The Physician Doth LP Too Much, Methinks

This is a guest post by Brian Lee and Dennis Ren:

“The Physician Doth LP Too Much, Methinks”

It seems only fitting that, given we are talking about performing lumbar punctures on well-appearing febrile infants again, that we start with another modern adaptation of Shakespeare. We covered the initial PECARN Febrile Infant Study “To LP or not to LP” a while ago. Since that time we also covered the guidelines on the management of well-appearing febrile infants from the American Academy of Pediatrics.

Tides are shifting as the age threshold for performing a full sepsis workup (blood, urine, cerebrospinal fluid) on a well-appearing febrile infant gradually decreases and decisions to pursue lumbar punctures are aided by the results of inflammatory markers.

Today we bring you the case of a well-appearing febrile infant with a positive urinalysis.

What’s the big deal?

Febrile infants less than or equal to 60 days of age are at higher risk for serious bacterial infections (SBI) including urinary tract infections (UTI), bacteremia, and meningitis [1-2]. However, prior studies have demonstrated a low prevalence of meningitis in infants with positive urinalysis, especially in infants between 29-60 days of life (0.2%) [3-6]. These studies, and others, have also highlighted risks to indiscriminate lumbar puncture, stemming from the relatively high rates of sterile pleocytosis, occurring in 18-24%[7,8]. Not surprisingly, these infants undergo longer hospitalizations with more IV antibiotics.

The paper

Mahajan P, VanBuren JM, Tzimenatos L, et al; Pediatric Emergency Care Applied Research Network (PECARN). Serious Bacterial Infections in Young Febrile Infants With Positive Urinalysis Results. Pediatrics. 2022 Oct 1;150(4):e2021055633. doi: 10.1542/peds.2021-055633. PMID: 36097858

The methods

This was a secondary analysis of a prospective observational study [9].

Patients: They included 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. Infants were excluded if they were born premature (<37 weeks), had significant comorbidities, reported antibiotic use in the preceding 48 hours, and those presenting critically ill (requiring intubation or vasoactive infusions). Infants were also excluded if UA or CSF were not obtained, or they were unable to contact parents at 7-day phone follow up.

Outcomes: The primary outcome was the prevalence of bacteremia or bacterial meningitis in infants with a positive urinalysis (growth of a pathogen in the urine or CSF culture). There were no secondary outcomes.

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. E. Coli was the most common cause of both UTI and bacteremia.

In terms of their primary outcome, 6% of infants with a positive UA had bacteremia, while only 1% of infants with a negative UA had bacteremia, with infants </= 28 days having higher rates of bacteremia as compared to infants >28 days (Table 1). In the first month of life, the rates of bacterial meningitis did not differ between those with positive and those with a negative urinalysis (Table 2).

Things get interesting in the second month of life. In the second month of life, there were no cases of meningitis, even in the 697 infants with a positive UA. Equally important, there were no cases of bacteremia and/or bacterial meningitis in any of the 148 infants with a positive UA, but normal inflammatory markers as defined by the PECARN low risk febrile infant prediction rule (absolute neutrophil count (ANC) <4,000 cells/mm³ and procalcitonin (PCT) <0.5 ng/mL).

Table 1: Prevalence of Bacteremia in Infants With and Without Positive Urinalysis

Age	UA (+) % Bacteremia	UA (-) % Bacteremia	Difference (95% CI)
All	5.8	1.1	4.7 (3.3 to 6.1)
≤ 28 days	8.9	1.9	7.1 (4.2 to 10.0)
22 – 28 days	2.5	0.9	1.7 (-1.3 to 4.6)
>28 days	4.0	0.8	3.2 (1.7 to 4.7)

Table 2: Prevalence of Bacterial Meningitis in Infants With and Without Positive Urinalysis

Age	UA (+) % Meningitis	UA (-) % Meningitis	Difference (95% CI)
All	0.4	0.6	-0.2 (-0.6 to 0.2)
≤ 28 days	1.0	1.3	-0.3 (-1.4 to 0.8)
22 – 28 days	0.8	0.5	0.3 (-1.4 to 2.0)
>28 days	0	0.2	-0.2 (-0.4 to -0.1)

Our thoughts

Not surprisingly, infants </= 60 days with a positive urinalysis demonstrated higher rates of bacteremia, supporting the current practice of obtaining a blood culture in this population. With respect to meningitis, the presence or absence of a positive urinalysis did not alter the risk of bacterial meningitis in the first month of life. In older infants (>28 days), the authors report no cases of bacterial meningitis in patients with a positive urinalysis. While certainly reassuring, the low prevalence of bacterial meningitis in this age group is blessing and a curse. A recent meta-analysis reported that infants with a positive urinalysis had similar rates of meningitis to those with negative urinalysis [13]. Ultimately, these finding further supports the most recent American Academy of Pediatrics guideline suggesting that not all infants >28 days old require CSF analysis and that the decision to perform lumbar puncture in this age group should be made using shared decision making with the family.

Equally important, when looking at a subset of patients with negative inflammatory markers as defined by the PECARN febrile infant clinical decision rule (ANC <4,000 cells/mm³ and PCT <0.5 ng/mL), there were also no cases of bacteremia or bacterial meningitis.

With regards to PCT, we recognize that not all emergency departments may have access to this test or timely results [10]. There is some evidence that PCT is more accurate in detecting invasive bacterial infections in infants compared to CRP [11]. (Justin edit: Although I think the evidence supporting procalcitonin is not very compelling.) Facilities may use alternate means to risk stratify these infants [11], recognizing that most of these studies are single-center or retrospective.

The bottom line

Overall, this study is consistent with the growing body of evidence recommending a less aggressive septic workups (urine, blood, and cerebrospinal fluid analysis) in well-appearing febrile infants.

In well-appearing febrile infants with positive urinalysis:

• Under 28 days: perform full septic workup (including lumbar puncture)
• >28 days: can likely avoid lumbar puncture as prevalence of bacterial meningitis is low
• >28 days with negative inflammatory markers (PCT and ANC): may consider discharge home with treatment for UTI
• >28 days with a positive inflammatory marker: treat with empiric antibiotics and admit to the hospital as there is still risk of bacteremia.

Now what about well-appearing febrile infants with negative urinalysis?

The previous post on updated AAP guidelines for management of well-appearing febrile infants demonstrates that there is ample room for shared decision making. We can acknowledge that there are multiple ways of interpreting the fact that 0.2% of infants >28 days in this study had bacterial meningitis. Some clinicians may find this a tolerable risk and defer LP after discussion with the family. Other clinicians will find this risk intolerable (1 in 500 patients) as we often screen for and treat diseases with much lower risk. As in many situations with evidence-based medicine, the answer is “it all depends.”

Justin edit: When I look at this data, I see an identical rate of meningitis in patients with positive and negative urinalyses. I think people are going to focus on the non-significant difference in the group of patients over 28 days old, but 0/697 is statistically identical to 1/500, and so I don’t think it can overweigh the larger dataset suggesting that meningitis diagnosis is not correlated with UA result.

Other FOAMed

The SGEM: Lumbar Punctures in Febrile Infants with Positive Urinalysis-It’s just Overkill

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. Mahajan P, Kuppermann N, Mejias A et al; Pediatric Emergency Care Applied Research Network (PECARN). Association of RNA Biosignatures With Bacterial Infections in Febrile Infants Aged 60 Days or Younger. JAMA. 2016 Aug 23-30;316(8):846-57. Doi:10.1001/jama.2016.9207. Erratum in: JAMA. 2016 Nov 8;316(18):1924. PMID: 27552618
10. Pandey M, Lyttle MD, Cathie K, et al. Point-of-care testing in Paediatric settings in the UK and Ireland: a cross-sectional study. BMC Emerg Med. 2022;22(1):6.
11. Milcent K et al. Use of Procalcitonin Assays to Predict Serious Bacterial Infection in Young Febrile Infants. JAMA Pediatr. 2016 Jan;170(1):62-9. doi: 10.1001/jamapediatrics.2015.3210. Erratum in: JAMA Pediatr. 2016 Jun 1;170(6):624. PMID: 26595253.
12. Kuppermann N, Mahajan P, Dayan PS. Fever, Absolute Neutrophil Count, Procalcitonin, and the AAP Febrile Infant Guidelines. Pediatrics. 2023 Jan 4:e2022059862. doi: 10.1542/peds.2022-059862. Epub ahead of print. PMID: 36597701.
13. Burstein B, Sabhaney V, Bone JN, Doan Q, Mansouri FF, Meckler GD. Prevalence of Bacterial Meningitis Among Febrile Infants Aged 29-60 Days With Positive Urinalysis Results: A Systematic Review and Meta-analysis. JAMA Netw Open. 2021;4(5):e214544. doi:10.1001/jamanetworkopen.2021.4544