Two current risk-stratification strategies1,2  and a recent guideline3  identify febrile young infants at low risk of invasive bacterial infections (IBIs; bacteremia and bacterial meningitis) using inflammatory markers (IMs) in different combinations of low-risk thresholds. These strategies were derived before the coronavirus disease 2019 (COVID-19) pandemic. Given the ongoing circulation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), knowledge of the IM values among febrile infants with COVID-19 is needed to understand the reliability of risk-stratification strategies for IBI in the current era. In this study, we compared serum IM values in a large prospective cohort of febrile infants ≤90 days of age with and without SARS-CoV-2 infections.

This was a secondary analysis of the global Pediatric Emergency Research Network (PERN)4  and Pediatric Emergency Research Canada (PERC)5  COVID-19 cohort studies. The parent studies were conducted in 48 emergency departments (EDs) in 10 countries (PERN; March 2020 to June 2021)4  and 14 Canadian EDs (PERC; August 2020 to February 2022).5  Both cohorts included infants tested for suspected SARS-CoV-2 infection using molecular approaches based on exposure or symptoms (95% symptomatic).4  All infants ≤90 days of age presenting with temperatures of ≥38.0°C in the ED or measured in the preceding 24 hours were included. Final infection outcomes were ascertained by culture results (65% with blood cultures performed), a 14-day telephone follow-up, and a medical record review performed a minimum of 30 days after the index ED visit. Bacteremia and bacterial meningitis were categorized per current definitions, and cultures growing contaminant bacteria were considered negative.3  Infants were classified as low-risk for IBI by using IM threshold combinations determined by recent risk-stratification strategies: procalcitonin ≤0.5ng/mL, C-reactive protein (CRP) ≤20.0mg/L, and absolute neutrophil count (ANC) ≤10 000/uL (Step-by-Step method);1  procalcitonin ≤0.5ng/mL and ANC ≤4000/uL (Pediatric Emergency Care Applied Research Network [PECARN] prediction rule);2  procalcitonin ≤0.5ng/mL and CRP ≤20.0mg/L (American Academy of Pediatrics [AAP] recommendation);3  CRP ≤20.0mg/L and ANC ≤5200/uL (AAP recommendation when procalcitonin unavailable).3  We evaluated the diagnostic accuracy (specificities, sensitivities, and negative predictive values [NPVs]) of serum IMs for IBIs among infants with and without SARS-CoV-2 infections. This study received ethics approval, and informed consent was obtained per local requirements.

We analyzed 563 infants (Table 1); 314 (55.8%) were ≤60 days of age, 300 (53.2%) were SARS-CoV-2-positive, and 19 (3.4%) had IBIs (11 bacteremia alone, 6 bacterial meningitis alone, 2 bacteremia and bacterial meningitis). Fewer SARS-CoV-2-positive infants had IBIs than test-negative infants (1.0% and 6.1%, respectively, P < .001). The diagnostic accuracy of specific IM thresholds alone and in combination are shown in Table 2. SARS-CoV-2-positive infants were less frequently misclassified as low-risk for IBI by all individual IMs and IM combinations. For all individual IMs, specificities for IBI were higher among infants with SARS-CoV-2 infections, ranging from 0.84 (95% confidence interval [CI] 0.79–0.89) using an ANC of ≤4000/uL alone to 0.99 (95% CI 0.96–1.00) using an ANC of ≤10 000/uL alone. Specificities for IBI were higher for all IM combinations among SARS-CoV-2-positive infants, and highest using the AAP-recommended combination of procalcitonin with CRP (0.97; 95% CI 0.88–1.00). Similarly, NPVs were higher for ruling out IBI among SARS-CoV-2-positive infants for all IMs, individually and using CRP and ANC together. Only 3 infants with SARS-CoV-2 infections had IBIs (1%; 3/300) and none underwent procalcitonin testing, limiting the reliability of the sensitivity estimates. The test characteristics of all IMs were similar when restricted to infants ≤60 days of age (Supplemental Table 3).

TABLE 1

Characteristics of Included Infants, n (%)

Study Population (n = 563)SARS-CoV-2-Positive (n = 300)SARS-CoV-2-Negative (n = 263)
Demographic information 
 0–28 d 41 (7.3) 22 (7.3) 19 (7.2) 
 29–60 d 273 (48.5) 139 (46.3) 134 (51) 
 61–90 d 249 (44.2) 139 (46.3) 110 (41.8) 
Country 
 Canada 317 (56.3) 157 (52.3) 160 (60.8) 
 United States 168 (29.8) 96 (32) 72 (27.4) 
 Australia 1 (0.2) 0 (0) 1 (0.4) 
 New Zealand 2 (0.4) 0 (0) 2 (0.8) 
 Spain 24 (4.3) 10 (3.3) 14 (5.3) 
 Argentina 5 (0.9) 3 (1.0) 2 (0.8) 
 Costa Rica 41 (7.3) 29 (9.7) 12 (4.6) 
 Paraguay 2 (0.4) 2 (0.7) 0 (0) 
 Italy 3 (0.5) 3 (1.0) 0 (0) 
General appearance 
 Well-appearing 420 (74.6) 231 (77.0) 189 (71.9) 
 Mildly ill 49 (8.7) 24 (8.0) 25 (9.5) 
 Moderately ill 11 (2.0) 3 (1.0) 8 (3.0) 
 Severely ill 0 (0) 0 (0) 0 (0) 
 Not available 83 (14.7) 42 (14.0) 41 (15.6) 
Disposition and outcome 
 Admitted from ED 233 (41.4) 107 (35.7) 126 (47.9) 
 Admitted to intensive care 12 (2.1) 3 (1.0) 9 (3.4) 
 Death 0 (0) 0 (0) 0 (0) 
 IBI (ie, bacteremia or bacterial meningitis) 19 (3.4) 3 (1.0) 16 (6.1) 
IM testing 
 Procalcitonin 122 (21.7) 69 (23.0) 53 (20.2) 
 CRP 313 (55.6) 170 (56.7) 143 (54.4) 
 ANC 419 (74.4) 222 (74.0) 197 (74.9) 
 Procalcitonin + CRP + ANC 95 (16.9) 56 (18.7) 39 (14.8) 
 Procalcitonin + ANC 119 (21.1) 67 (22.3) 52 (19.8) 
 Procalcitonin + CRP 97 (17.2) 57 (19.0) 40 (15.2) 
 CRP + ANC 303 (53.8) 163 (54.3) 140 (53.2) 
Study Population (n = 563)SARS-CoV-2-Positive (n = 300)SARS-CoV-2-Negative (n = 263)
Demographic information 
 0–28 d 41 (7.3) 22 (7.3) 19 (7.2) 
 29–60 d 273 (48.5) 139 (46.3) 134 (51) 
 61–90 d 249 (44.2) 139 (46.3) 110 (41.8) 
Country 
 Canada 317 (56.3) 157 (52.3) 160 (60.8) 
 United States 168 (29.8) 96 (32) 72 (27.4) 
 Australia 1 (0.2) 0 (0) 1 (0.4) 
 New Zealand 2 (0.4) 0 (0) 2 (0.8) 
 Spain 24 (4.3) 10 (3.3) 14 (5.3) 
 Argentina 5 (0.9) 3 (1.0) 2 (0.8) 
 Costa Rica 41 (7.3) 29 (9.7) 12 (4.6) 
 Paraguay 2 (0.4) 2 (0.7) 0 (0) 
 Italy 3 (0.5) 3 (1.0) 0 (0) 
General appearance 
 Well-appearing 420 (74.6) 231 (77.0) 189 (71.9) 
 Mildly ill 49 (8.7) 24 (8.0) 25 (9.5) 
 Moderately ill 11 (2.0) 3 (1.0) 8 (3.0) 
 Severely ill 0 (0) 0 (0) 0 (0) 
 Not available 83 (14.7) 42 (14.0) 41 (15.6) 
Disposition and outcome 
 Admitted from ED 233 (41.4) 107 (35.7) 126 (47.9) 
 Admitted to intensive care 12 (2.1) 3 (1.0) 9 (3.4) 
 Death 0 (0) 0 (0) 0 (0) 
 IBI (ie, bacteremia or bacterial meningitis) 19 (3.4) 3 (1.0) 16 (6.1) 
IM testing 
 Procalcitonin 122 (21.7) 69 (23.0) 53 (20.2) 
 CRP 313 (55.6) 170 (56.7) 143 (54.4) 
 ANC 419 (74.4) 222 (74.0) 197 (74.9) 
 Procalcitonin + CRP + ANC 95 (16.9) 56 (18.7) 39 (14.8) 
 Procalcitonin + ANC 119 (21.1) 67 (22.3) 52 (19.8) 
 Procalcitonin + CRP 97 (17.2) 57 (19.0) 40 (15.2) 
 CRP + ANC 303 (53.8) 163 (54.3) 140 (53.2) 
TABLE 2

Diagnostic Accuracy of Serum IMs Alone and in Combination for Identifying Febrile Infants With IBIs, With and Without SARS-CoV-2 Infections

Misclassified as Low-Risk, n/N (%)Specificity for IBI, (95% CI)Sensitivity for IBI, (95% CI)Negative Predictive Value for IBI, (95% CI)
OverallSARS-CoV-2-positiveSARS-CoV-2-negativeOverallSARS-CoV-2-positiveSARS-CoV-2-negativeOverallSARS-CoV-2-positiveSARS-CoV-2-negativeOverallSARS-CoV-2-positiveSARS-CoV-2-negative
Individual serum IMs 
 Procalcitonin ≤0.5 ng/mLa 2/106 (1.9%) 0/68 (0%) 2/38 (5.3%) 0.88 (0.81–0.93) 0.99 (0.92–1.00) 0.74 (0.59–0.85) 0.50 (0.07–0.93) N/A* 0.50 (0.07–0.93) 0.98 (0.93–1.00) N/A* 0.95 (0.82–0.99) 
 CRP ≤20 mg/Lb 6/243 (2.5%) 2/156 (1.3%) 4/87 (4.6%) 0.80 (0.75–0.85) 0.92 (0.87–0.96) 0.64 (0.55–0.73) 0.65 (0.38–0.86) 0.33 (0.01–0.91) 0.71 (0.42–0.92) 0.98 (0.95–0.99) 0.99 (0.95–1.00) 0.95 (0.89–0.99) 
 ANC ≤4000 cells/uLc 3/303 (1.0%) 1/185 (0.5%) 2/118 (1.7%) 0.75 (0.70–0.79) 0.84 (0.79–0.89) 0.64 (0.56–0.71) 0.83 (0.59–0.96) 0.67 (0.09–0.99) 0.87 (0.60–0.98) 0.99 (0.97–1.00) 1.00 (0.97–1.00) 0.98 (0.94–1.00) 
 ANC ≤5200 cells/uLc 3/336 (0.9%) 1/199 (0.5%) 2/137 (1.5%) 0.83 (0.79–0.87) 0.90 (0.86–0.94) 0.74 (0.67–0.80) 0.83 (0.59–0.96) 0.67 (0.09–0.99) 0.87 (0.60–0.98) 0.99 (0.97–1.00) 1.00 (0.97–1.00) 0.99 (0.95–1.00) 
 ANC ≤10 000 cells/uLc 8/394 (2.0%) 2/218 (0.9%) 6/176 (3.4%) 0.96 (0.94–0.98) 0.99 (0.96–1.00) 0.93 (0.89–0.97) 0.56 (0.31–0.79) 0.33 (0.01–0.91) 0.60 (0.32–0.84) 0.98 (0.96–0.99) 0.99 (0.97–1.00) 0.97 (0.93–0.99) 
Serum IMs in combination 
 Step-by-Step method:d Procalcitonin <0.5 ng/mL, CRP ≤20 mg/L, and ANC ≤10 000 cells/uL 0/71 (0%) 0/52 (0%) 0/19 (0%) 0.77 (0.67–0.85) 0.93 (0.83–0.98) 0.53 (0.36–0.70) 1.00 (0.29–1.00) N/A* 1.00 (0.29–1.00) 1.00 (0.95–1.00) N/A* 1.00 (0.82–1.00) 
 PECARN prediction rule:e Procalcitonin ≤0.5 ng/mL and ANC ≤4000 cells/uL 0/79 (0%) 0/56 (0%) 0/23 (0%) 0.68 (0.59–0.76) 0.84 (0.73–0.92) 0.47 (0.33–0.62) 1.00 (0.29–1.00) N/A* 1.00 (0.29–1.00) 1.00 (0.95–1.00) N/A* 1.00 (085–1.00) 
 AAP recommendation (with procalcitonin):f  Procalcitonin ≤0.5 ng/mL and CRP ≤20 mg/L 1/75 (1.3%) 0/55 (0%) 1/20 (5.0%) 0.80 (0.70–0.87) 0.97 (0.88–1.00) 0.53 (0.36–0.70) 0.75 (0.19–0.99) N/A* 0.75 (0.19–0.99) 0.99 (0.93–1.00) N/A* 0.95 (0.75–1.00) 
 AAP recommendation (without procalcitonin):gCRP ≤20mg/L and ANC ≤5200 cells/uL 2/207 (1.0%) 1/134 (0.7%) 1/73 (1.4%) 0.71 (0.66–0.77) 0.83 (0.76–0.89) 0.57 (0.48–0.66) 0.88 (0.62–0.98) 0.67 (0.09–0.99) 0.92 (0.64–1.00) 0.99 (0.97–1.00) 0.99 (0.96–1.00) 0.99 (0.93–1.00) 
Misclassified as Low-Risk, n/N (%)Specificity for IBI, (95% CI)Sensitivity for IBI, (95% CI)Negative Predictive Value for IBI, (95% CI)
OverallSARS-CoV-2-positiveSARS-CoV-2-negativeOverallSARS-CoV-2-positiveSARS-CoV-2-negativeOverallSARS-CoV-2-positiveSARS-CoV-2-negativeOverallSARS-CoV-2-positiveSARS-CoV-2-negative
Individual serum IMs 
 Procalcitonin ≤0.5 ng/mLa 2/106 (1.9%) 0/68 (0%) 2/38 (5.3%) 0.88 (0.81–0.93) 0.99 (0.92–1.00) 0.74 (0.59–0.85) 0.50 (0.07–0.93) N/A* 0.50 (0.07–0.93) 0.98 (0.93–1.00) N/A* 0.95 (0.82–0.99) 
 CRP ≤20 mg/Lb 6/243 (2.5%) 2/156 (1.3%) 4/87 (4.6%) 0.80 (0.75–0.85) 0.92 (0.87–0.96) 0.64 (0.55–0.73) 0.65 (0.38–0.86) 0.33 (0.01–0.91) 0.71 (0.42–0.92) 0.98 (0.95–0.99) 0.99 (0.95–1.00) 0.95 (0.89–0.99) 
 ANC ≤4000 cells/uLc 3/303 (1.0%) 1/185 (0.5%) 2/118 (1.7%) 0.75 (0.70–0.79) 0.84 (0.79–0.89) 0.64 (0.56–0.71) 0.83 (0.59–0.96) 0.67 (0.09–0.99) 0.87 (0.60–0.98) 0.99 (0.97–1.00) 1.00 (0.97–1.00) 0.98 (0.94–1.00) 
 ANC ≤5200 cells/uLc 3/336 (0.9%) 1/199 (0.5%) 2/137 (1.5%) 0.83 (0.79–0.87) 0.90 (0.86–0.94) 0.74 (0.67–0.80) 0.83 (0.59–0.96) 0.67 (0.09–0.99) 0.87 (0.60–0.98) 0.99 (0.97–1.00) 1.00 (0.97–1.00) 0.99 (0.95–1.00) 
 ANC ≤10 000 cells/uLc 8/394 (2.0%) 2/218 (0.9%) 6/176 (3.4%) 0.96 (0.94–0.98) 0.99 (0.96–1.00) 0.93 (0.89–0.97) 0.56 (0.31–0.79) 0.33 (0.01–0.91) 0.60 (0.32–0.84) 0.98 (0.96–0.99) 0.99 (0.97–1.00) 0.97 (0.93–0.99) 
Serum IMs in combination 
 Step-by-Step method:d Procalcitonin <0.5 ng/mL, CRP ≤20 mg/L, and ANC ≤10 000 cells/uL 0/71 (0%) 0/52 (0%) 0/19 (0%) 0.77 (0.67–0.85) 0.93 (0.83–0.98) 0.53 (0.36–0.70) 1.00 (0.29–1.00) N/A* 1.00 (0.29–1.00) 1.00 (0.95–1.00) N/A* 1.00 (0.82–1.00) 
 PECARN prediction rule:e Procalcitonin ≤0.5 ng/mL and ANC ≤4000 cells/uL 0/79 (0%) 0/56 (0%) 0/23 (0%) 0.68 (0.59–0.76) 0.84 (0.73–0.92) 0.47 (0.33–0.62) 1.00 (0.29–1.00) N/A* 1.00 (0.29–1.00) 1.00 (0.95–1.00) N/A* 1.00 (085–1.00) 
 AAP recommendation (with procalcitonin):f  Procalcitonin ≤0.5 ng/mL and CRP ≤20 mg/L 1/75 (1.3%) 0/55 (0%) 1/20 (5.0%) 0.80 (0.70–0.87) 0.97 (0.88–1.00) 0.53 (0.36–0.70) 0.75 (0.19–0.99) N/A* 0.75 (0.19–0.99) 0.99 (0.93–1.00) N/A* 0.95 (0.75–1.00) 
 AAP recommendation (without procalcitonin):gCRP ≤20mg/L and ANC ≤5200 cells/uL 2/207 (1.0%) 1/134 (0.7%) 1/73 (1.4%) 0.71 (0.66–0.77) 0.83 (0.76–0.89) 0.57 (0.48–0.66) 0.88 (0.62–0.98) 0.67 (0.09–0.99) 0.92 (0.64–1.00) 0.99 (0.97–1.00) 0.99 (0.96–1.00) 0.99 (0.93–1.00) 
a

Procalcitonin results were available for 122 infants (4 IBIs).

b

CRP results were available for 313 infants (17 IBIs).

c

ANC results were available for 419 infants (18 IBIs).

d

Procalcitonin + CRP + ANC results were available for 95 infants (3 IBIs).

e

Procalcitonin + ANC results were available for 119 infants (3 IBIs).

f

Procalcitonin + CRP results were available for 97 infants (4 IBIs).

g

CRP + ANC results were available for 303 infants (16 IBIs).

*

Concomitant SARS-CoV-2 infections and IBIs n = 3, none with procalcitonin results available (1 Staphylococcus epidermidis bacteremia and meningitis, 1 Escherichia coli urosepsis, and 1 Pseudomonas aeruginosa urosepsis).

In a cohort of febrile infants ≤90 days of age tested for SARS-CoV-2 in EDs globally, those with SARS-CoV-2 infections were less frequently misclassified as low-risk for IBI by current risk-stratification strategies than SARS-CoV-2-negative infants. Specificity for IBIs was higher among SARS-CoV-2-positive infants for all strategies (range 0.83–0.97) and higher than reported before the pandemic (range 0.47–0.60).1,2,6  This suggests that infants with SARS-CoV-2 infections without IBIs will infrequently be misclassified. Recent studies of febrile infants 8 to 60 days of age have revealed a low overall prevalence of IBIs among SARS-CoV-2-infected infants7,8  with normal and abnormal IMs (2/2248 [<0.1%] and 8/436 [1.8%], respectively).8  Taken together with the high NPVs seen in this study, IBIs remain unlikely when IMs are below current risk-stratification thresholds among SARS-CoV-2-positive infants.

This study had only 19 infants with IBIs, and none of the 3 SARS-CoV-2-positive infants with IBIs had procalcitonin testing. This limited the precision of sensitivity estimates for IBIs in general among SARS-CoV-2-positive infants and particularly for serum procalcitonin. However, NPV could be estimated with greater confidence for ruling out IBI among SARS-CoV-2-positive infants. We assessed serum IM values; urinalyses1 3  and maximal temperatures3  were not evaluated. We did not routinely test for SARS-CoV-2 variants, which may produce different IM responses. However, given that specificities and NPVs were maintained, clinicians can feel confident using current risk-stratification strategies to exclude IBIs in febrile young infants during the COVID-19 era.

PERN COVID-19 Study Team: Fahd A. Ahmad, MD, MScI; Lilliam Ambroggio, PhD, MPH; Usha R. Avva, MD; Sarah M. Becker, MD; Isabel Beneyto Ferre, MD; Kelly R. Bergmann, DO, MS; Maala Bhatt, MD; Meredith L. Borland, MD; Kristen A. Breslin, MD; Carmen Campos, MD; Kerry Caperell, MD, MS, MBA; Pradip P. Chaudhari, MD; Jonathan C. Cherry, MD; Shu-Ling Chong, MPH; Andrew C. Dixon, MD; Stuart R. Dalziel, MBChB, FRACP, PhD; Michelle Eckerle, MD; Yaron Finkelstein, MD; Iker Gangoiti, MD; Michael A. Gardiner, MD; April J. Kam, MD; Nirupama Kannikeswaran, MD; Kelly Kim, BSc; Terry P. Klassen, MD, MSc; Maria Y. Kwok, MD, MPH; Maren M. Lunoe, MD; Richard Malley, MD; Santiago Mintegi, MD, PhD; Claudia R. Morris, MD; Andrea K. Morrison, MD, MS; Nidhya Navanandan, MD; Jasmine R. Nebhrajani, MD; Mark I. Neuman, MD, MPH; Laura Palumbo, MD; Viviana Pavlicich, MD; Amy C. Plint, MD; Naveen Poonai, MD; Pedro B. Rino, MD; Alexander J. Rogers, MD; Marina I. Salvadori, MD; Laura F. Sartori, MD, MPH; Nipam P. Shah, MD, MBBS, MPH; Norma-Jean Simon, MPH; Muhammad Wassem, MD; Adriana Yock-Corrales, MD.

PERC COVID-19 Study Team: Darcy Beer, MD; Simon Berthelot, MD, MSc; Jason Emsley, MD; Gabrielle Freire, MD; Jocelyn Gravel, MD; April Kam, MD; Ahmed Mater, MD; Anne Moffatt, MD; Naveen Poonai, MD; Robert Porter, MD, MSc; Roger Zemek, MD.

Dr Burstein assisted in study conceptualization and design, data collection, analysis, and interpretation and drafted the manuscript; Drs Florin, Freedman, and Kuppermann assisted in study conceptualization and design, data collection, analysis, and interpretation and secured funding for the parent study; Dr Sabhaney assisted in data collection, analysis, and interpretation; Dr Xie assisted in data collection and analysis; and all authors reviewed and critically revised the manuscript, approved the final manuscript as submitted, and agree to be accountable for all aspects of the work.

FUNDING: This study was supported by grants from the Canadian Institutes of Health Research (Operating grant: COVID-19, clinical management), the Public Health Agency of Canada, the Alberta Health Service, University of Calgary, Clinical Research Fund, the Alberta Children’s Hospital Research Institute, the COVID-19 Research Accelerator Funding Track (CRAFT) Program at the University of California, Davis. Dr Burstein is the recipient of a career award from the Quebec Health Research Fund (FRQ-S). Dr Florin is supported by grants from the Cincinnati Children’s Hospital Medical Center Division of Emergency Medicine Small Grant Program. Dr Freedman is supported by the Alberta Children’s Hospital Foundation Professorship in Child Health and Wellness. Dr Kuppermann is supported by the Bo Tomas Brofeldt endowed professorship from the University of California, Davis School of Medicine. The other authors received no additional funding.

CONFLICT OF INTEREST DISCLOSURES: The authors have indicated they have no potential conflicts of interest relevant to this article to disclose.

AAP

American Academy of Pediatrics

ANC

absolute neutrophil count

CI

confidence interval

COVID-19

coronavirus disease 2019

CRP

C-reactive protein

ED

emergency department

IBI

invasive bacterial infection

IM

inflammatory marker

NPV

negative predictive value

PECARN

Pediatric Emergency Care Applied Research Network

PERC

Pediatric Emergency Research Canada

PERN

Pediatric Emergency Research Network

SARS-CoV-2

severe acute respiratory syndrome coronavirus 2

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Supplementary data