a b s t r a c t

Background: We sought to investigate risk factors for serious bacterial infection (SBI: Bacterial meningitis, bacter- emia, and urinary tract infection [UTI]) among infants <=60 days of age presenting to the emergency department (ED) with hypothermia (temperature b 36 ?C).

Methods: We performed a single center study over a 12-year period including all patients <=60 days old with hy- pothermia, excluding patients who did not receive a blood culture and patients who received antibiotics prior to culture acquisition. The primary outcome was SBI. Secondary outcomes were mortality and Herpes simplex infec- tion. We performed multivariable logistic regression to identify risk factors for primary outcomes reporting ad- justed odds ratios with 95% confidence intervals (aOR, 95% CI).

Results: 360 infants were identified. 10/360 (2.8%) had an SBI. All episodes of SBI occurred in infants <=28 days of age. Two patients had meningitis, two had meningitis with bacteremia, one had isolated bacteremia, and five had UTI. Associated diagnoses included prematurity (46.9%), hyperbilirubinemia (28.3%) and dehydration (14.7%). In multivariable analysis, presentation at 15-28 days (7.60, 1.81-31.86; p = 0.005) compared to 0-14 days, higher absolute Neutrophil count (1.25, 1.04-1.50; p = 0.015) and lower platelet count (0.99, 0.99-1.00; p = 0.046) were associated with SBI. Three patients without SBI died during or soon after their hospitalization. One patient had positive testing for herpes simplex.

Conclusion: In this cohort of Hypothermic infants, 2.8% had a SBI. Age of presentation, ANC, and lower platelet count were associated with serious infections. Hypothermic infants presenting to the ED carry significant mor- bidity and require prospective study to better risk-stratify this population.

(C) 2019

Introduction

Serious bacterial infections in infants carry significant morbid- ity if untreated [1]. Unlike febrile infants, for whom rigorous decision rules have been published [2,3], the management of hypothermic in- fants presenting to the emergency department (ED) is poorly established. The etiology of hypothermia may be related to an over- whelming immunosuppressed state [4-6] or altered levels of inflamma- tory cytokines [7].

Older studies have suggested a high rate of infections and mortality in infants with hypothermia, though these studies evaluated infants that were critically ill [8-11] or were performed in resource-limited re- gions [10]. More recent studies evaluating infants with hypothermia have been limited by small sample size and potential confounding [12-14]. One challenge throughout the literature lies in a varying defini- tion of hypothermia, with investigators using cutoff temperatures for

* Corresponding author at: Division of Emergency Medicine, Children’s Hospital of Pittsburgh, AOB 2400, 4401 Penn Avenue, Pittsburgh, PA 15224, United States of America.

E-mail address: [email protected] (S. Ramgopal).

hypothermia as high as 36.5 degrees Celsius (?C) [12] and as low as

34.0 ?C [8]. In the absence of rigorous evidence, many practitioners eval- uate young infants with hypothermia for SBIs due to the proposed asso- ciation between depressed temperature and severe infection. Better understanding of risk factors for SBI in this population may facilitate fu- ture prospective study with the goal of identifying a cohort of patients at low-risk of SBI.

In this study, we aim to identify rates of and risk factors for SBI among infants presenting to the ED with reported or documented hypo- thermia. In addition, we aim to identify rates of mortality and herpes simplex infections in this population.

Methods

Setting

We performed a single center retrospective study of infants <=60 days of age who received testing for SBI. Eligible patients were identified by performing an electronic medical record (EMR) search of all patients

<=60 days of age presenting to the ED between January 1, 2006 to

https://doi.org/10.1016/j.ajem.2019.04.015

0735-6757/(C) 2019

December 31, 2017 who received any culture of blood, CSF or urine. Prior to data collection, institutional board review approval was ob- tained with a waiver of informed consent.

Patient inclusion

Patients were considered eligible for inclusion if they had a history of hypothermia, defined as a reported temperature below 36.0 ?C prior to arrival, or if they had documented hypothermia below 36.0 ?C within the first 4 h of hospital stay. This cutoff has been recommended by the International Pediatric Sepsis Consensus Conference [15] and is often used in research among infants evaluated in Neonatal intensive care units [16,17]. Only rectal temperatures were included. Patients were ex- cluded if they could not be assessed for SBI due to lack of a blood culture, received antibiotics prior to blood culture acquisition, or if they pre- sented as following known trauma or cardiac arrest.

Data acquisition

Table 1

Patient demographics, laboratory values, and outcomes.

All patients No SBI With SBI

Demographics

Number 360 350 10

Age (%)a
0-14 days	263 (73.1)	257 (73.4)	6 (60.0)
15-28 days	43 (11.9)	39 (11.1)	4 (40.0)
29-42 days	35 (9.7)	35 (10.0)	0 (0.0)
43-60 days	19 (5.3)	19 (5.4)	0 (0.0)
Male sex (%)a	180 (50)	175 (50.0)	5 (50.0)
Race (%)a
White	279 (77.5)	272 (77.7)	7 (70.0)
Black	53 (14.7)	50 (14.3)	3 (30.0)
Other/unknown Season (%)a	28 (7.8)	28 (8.0)	0 (0.0)
Winter	104 (28.9)	101 (28.9)	3 (30.0)
Summer	85 (23.6)	81 (23.1)	4 (40.0)
Spring	74 (20.6)	71 (20.3)	3 (30.0)
Fall	97 (26.9)	97 (27.7)	0 (0.0)
a

gestational age (%)

	>=36 weeks	191 (53.1)	184 (52.6)	7 (70.0)
We abstracted clinical and laboratory data from the EMR. Clinical	b36 weeks	169 (46.9)	166 (47.4)	3 (30.0)

data included patient age classified into 2-week categories (0-14 days, 15-28 days, 29-42 days, and 43-60 days), sex, race (in categories of black, white, other and unknown), gestational age, minimum tempera- ture in the first 4 h of hospitalization, and whether hypothermia was historical only (i.e. no measured temperature b 36.0 ?C in the first 4 h of hospitalization), and season of presentation. We reviewed laboratory results of blood, urine and cerebrospinal fluid cultures, total white blood cell count (WBC, 10⁹/L), absolute neutrophil count (ANC, 10⁹/L), abso- lute band count (ABC, 10⁹/L), and platelet count (10⁹/L). We defined hyperbilirubinemia as any bilirubin level N 205.2 umol/L (12 mg/dL).

Study outcomes

Our primary outcome was SBI. Our secondary outcomes were final diagnosis of herpes simplex viral infection and death. SBI was defined as bacteremia, bacterial meningitis or urinary tract infection . Bac- teremia and bacterial meningitis were defined as growth of a single or- ganism from blood culture or CSF culture, respectively. We used a standard definition of UTI based on colony counts and urinalysis [18]. In ambiguous cases, an infectious disease specialist (L.W. or A.N.) blinded to the Clinical context reviewed the results.

Analysis

Summary statistics of clinical and laboratory parameters are re- ported. We aimed to identify factors associated with SBIs using multi- variable logistic regression. For analysis, temperature data was multiplied by 10 to provide effect sizes for each tenth of degree change. We performed univariate logistic regression for each variable. Predic- tors with p b 0.1 in univariate analysis were used in bidirectional step- wise multivariable regression in order to achieve the minimum Akaike Information Criterion. Results were presented as adjusted odds ratios (aOR) with 95% confidence intervals (CI). p b 0.05 in multivariable anal- ysis were considered statistically significant. For secondary outcomes, descriptions of patients are provided as proportions. Analysis was per- formed using the MASS package [19] (version 7.3-51.1) in R, version

3.5.2 (R Foundation for Statistical Computing, Vienna, Austria https:// www.R-project.org/).

Results

Patient inclusion

Of 5508 infants <=60 days screened for inclusion, 447 had docu- mented or reported hypothermia. 360 (50% male, median age 6.8 days, IQR 4.8-16.0) were included (Table 1). Reasons for exclusion

Initial temperature, median (IQR) minimum temperature, median (IQR)	35.8 (35.0-36.0) 35.6 (34.9-35.9)	35.8 (35.3-36.3) 35.6 (35.1-35.9)	35.8 (35.0-36.0) 35.6 (35.1-35.9)
Historical hypothermia only (%)a	85 (23.6)	83 (23.7)	2 (20.0)
Laboratory parameters Hyperbilirubinemia (%)a	117 (32.5)	116 (33.1)	1 (10.0)
White blood cell count (109/L),	9.0	9.1	9.85
median (IQR)	(7.0-11.1)	(7.1-10.9)	(6.8-13.1)
Absolute neutrophil count (109/L),	2.84	2.90	2.96
median (IQR)	(1.82-4.01)	(1.97-4.00)	(2.37-8.01)
Absolute band count (109/L), median	0.02	0	0.35
(IQR)	(0.00-0.18)	(0.00-0.13)	(0.08-0.84)
Platelet count (109/L), median (IQR)	302	298	213
	(239-370)	(238-358)	(111-359)

SD, standard deviation; IQR, interquartile range.

^a Figures in parenthesis represent column percent (denominator listed in top row).

were: no blood culture (n = 12), antibiotics given prior to blood culture (n = 72), history of trauma (n = 2), and cardiac arrest (n = 1). 354 (98.1%) had a urine culture, 328 (90.9%) had a CSF culture, and 140 (38.8%) had HSV testing. Additional diagnoses (n, %) included hyperbilirubinemia (102, 28.3%), dehydration (53, 14.7%), weight loss

(49, 13.6%), respiratory disease (31, 8.6%), apnea or cyanosis (23,

6.4%), hypoglycemia (10, 2.8%), pneumonia (9, 2.5%) and apparent

life-threatening event (8, 2.2%).

Primary outcome (Table 2)

10/360 patients (2.8%) had a SBI. Bacteremia was present in 3 (0.8%), meningitis in 4 (1.1%), and UTI in 5 (1.4%). Some had concurrent infec- tions. No SBIs occurred in infants N28 days of age.

Factors associated with SBI

In univariate analysis, SBI was associated with presentation at 15-28 compared to 0-14 days, greater WBC and ANC, and lower platelet count. Following multivariable analysis, presentation on days 15-28 compared to days 1-14, higher ANC and lower platelets were independently asso- ciated with SBI (Table 3).

Secondary outcomes

Three patients (0.8%) died, none of whom had an SBI. The first case was a 31-day old term infant who presented with an apneic episode and temperature of 33.5 ?C. This infant was intubated and had neuroim- aging which revealed severe hemorrhagic encephalitis, the etiology of

Table 2

Clinical and laboratory characteristics of 10 infants with serious bacterial infections

No.	Age (days), sex	History of prematurity	Initial temperature	Minimum temperature	WBCa	ANCa	ABCa	Plateletsa	SBI
1	4, boy	No	35.7	35.7	6.5	1.6	0.0	381	Enterobacter cloacae UTI
2	4, girl	No	36.4	35.9	12.1	4.7	0.0	210	Enterococcus faecalis UTI
3	5, boy	Yes	35.9	35.9	7.1	2.3	0.1	216	Staphylococcus lugdunensis bacteremia
4	6, girl	No	35.6	35.6	11.1	3.0	0.9	77	Enterococcus faecalis meningitis
5	6, boy	No	33.2	33.2	4.8	1.2	0.58	109	Group B Streptococcus bacteremia and meningitis
6	7, girl	No	36.0	36.0	19.4	9.8	1.8	108	Bacteroides fragilis meningitis
7	16, girl	No	34.0	34.0	6.7	2.9	1.1	118	Group B Streptococcus UTI
8	21, boy	No	36.6	36.5	8.8	2.5	0.1	489	Escherichia coli UTI
9	22, boy	Yes	34.8	34.8	23.1	14.8	0.7	442	Listeria monocytogenes bacteremia and meningitis
10	27, girl	Yes	35.8	35.5	13.4	9.1	0.1	293	Group B Streptococcus UTI

SBI, serious bacterial infection; WBC, white blood cell count; ANC, absolute neutrophil count; ABC, absolute band cell count, UTI, urinary tract infection.

^a Cells 10⁹/L.

which was indeterminate despite extensive testing. The second infant was a 29-day old full term infant who presented with lethargy and a temperature of 35.0 ?C. This infant was found to have extensive encephalomalacia, likely related to an undetected congenital infection. The third was a 16-day old full term infant who presented following an apneic episode. This infant was hypothermic to 33.7 ?C and had re- current episodes of apnea and bradycardia before the family ultimately transitioned to comfort-oriented care. This infant had positive testing for ketoglutaric aciduria and had multiple white matter lesions at au- topsy. One patient (0.3%) had positive testing for HSV from a nasopha- ryngeal specimen.

Discussion

We performed a multivariable analysis to identify risk factors for SBI in infants <=60 days old with hypothermia in the ED. 2.8% of infants with hypothermia had an SBI. Presentation during days 15-28 of life, higher ANC and lower platelets were independently associated with SBI. Find- ings from this study suggest that infants with hypothermia in the ED carry significant morbidity, although SBI was not associated with any of the three fatal outcomes in this group.

Overall, the rate of SBI in hypothermic infants <=60 days of age in the ED appears to be lower than that in febrile infants of the same age, where rates are estimated to be 9-14% [20-23]. Kasmire et al. identified 3 SBIs in 116 hypothermic patients <=60 days of age (2.6%; one with bac- teremia and two with UTI) [13]. Wood et al. found 2 confirmed SBIs in 68 infants <=28 days of age (2.9%; both UTIs) [14]. Perry et al. identified 8 SBIs out of 104 infants with hypothermia (7.6%; 2 with bacteremia, 1 with meningitis and bacteremia, and 5 with UTI) [12]. The rate of SBI in our study is 2.8%, similar to other reported studies. However, our cohort was larger than the previous cited studies combined, making it the largest experience to date. Some patients who were excluded from analysis, such as those given antibiotics prior to culture acquisi- tion, may have resulted in a higher rate of SBI if they could have been re- liably included. Conversely, if a large number of infants with hypothermia were not tested for SBI, this group may have resulted in a lower rate of SBI, though this is unlikely to have been the case.

A notable finding of our analysis is the variation of SBI rate by age. While the rate of SBI in febrile infants is inversely proportional to age [20,24], in our series of hypothermic infants the youngest age group had a lower rate of SBIs (2.2%) compared to those 15-28 days of age (9.3%). One explanation for this finding is that a large number of youn- ger infants were admitted for hypothermia related to temperature

Table 3

Factors associated with SBI in univariate and multivariable analysis

Variable	Univariate OR (95% CI)	p	Multivariable aOR (95% CI)	p
Age
0-14 days	Ref	–	Ref	–
15-28 days	4.39 (1.19-16.27)	0.027	7.60 (1.81-31.86)	0.005
29-42 days	0.00 (0.00-infinity)	0.993	0.00 (0.00-infinity)	0.993
43-60 days	0.00 (0.00-infinity)	0.995	0.00 (0.00-infinity)	0.995
Male sex	1.00 (0.28-3.51)	1.000
Race
White	Ref	–
Black	2.33 (0.58-9.32)	0.231
Other/unknown	0.00 (0.00-infinity)	0.990
Season Winter	Ref	–
Summer	1.66 (0.36-7.64)	0.514
Spring	1.42 (0.28-7.25)	0.672
Fall	0.00 (0.00-infinity)	0.992
Gestational age Term	Ref	–
b36 weeks	0.48 (0.12-1.87)	0.286
Historical hypothermia only	0.80 (0.17-3.86)	0.785
First temperature (0.1 ?C temperature increment)	0.96 (0.90-1.02)	0.173
Minimum temperature (0.1 ?C temperature increment)	0.98 (0.91-1.05)	0.592
Laboratory values
White blood cell count	1.12 (0.98-1.28)	0.093
Absolute neutrophil count	1.25 (1.05-1.49)	0.014	1.25 (1.04-1.50)	0.015
Absolute band count	1.40 (0.83-2.38)	0.210
Platelet count	0.99 (0.99-1.00)	0.063	0.99 (0.99-1.00)	0.046
Hyperbilirubinemia	0.22 (0.03-1.79)	0.158

OR, odds ratio; aOR, adjusted odds ratio; CI, confidence interval. Bold text indicates significant values in univariate (p b 0.10) and multivariable (p b 0.05) analyses.

dysregulation in the setting of low birthweight and/or prematurity [25], diluting the risk of SBI in similarly-aged infants without these condi- tions. The 15-28 days of age cohort had an SBI incidence of 9.3%, sug- gesting that the true rate of SBI in hypothermic infants past the first two weeks approaches that of febrile infants, and that complete evalua- tion is warranted in these patients.

We identified that presentation between days 15-28 compared to 0-14 days, higher ANC and lower platelets were risk factors for SBI in multivariable analysis. We did not identify any instances of SBI in pa- tients over 28 days of age, which may be partially due to the relative in- frequency of hypothermia in older ages. A repeated analysis limited only to patients <=28 days of age produced similar findings in multivari- able regression (not shown). A higher neutrophil count is associated with invasive infections in febrile neonates [21,26]. Similarly, thrombo- cytopenia has been associated with serious infections in critically ill adult [27] and pediatric patients [24,28]. We did not identify an associ- ation between band counts [12] or gestational age [13] and SBI as found in other studies, which may relate to varying definitions of SBI. Wood et al. [14] suggested an association between lower temperatures and SBI, a finding which is also corroborated by older studies [8-10]. While we did not find direct correlation between lower temperatures and SBI, 2/3 patients with mortality had a presenting temperature below 34 ?C. Though an association between jaundice and sepsis is typically described [29], we did not identify an association with hyperbilirubinemia and SBI. This may be due to the large number of young infants with physiologic jaundice of the newborn and/or dehy- dration with associated temperature-dysregulation.

Additional data are needed to better risk stratify patients with hypo- thermia, ideally using prospective data. Use of additional biomarkers may also yield significant results. For example, C-reactive protein [24] and procalcitonin [2,3] have improved accuracy over parameters of the complete blood in identifying young febrile infants at low risk for SBI. The utility of these parameters in hypothermic infants warrants fur- ther evaluation.

This study is subject to limitations from a retrospective chart review. Patients who did not receive any cultures would not have been screened for study inclusion. However, the majority of infants in our center who receive no testing for hypothermia generally have temperatures above 36.0, which is above the threshold for hypothermia used in this study [12]. Therefore, few patients would have been excluded on this basis. Aside from a blood culture, not all patients received cultures or tests in- cluding lumbar puncture, urinalysis, or herpes simplex virus testing. De- spite these limitations, this study is the largest investigation to our knowledge identifying rates of SBI among young infants with hypother- mia and is the first to identify potential risk factors for serious infections in this population.

Conclusion

In this 12-year review of infants <=60 days old presenting to the ED with hypothermia, SBIs occurred in 2.8%. Presentation during days 15-28 of life, ANC and platelets were independently associated with SBI. 0.8% of infants in this population died, and important comorbid di- agnoses included hyperbilirubinemia and dehydration. These findings suggest that infants with hypothermia presenting to the ED carry risk of significant morbidity. Additional prospective research is needed to better risk-stratify this vulnerable population.

Declarations of interest

None.

Funding source

This research did not receive any specific grant from funding agen- cies in the public, commercial, or not-for-profit sectors.

Acknowledgements

None.

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