Fever without a source, think UTI first

July 1, 2017

In children aged older than 2 months, the pediatrician is often faced with the scenario of fever with no apparent source. Because symptoms in young patients are nonspecific and reliable urine samples require invasive testing, there can be a delay in both diagnosis and treatment of urinary tract infections (UTIs). This delay may be associated with increased risk of renal scarring and a longer duration symptomology for the young child.

In children aged older than 2 months, the pediatrician is often faced with the scenario of fever with no apparent source. Because symptoms in young patients are nonspecific and reliable urine samples require invasive testing, there can be a delay in both diagnosis and treatment of urinary tract infections (UTIs). This delay may be associated with increased risk of renal scarring and a longer duration symptomology for the young child.1-3

Assessing the patient

When the pediatrician believes that immediate antibiotic therapy is warranted for the febrile infant without an identifiable source, a urine sample for culture should be obtained through either suprapubic aspirate (SPA) or catheterization as part of the workup. Given that antibiotics are commonly used in pediatric practice, failure to do so will sterilize the urine and likely make diagnosis of UTI more difficult or mask the diagnosis altogether.4,5

Whereas the complete management of infants with fever without a source (FWS) is beyond the scope of this article, it has been addressed in older as well as newer clinical practice guidelines.6,7

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The pediatrician also needs to consider the following genitourinary system diagnoses when caring for a patient with fever and no obvious source of infection:

·      Asymptomatic bacteriuria may occur in 1% to 3% of younger children and in 1% of older children. It usually resolves spontaneously without any significant or long-term complications or symptoms.8-11

·      Among children presenting with fever and no source of infection, the risk of UTI is much greater (7%) than the risk of occult bacteremia among infants appropriately immunized (1%).12-14

·      A number of diseases other than UTI have a similar presentation including group A streptococcal infection, appendicitis, and Kawasaki disease.

Urine cultures obtained through catheterization have a sensitivity and specificity of 95% and 99%, respectively, compared with samples obtained though SPA. Bag cultures are found to have an unacceptably high false-positive rate (88%–95% depending on the pretest probability of UTI). Guidelines from the American Academy of Pediatrics (AAP) state that the only utility of a bagged culture is if negative, and that if the pediatrician plans on initiating treatment, urine should be obtained from either a catheterized or SPA specimen.4,5

What is the risk of UTI?

When the pediatrician does not believe that immediate antibiotics are warranted, the guideline allows for different paths based on “low likelihood” of UTI. Although the guideline does not provide a definition or provide specific action steps based on “low likelihood,” it does provide flexibility allowing the pediatrician to set a 1% or 2% threshold of UTI as “low likelihood.”

The overall rate of UTI in young children with FWS is 5%. Young females are more than twice as likely to have a UTI in this scenario compared with boys. The rate of UTI in circumcised boys is 0.2% to 0.4% with uncircumcised boys having a 4-times to 20-times increased risk over that baseline. When another source of infection is identified, the risk of UTI is decreased by 50%.5

Probability of UTI in girls is less than or equal to 1% when not more than 1 risk factor and less than or equal to 2% when no more than 2 risk factors listed in the Table are present.5

In the uncircumcised male when there is FWS, the probability of UTI is greater than 1% at baseline and less than or equal to 2% only if none of the risk factors in the Table are present. In the circumcised male, risk of infection is less than or equal to 1% when no more than 2 risk factors and less than or equal to 2% when no more than 3 risk factors in the Table are present.5

If the infant is deemed not likely to have a UTI depending on the above discussion and the pediatrician’s comfort level, it is reasonable to follow up clinically without further testing. If the pediatrician decides the patient is not a low risk, he or she can proceed with obtaining a urine specimen via SPA or catheterization. Alternatively, a sample may be obtained via another method, and only proceeding to SPA or catheterization if the urinalysis suggests UTI-positive leukocyte esterase, nitrite, pyuria, or bacteriuria.5

NEXT: Laboratory testing and diagnosis

 

Laboratory testing and diagnosis

The 2011 AAP guideline on UTI5 and its reaffirmation in 20164 suggest that UTI is best diagnosed when a combination of bacteriuria (of at least 50,000 colony-forming units (CFUs) and pyuria are present.15

SIGNIFICANT BACTERIURIA

Significant bacteriuria is operationally defined differently by various authors, and methodologic issues preclude saying which mechanism is best for a diagnosis of UTI.16

However growth of uropathogenic bacteria in the following amounts has been considered significant in practice and the pediatric literature for some time:4,5,17,18

·      Clean voided: ≥100,000 CFU/mL.

·      Catheter: ≥50,000 CFU/mL (10,000-50,000 CFU/mL may indicate an increased risk of gram-positive or mixed organisms).19

·      SPA: growth of any uropathogenic bacteria.

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There is also discussion of whether or not cutoffs mentioned above are appropriate because as many as 20% of UTIs might be missed using conventional cutoffs.20 As a result, there is a need for other diagnostic tests.

PYURIA

Pediatricians rely on pyuria to make a diagnosis of UTI. However, as many as 10% of children with a positive urine culture and symptoms of UTI may lack pyuria on urinalysis.3 Pyuria may not be present because an inflammatory response has not yet had time to develop or the particular pathogen (Enterococcus, Klebsiella species, or Pseudomonas aeruginosa) may not as commonly produce pyuria.

In a 2016 study published in Pediatrics, Shaikh and colleagues looked at more than 1181 children diagnosed with UTI at the Children’s Hospital of Pittsburgh of UPMC, Pennsylvania, emergency department (ED) between 2007 and 2013. Pyuria was present in 87% of the children and absent in 13%. This pattern held true when the researchers’ analysis looked at only patients diagnosed via bladder catheterization.

Children diagnosed with an organism other than Escherichia coli were significantly less likely to have pyuria-3 to 5 times less likely when Enterococcus, Klebsiella species, or P aeruginosa was the diagnosis.3 Further, it was unlikely that asymptomatic bacteriuria accounted for these findings. Rather, the more likely explanation for the lack of pyuria is that some uropathogens do not produce a strong inflammatory response.

NEXT: Other tests

 

OTHER TESTS

The pediatrician, however, is not always able to obtain an SPA or catheterized specimen and can only diagnose and treat based off a clean catch or bagged culture. Although there is no simple solution, the pediatrician needs to make the most informed decision possible.

A positive nitrite test significantly increases odds of a UTI, but the sensitivity is reported around 50%.20

Procalcitonin and C-reactive protein (CRP) also have been studied extensively in the diagnosis and management of UTI.21-26 A procalcitonin of >0.5 ng/mL was found to increase odds of UTI by a factor of more than 14.25 It also has been shown to have a sensitivity and specificity of 71% and 72%, respectively, for the diagnosis of acute pyelonephritis as well as 79% and 50%, respectively, for the presence of late renal scars.22

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Procalcitonin performed better than CRP or white blood cell (WBC) counts. Further, procalcitonin testing may provide several additional benefits such as aiding the pediatrician in deciding what further imaging tests are necessary and which antibiotics to use.22 Procalcitonin also has been noted to better identify serious bacterial infections in the blood or nervous system compared with CRP.26

Whereas exact imaging choices in UTI have been debated significantly over the last 15 years, routine dimercaptosuccinic acid (DMSA) screening in UTI suffers a number of criticisms. First, the scans are not equally available across all geographic areas. Second, the scans are expensive, invasive, and they expose children to radiation with the primary outcome being close follow-up. In this scenario, an elevated procalcitonin might be considered in the future as a marker to more strongly consider DMSA scanning. It is also suggested that procalcitonin levels might be useful in determining whether intravenous or oral antibiotics are needed early in the infection.22 Currently an elevated CRP can be used as a marker of acute pyelonephritis in children without another source of infection even if the bacterial counts in the urine are low.20

NEXT: Concluding thoughts

 

Conclusion

Urinary tract infection is sometimes difficult to diagnose in young pediatric patients. However, additional less-invasive testing may aid the pediatrician in identifying patients who are sicker or who need further diagnostics.

REFERENCES

1. Coulthard MG, Lambert HJ, Vernon SJ, Hunter EW, Keir MJ, Matthews JN. Does prompt treatment of urinary tract infection in preschool children prevent renal scarring: mixed retrospective and prospective audits. Arch Dis Child. 2014;99(4):342-347.

2. Shaikh N, Mattoo TK, Keren R, et al. Early antibiotic treatment for pediatric febrile urinary tract infection and renal scarring. JAMA Pediatr. 2016;170(9):848-854.

3. Shaikh N, Shope TR, Hoberman A, Vigliotti A, Kurs-Lasky M, Martin JM. Association between uropathogen and pyuria. Pediatrics. 2016;138(1):e20160087.

4. Subcommittee on Urinary Tract Infection. Reaffirmation of AAP clinical practice guideline: the diagnosis and management of the initial urinary tract infection in febrile infants and young children 2-24 months of age. Pediatrics. 2016;138(6):e20163026.

5. Subcommittee on Urinary Tract Infection; Steering Committee on Quality Improvement and Management; Roberts KB. Urinary tract infection: clinical practice guideline for the diagnosis and management of the initial UTI in febrile infants and children 2 to 24 months. Pediatrics. 2011;128(3):595-610.

6. Baraff LJ, Bass JW, Fleisher GR, et al. Practice guideline for the management of infants and children 0 to 36 months of age with fever without source. Agency for Health Care Policy and Research. Ann Emerg Med. 1993;22(7):1198-1210.

7. Gomez B, Mintegi S, Bressan S, et al; European Group for Validation of the Step-by-Step Approach. Validation of the “Step-by-Step” approach in the management of young febrile infants. Pediatrics. 2016;138(2):e20154381.

8. Wettergren B, Jodal U, Jonasson G. Epidemiology of bacteriuria during the first year of life. Acta Paediatr Scand. 1985;74(6):925-933.

9. Linshaw M. Asymptomatic bacteriuria and vesicoureteral reflux in children. Kidney Int. 1996;50(1):312-329.

10. Lindberg U, Claesson I, Hanson LA, Jodal U. Asymptomatic bacteriuria in schoolgirls. VIII. Clinical course during a 3-year follow-up. J Pediatr. 1978;92(2):194-199.

11. Hansson S, Martinell J, Stokland E, Jodal U. The natural history of bacteriuria in childhood. Infect Dis Clin North Am. 1997;11(3):499-512.

12. Stoll ML, Rubin LG. Incidence of occult bacteremia among highly febrile young children in the era of the pneumococcal conjugate vaccine: a study from a children’s hospital emergency department and urgent care center. Arch Pediatr Adolesc Med. 2004;158(7):671-675.

13. Shaikh N, Morone NE, Bost JE, Farrell MH. Prevalence of urinary tract infection in childhood: a meta-analysis. Pediatr Infect Dis J. 2008;27(4):302-308.

14. Hsiao AL, Chen L, Baker MD. Incidence and predictors of serious bacterial infections among 57- to 180-day-old infants. Pediatrics. 2006;117(5):1695-1701.

15. Roberts KB. Revised AAP guideline on UTI in febrile infants and young children. Am Fam Physician. 2012;86(10):940-946.

16. Doern CD, Richardson SE. Diagnosis of urinary tract infections in children. J Clin Microbiol. 2016;54(9):2233-2242.

17. Kass EH. Asymptomatic infections of the urinary tract. Trans Assoc Am Physicians. 1956;69:56-64.

18. Kass EH. Pyelonephritis and bacteriuria. A major problem in preventive medicine. Ann Intern Med. 1962;56:46-53.

19. Hoberman A, Wald ER, Reynolds EA, Penchansky L, Charron M. Pyuria and bacteriuria in urine specimens obtained by catheter from young children with fever. J Pediatr. 1994;124(4):513-519.

20. Tullus K. Low urinary bacterial counts: do they count? Pediatr Nephrol. 2016;31(2):171-174.

21. Montini G, Tullus K, Hewitt I. Febrile urinary tract infections in children. N Engl J Med. 2011;365(3):239-250.

22. Leroy S, Fernandez-Lopez A, Nikfar R, et al. Association of procalcitonin with acute pyelonephritis and renal scars in pediatric UTI. Pediatrics. 2013;131(5):870-879.

23. Leroy S, Romanello C, Galetto-Lacour A, et al. Procalcitonin is a predictor for high-grade vesicoureteral reflux in children: meta-analysis of individual patient data. J Pediatr. 2011;159(4):644.e4-651.e4.

24. Gervaix A, Galetto-Lacour A, Gueron T, et al. Usefulness of procalcitonin and C-reactive protein rapid tests for the management of children with urinary tract infection. Pediatr Infect Dis J. 2001;20(5):507-511.

25. Mantadakis E, Plessa E, Vouloumanou EK, Karageorgopoulos DE, Chatzimichael A, Falagas ME. Serum procalcitonin for prediction of renal parenchymal involvement in children with urinary tract infections: a meta-analysis of prospective clinical studies. J Pediatr. 2009;155(6):875.e1-881.e1.

26. Gomez B, Bressan S, Mintegi S, et al. Diagnostic value of procalcitonin in well-appearing young febrile infants. Pediatrics. 2012;130(5):815-822.