammation is essential for diagnosing gram-negative UTIs.

2. We also have more evidence that 50,000 CFU/mL is a good threshold for diagnosing UTIs.

3. It appears that microscopic bacteriuria did not add significantly to the either sensitivity or specificity.

4. And we now have more evidence that these criteria also apply to infants < 2 months of age.

To close the loop on our case, the child’s CSF and blood cultures were negative, but the urine culture revealed > 100,000 CFU/mL of E. coli susceptible to second- and third-generation cephalosporins, ciprofloxacin, and nitrofurantoin, but resistant to trimethoprim-sulfamethoxazole.

Have a great summer and watch for UTIs in your young patients < 90 days old and fever without apparent focus.

Dr. Harrison is professor of pediatrics and pediatric infectious diseases at Children’s Mercy Hospitals and Clinics, Kansas City, Mo. He said he had no relevant financial disclosures. E-mail Dr. Harrison at pdnews@frontlinemedcom.com.