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Date: Dec 15, 2022

Reference: Mahajan et al. Serious bacterial infections in young febrile infants with positive urinalysis results. Pediatrics. October 2022

Dr. Brian Lee

Guest Skeptic: Dr. Brian Lee is a pediatric emergency medicine attending at the Children’s Hospital of Philadelphia and Assistant Professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania.

Guest Authors:

Dr. Prashant Mahajan

Dr. Prashant Mahajan is a Professor of Emergency Medicine and Pediatrics at the University of Michigan Department of Emergency Medicine in Ann Arbor, Michigan. He is the Vice-Chair for the Department of Emergency medicine and Section chief for Pediatric Emergency Medicine in CS Mott Children’s Hospital. Currently, he is the founding chair of Emergency Medicine Education and Research by Global Experts (EMERGE), a global emergency research network across 17 countries and 23 emergency departments.

Dr. Nathan Kuppermann is a Distinguished Professor of Emergency Medicine and Pediatrics, and the Bo Tomas Brofeldt Endowed Chair of the Department of Emergency Medicine at UC Davis and Associate Dean for Global Health at UC Davis Health. He chaired the first US research network in Pediatric Emergency Medicine (the Pediatric Emergency Medicine Collaborative Research Committee of the American Academy of Pediatrics) then became founding chair of the Pediatric Emergency Care Applied Research Network (PECARN). He also recently completed a term as Chair of the Executive Committee of the global Pediatric Emergency Research Network (PERN).

Dr. Nathan Kuppermann

Both of our guests have received federal funding for their research and played huge roles in establishing multicenter research networks dedicated to improving the care of children across the world.

Case: A 6-week-old girl is brought into the emergency department (ED) for fever of 38.5°C that started four hours prior to presentation. Her parents noted that she has been fussier today and has had feeding a little less than normal, but she’s had no other symptoms. She is otherwise healthy, full-term female who had no pre- or postnatal complications. On exam she is well-appearing, and there are no focal signs of infection. You decide to start by obtaining blood and catheterized urine for testing.

The urinalysis shows 15 WBCs, 2+ leukocyte esterase and positive nitrites. While waiting for the results of the blood tests, you tell the family the news that their child likely has a urinary tract infection. The family asks you, “does this mean we found the source of her fever? Our son also had a fever when he was very young, and he had to get a lumbar puncture? Do we need to do a lumbar puncture for her today?”

Background: Febrile infants ≤ 60 days are at higher risk for serious bacterial infections (SBI) including urinary tract infections (UTI), bacteremia, and meningitis. While UTIs tend to be the most common, we really do not want to miss those infants with bacteremia and meningitis, termed invasive bacterial infections (IBI).

Multiple groups have worked to risk stratify these infants and have listed positive urinalysis as a risk factor for IBI. The SGEM covered the Step-by-Step Approach on SGEM #171 and PECARN Clinical Prediction Rule for Low Risk Febrile Infants on SGEM #296. Recently, the American Academy of Pediatrics (AAP) published guidelines for the management of febrile infants 8-60 days old covered in SGEM #241. In infants 22 days and older, the AAP guidelines state that lumbar puncture may be performed (rather than should) in those with positive urinalysis but normal inflammatory markers.

There is wide practice variability in evaluation febrile infants [1-2]. Prior studies have demonstrated low prevalence of meningitis in infants with positive urinalysis [3,4].  Infants between 29-60 days of age are at a comparatively lower risk, with studies estimating their risk to be 0.2% in those with a positive urinalysis [5-6]. These studies, and others, have also highlighted risks to indiscriminate lumbar puncture, stemming from the relatively high rates of sterile pleocytosis in these infants, occurring in 18-24% of these infants [7,8]. Not surprisingly, these infants undergo longer hospitalizations with more IV antibiotics.

Clinical Question: In a febrile infant ≤60 days with an abnormal urinalysis suggesting a UTI, do they really need a lumbar puncture or blood work?

Reference: Mahajan et al. Serious bacterial infections in young febrile infants with positive urinalysis results. Pediatrics. October 2022

  • Population: Infants ≤ 60 days of age presenting to 26 emergency departments in the PECARN network between March 2011 and April 2019 with temperature ≥38°C who had urine, blood, and cerebrospinal fluid (CSF) testing at the time of visit
    • Excluded: Prematurity (<37 weeks), significant comorbidities, antibiotic use in the preceding 48 hours, and those critically ill (requiring intubation or vasoactive infusions), UA was nor obtained, CSF not obtained and unable to contact parents at 7-day phone follow up.
  • Intervention: Evaluation of invasive bacterial infections in blood and cerebrospinal fluid (CSF)
  • Comparison: None
  • Outcome:
    • Primary Outcome: Prevalence of bacteremia or bacterial meningitis in infants with a positive urinalysis (growth of a pathogen in the urine or CSF culture)
    • Secondary Outcomes: none
  • Type of Study: Secondary analysis of prospective observational study

Authors’ Conclusions: Among noncritical febrile infants ≤ 60 days of age with positive UA results, there were no cases of bacterial meningitis in those aged 29 to 60 days and no cases of bacteremia and/or bacterial meningitis in any low-risk infants based on low-risk blood thresholds in both months of life. These findings can guide lumbar puncture use and other clinical decision making.

Quality Checklist for Observational Study:

  1. Did the study address a clearly focused issue? Yes
  2. Did the authors use an appropriate method to answer their question? Yes
  3. Was the cohort recruited in an acceptable way? Yes
  4. Was the exposure accurately measured to minimize bias? Yes
  5. Was the outcome accurately measured to minimize bias? Yes
  6. Have the authors identified all-important confounding factors? Yes
  7. Was the follow up of subjects complete enough? Yes (excluded if unable to contact at 7 days)
  8. How precise are the results? Unsure.
  9. Do you believe the results? Yes
  10. Can the results be applied to the local population? Unsure 
  11. Do the results of this study fit with other available evidence? Yes
  12. Conflicts of Interest: No

Results: 7,180 infants were included in the analysis. 1090 (15.2%) had positive urinalysis results. Of those with a positive urinalysis, 541 (50.2%) had UTI. For those with a negative urinalysis, only 45 (0.8%) had a UTI. E. Coli was the most common cause of both UTI and bacteremia.

Key Results: Risk of IBI was higher in infants with positive UA, largely driven the prevalence in bacteremia. No infants >28 days with positive UA had bacterial meningitis.

Primary Outcome:

Bacteremia

Overall, 6% of infants with positive UA had bacteremia while only 1% of infants with negative UA had bacteremia.

Bacterial Meningitis

For infants in first month of life, rates of bacterial meningitis did not differ with positive or negative UA. For infants in second month of life, there were no cases of meningitis even with positive UA.

No cases of meningitis in any infants with positive UA results and normal inflammatory markers based on PECARN febrile infant SBI prediction rule, ANC <4,000 cells/mm3 and procalcitonin <0.5 ng/mL.

Listen to the SGEM Podcast for to hear Drs. Mahajan and Kuppermann respond to our 5 nerdy questions.

1) Urinalysis and UTI – We mentioned earlier that only around 50% of those with positive UA truly had a UTI. Why do you think there was such a pronounced discrepancy [9]?

Bacterial Meningitis in those UTI

2) Community Setting: If I am working in a setting where I do not have access to procalcitonin, what laboratory or clinical criteria would you recommend to help risk stratify these infants [10-11]?

3) Quaternary Care Setting: If I am working in a setting where I have access to it all (procalcitonin, CRP, temperature, ANC), is there any benefit in using all of it to risk stratify?

4) Low Prevalence of Bacterial Meningitis and Bacteremia- How do you think the low rates of bacteremia and bacterial meningitis impact the power of your conclusions? Any thoughts on how we can overcome this barrier in future studies?

5) Generalizability- How can we leverage global research networks to help us solve the riddle of the febrile infant? Do you think we will ever get to a point where we find a clinical prediction rule that can be applied everywhere or are there too many shifting variables to consider [12]?

Comment on Authors’ Conclusion Compared to SGEM Conclusion: We agree with the authors’ conclusions.

SGEM Bottom Line: In well-appearing infants ≤60 days with positive UA, continue to perform blood work and blood culture. However, infants with positive UA in the second month of life may not routinely need a lumbar puncture.

Case Resolution: Blood test results demonstrate that procalcitonin is <0.5 ng/dL and the ANC is <4000. You have a conversation with the parents and tell them the results of both the blood and urine testing. You review the risks and benefits of performing a lumbar puncture versus empirically treating with antibiotics. Ultimately, the parents opt to forgo the lumbar puncture and receive empiric antibiotics with the plan to follow up closely with their pediatrician the next day.

Clinical Application: In well-appearing febrile infants >28 days with positive UA and meeting low-risk laboratory criteria, it may not be necessary to perform a lumbar puncture.

What Do I Tell My Patient?

We asked Dr. Kuppermann to tell us what he would say to the patient and family.

BONUS: We asked Dr. Kuppermann what he would do in this case if the either the procalcitonin or ANC came back elevated. Listen to the podcast to hear his answer.

Other FOAMed

Remember to be skeptical of anything you learn, even if you heard it on the Skeptics’ Guide to Emergency Medicine.

References:

  1. Aronson PL, Thurm C, Alpern ER, et al. Variation in care of the febrile young infant <90 days in US pediatric emergency departments. Pediatrics. 2014;134(4):667-677.
  2. Rogers AJ, Kuppermann N, Anders J, et al. Practice variation in the evaluation and disposition of febrile infants ≤60 days of age. J Emerg Med. 2019;56(6):583-591.
  3. Wang ME, Biondi EA, McCulloh RJ, et al. Testing for meningitis in febrile well-appearing young infants with a positive urinalysis. Pediatrics. 2019;144(3):e20183979.
  4. Wallace SS, Brown DN, Cruz AT. Prevalence of concomitant acute bacterial meningitis in neonates with febrile urinary tract infection: a retrospective cross-sectional study. J Pediatr. 2017;184:199-203.
  5. Nugent J, Childers M, Singh-Miller N, Howard R, Allard R, Eberly M. Risk of meningitis in infants aged 29 to 90 days with urinary tract infection: a systematic review and meta-analysis. J Pediatr. 2019;212:102-110.e5.
  6. Thomson J, Cruz AT, Nigrovic LE, et al. Concomitant bacterial meningitis in infants with urinary tract infection. Pediatr Infect Dis J. 2017;36(9):908-910.
  7. Schnadower D, Kuppermann N, Macias CG et al. “Sterile Cerebrospinal Fluid Pleocytosis in Young Febrile Infants with Urinary Tract Infections.” JAMA Pediatrics. 2011;165(7)635-641.
  8. Shah SS, Zorc JJ, Levine DA, Platt SL, Kuppermann N. “Sterile Cerebrospinal Fluid Pleocytosis in Young Infants with Urinary Tract Infections.” J Pediatr. 2008;154(2):290-292.
  9. Tzimenatos L, Mahajan P, Dayan PS, et al. Accuracy of the urinalysis for urinary tract infections in febrile infants 60 days and younger. Pediatrics. 2018;141(2):e20173068..
  10. Pantell RH, Roberts KB, Adams WG, et al. Evaluation and management of well-appearing febrile infants 8 to 60 days old. Pediatrics. 2021;148(2):e2021052228.
  11. Burstein B, Alathari N, Papenburg J. Guideline-based risk stratification for febrile young infants without procalcitonin measurement. Pediatrics. 2022;149(6):e2021056028.
  12. Velasco R, Gomez B, Benito J, Mintegi S. Accuracy of PECARN rule for predicting serious bacterial infection in infants with fever without a source. Arch Dis Child. 2021;106(2):143-148.