Neutropenia/procalcitonin

Introduction

Each year, U.S. emergency departments face the challenge of evaluating around 200,000 infants aged 60 days and younger, with 8-10% having serious bacterial infections, including the serious categories of bacteremia and bacterial meningitis. The PECARN febrile infant working group previously derived a clinical prediction rule to identify febrile infants at low risk for serious bacterial infections (SBI) [1]. The group now aims to refine the assessment and management of these vulnerable patients through advanced clinical prediction rules and innovative biomarkers like serum procalcitonin (PCT) to identify children with invasive bacterial infections (IBI) [2].”

Study question

How does the presence of leukopenia and varying levels of absolute neutrophil count (ANC) affect the frequency of SBIs and IBIs in non-critically ill febrile infants younger than 60 days, especially when analyzed with and without the inclusion of PCT levels?

Study design

This is a secondary analysis of a prospective observational cohort involving 7,407 non-critically ill, febrile infants aged 60 days and younger. These infants were assessed at one of 26 pediatric emergency departments (EDs) within the Pediatric Emergency Care Applied Research Network (PECARN) during two distinct periods from December 2008 to May 2013 and June 2016 to April 2019. The infants were included if they had a documented fever of at least 38°C and underwent evaluations for SBIs. These involved at least blood and urine cultures among other screening tests. The analysis focused on the relationship between WBC counts, ANC, and PCT levels across varying thresholds to determine their association with the occurrence of SBIs and IBIs. The ultimate goal was to evaluate the impact of PCT on the associations of WBC and ANC with SBIs and IBIs.

Definitions

  • Serious bacterial illness: Bacterial UTI, meningitis, and/or bacteremia
  • Invasive bacterial illness (subset of serious bacterial illness): Bacteremia and/or bacterial meningitis
  • Leukopenia: Low serum WBC count <5,000 cells/μL
  • Neutropenia: Absolute neutrophil count <1,000 cells/μL

Results

Study Population Details

Out of 7,407 infants originally enrolled, 6,865 (93%) were included in the secondary analysis. Two-thirds were in their second month of life. SBIs and IBIs were identified in 671 (9.8%) and 150 (2.2%) infants, respectively. Only 45% had PCT measured

Infection rates and biomarkers

Breakdown of SBIs (671 infants)

  • UTI only: 517 (77%)
  • Bacteremia without meningitis: 111 (16.5%)
  • Bacterial meningitis without bacteremia: 18 (2.6%)
  • Both bacteremia and meningitis: 19 (2.8%)

Lab Testing to Risk Stratify

  • Leukopenia:
    • Low WBC counts (<2500 cells/μL) significantly increased the odds of IBIs and SBIs, with additional risk factors including higher body temperature, positive urine analysis (UA), and elevated ANC.
    • However, there were no cases of IBIs in patients with low WBC but normal PCT levels.
  • Procalcitonin and ANC:
    • Elevated PCT levels (>0.5 ng/mL) and ANC >4000 cells/μL were strongly associated with higher risks of SBIs and SBIs.
    • No IBIs are found in infants with low WBC/ANCs if the PCT was normal (≤0.5 ng/mL).

Additional Findings: Although our analysis highlighted significant PCT elevations in patients with SBIs and leukopenia, one patient with Pseudomonas aeruginosa UTI was initially missed by our clinical prediction rules but had severe leukopenia.

Caution

There were very few patients who had leukopenia or neutropenia even in this large multicenter cohort, so approach our results with caution. Also only 45% of patients had PCT measured. PCT is an important biomarker to identify SBI/IBI when available but many hospitals still do not have the test available. Nevertheless, if PCT is available, there were no patients with IBIs who had leukopenia and normal PCT levels.

Take home messages

  • If available, incorporate procalcitonin in your risk stratification of pediatric patients for a serious and/or invasive bacterial illness.
  • If procalcitonin is not available, encourage your hospital administration and laboratory staff to add it to your testing options.

“Although there is an association between leukopenia and IBIs in this study, if the PCT was normal there were no patients with leukopenia who had IBIs. This further highlights the importance of having PCT available to evaluate these young febrile infants.”

Dr. Nathan Kuppermann, senior investigator
Professor of Emergency Medicine and Pediatrics, University of California Davis School of Medicine

References

  1. Kuppermann N, Dayan PS, Levine DA, Vitale M, Tzimenatos L, Tunik MG, Saunders M, Ruddy RM, Roosevelt G, Rogers AJ, Powell EC, Nigrovic LE, Muenzer J, Linakis JG, Grisanti K, Jaffe DM, Hoyle JD Jr, Greenberg R, Gattu R, Cruz AT, Crain EF, Cohen DM, Brayer A, Borgialli D, Bonsu B, Browne L, Blumberg S, Bennett JE, Atabaki SM, Anders J, Alpern ER, Miller B, Casper TC, Dean JM, Ramilo O, Mahajan P; Febrile Infant Working Group of the Pediatric Emergency Care Applied Research Network (PECARN). A Clinical Prediction Rule to Identify Febrile Infants 60 Days and Younger at Low Risk for Serious Bacterial Infections. JAMA Pediatr. 2019 Apr 1;173(4):342-351. doi: 10.1001/jamapediatrics.2018.5501. PMID: 30776077; PMCID: PMC6450281.
  2. Krack AT, Eckerle M, Mahajan P, Ramilo O, VanBuren JM, Banks RK, Casper TC, Schnadower D, Kuppermann N; Febrile Infant Working Group of the Pediatric Emergency Care Applied Research Network (PECARN). Leukopenia, neutropenia, and procalcitonin levels in young febrile infants with invasive bacterial infections. Acad Emerg Med. 2024 Apr 25. doi: 10.1111/acem.14921. Epub ahead of print. PMID: 38661246.

Author

  • Julia Magaña, MD
    Julia Magaña, MDTwitter: @julmaganaAssociate Professor of Emergency Medicine-Pediatrics Emergency Medicine, UC Davis Child Protection Team, EM Pulse Podcast™ Host