Do all Emergency Room Patients With Influenza-like Symptoms Need Blood Cultures? A Retrospective Cohort Study of 2 Annual Influenza Seasons

Abstract In this retrospective cohort study, we evaluated risk factors for bacteremia in emergency department patients presenting with influenza-like symptoms during influenza epidemic seasons. In patients without fever, chronic heart or chronic liver disease, blood culture collection might be omitted.

Diagnosis of influenza and other respiratory virus infections is based on a syndrome complex including upper respiratory symptoms and often fever, confirmed by a diagnostic test.Common syndromal case definitions, however, have poor sensitivity and specificity to diagnose influenza [1][2][3].The sensitivity of the 2011 case definition recommended by the World Health Organization for influenza-like-illness has been reported to be as low as 55%-69% [4,5].In addition, signs and symptoms of influenza vary by age, immune status, and presence of underlying comorbidities [6].Test turnaround times of reverse transcription-polymerase chain reaction in emergency medicine are still too long to exclude alternative differential diagnoses as cause of fever in particular, whereas rapid antigen tests have only low to moderate sensitivity to diagnose influenza [1].
This diagnostic dilemma contributes to a high proportion of blood culture collection in this patient population and may lead to overuse of antibiotics in patients with viral infections [7][8][9].However, bacteremia is described to be rare in patients with acute respiratory virus infections: 4.0% (95% confidence interval [CI], 1.9-6.1) of the patients with influenza A, 3.0% (95% CI, 1.2-4.9)with influenza B, and 1.0% (95% CI, .3-1.8) of patients with SARS-CoV-2 infection are bacteremic [10].Unnecessary collection of blood cultures may harm patients and raise health care costs [11,12], and inappropriate use of antibiotics has many disadvantages, especially in the view of a rising rate of antibiotic resistance [13].
Therefore, this study aimed to identify risk factors for bacteremia in a cohort of patients presenting with influenza-like symptoms to a tertiary emergency department (ED) during the annual influenza seasons (before the COVID-19 pandemic).In a diagnostic stewardship effort, we tried to identify subpopulations where blood culture sampling can be safely omitted to reduce blood culture collection in patients with suspected viral infection in our ED.

Study Design
This retrospective cohort study was conducted at the ED of a tertiary Swiss hospital (Inselspital Bern University Hospital, Switzerland) during2 pre-COVID- ).All patients aged ≥ 16 years who presented to the ED with influenza-like symptoms and therefore underwent nasopharyngeal swabbing for influenza A and B polymerase chain reaction according to hospital infection prevention and control policy with concurrent blood culture sampling were included.

Data Collection
Medical data (eg, demographics, clinical complaints, vital values, comorbidities, antibiotic treatment) were extracted from the Eds' electronic medical record database (Ecare, Turnhout, Belgium).Comorbidities in this retrospective analysis were defined according to US Centers for Disease Control and Prevention health and age factors that are known to increase a person's risk of serious complications from the flu [14].Blood culture positivity was defined as any blood culture growth, with the exception of known skin contaminants (eg, coagulase negative staphylococci) that were considered contaminants.

Statistical Analysis
The statistical analysis was performed with Stata  Categorical variables were compared between positive and negative blood cultures using chi-squared tests.A P value < .05 was considered significant.
A univariable logistic regression analysis was performed with variables with <5% missing values to identify factors associated with blood culture growth.The variables associated with blood culture positivity (P < .05) in the univariable logistic regression were further analyzed with a multivariable logistic regression analysis with forward-stepwise selection of the identified variables at a significance level of P < .05.The performance of the final model was evaluated using the AUROC metric, where a threshold of 0.7 was considered acceptable for accuracy assessment.

Ethical Considerations
The study was approved by the regional ethics committee of the Canton of Bern, Switzerland (KEK: 2019-01149).Patients who refused to give general consent for the use of their anonymized data or subsequently withdrew it were excluded from the study.

Demographics
During the study period, 1448 patients were tested for influenza; blood cultures were obtained in 546 (37.7%) of these patients.Blood culture positivity in this population was 8.1% (44/546 patients).The median age was 68.0 (IQR 53-77) years and 345 (63.2%) patients were male.The subgroup with a bacteremia had a slightly younger median age with 66.5 (IQR 55-77) years.
Patients with bacteremia had significantly lower systolic and diastolic blood pressure values and higher temperatures compared with patients without bacteremia (P < .001,respectively).The respiratory rate was significantly higher in patients with bacteremia (26 vs 29, P = .038),and C-reactive protein and procalcitonin levels were also significantly higher (53 mg/L vs 105 mg/L, P = .002and .27vs 1.24, P = .031,respectively).
Patients with bacteremia were significantly more likely to be hospitalized in the intensive care unit (P = .001);28-day mortality was comparable in both groups (P = .969).(Table 1)

DISCUSSION
During 2 influenza epidemic seasons before the COVID-19 pandemic, bacteremia was detected in only 8.1% of patients presenting with influenza-like symptoms in a tertiary ED, which is comparable to an earlier report [15].Our retrospective data suggest that the collection of blood cultures could be omitted in patients presenting with influenza-like symptoms during influenza season that have neither fever nor chronic heart or liver disease.However, this finding should be prospectively validated.A meaningful score to identify patients without bacteremia in febrile or hypothermic patients presenting with influenza-like symptoms could not be derived from the retrospective dataset of this study.In addition, the identified predictors of bacteremia might be less reliable in elderly patients with a suspicion of influenza, where fever is not as commonly present even in bacteremia.The predictors found in our study have some overlap with predictors for bacteremia identified in a general ED population (not focusing on influenza-like symptom subpopulation), but in that broader population the association with the comorbidities heart disease or liver diseases was not mentioned [16].
Febrile illness with suspected blood stream infection is a leading cause for hospital admission [17,18], and obtaining blood cultures is a common practice during initial ED presentation of patients who may have an infection [12].It has been shown that physicians overestimate the likelihood of bacteremia in patients in general [19,20].In high-income countries, blood stream infection has been documented in only 1.4% to 8.3% of blood cultures taken from patients presenting to EDs [12,[21][22][23].In contrast, rapid identification of patients at risk for bacteremia is critical in the ED because untreated bacteremia can lead to sepsis and septic shock with an estimated mortality rate of 30% to 50% [12,17,[24][25][26][27].Therefore, the ED is an important setting for diagnostic and therapeutic stewardship approaches [11].
The proportion of positive blood cultures both in patients with an influenza infection, and, more recently, with a SARS-CoV-2 infection, is low, and in the mentioned subgroups it might be low enough to justify omitting blood culturing.
Our study has several limitations.It was performed in a retrospective cohort from before the COVID-19 pandemic; the findings of this study should be confirmed in a mixed SARS-CoV-2 and influenza respiratory virus infection season in the future.Nevertheless, observed blood culture positivity in COVID-19 patients are in a comparable range to influenza patients.Therefore, the results might be transferable to a more current setting.Furthermore, blood cultures were obtained in only about 40% of all patients with influenza-like symptoms, and the results of the subpopulation studied may differ from those of the total population because of potential selection bias.

CONCLUSION
Bacteremia is rarely found in ED patients presenting with influenza-like symptoms during epidemic seasons, especially in the absence of identified predictors such as fever and chronic heart and liver disease.In the sense of a diagnostic stewardship approach, blood culture collection could be omitted in a relevant proportion of patients presenting with flu-like symptoms during the annual epidemic season.Identified risk factors for bacteremia should be externally validated, ideally in a prospective cohort.

Notes
Author Contributions.All authors have contributed substantially to conception and design of the study.L. H. did the manual coding of the data.M. M. performed the analysis.S. E., L. H., and P. J. did the interpretation of the data supported by M. M. S. E., L. H., and P. J. drafted the manuscript and M. R., F. S., A. E., W. H., and M. M. revised it critically.All approved the final version to be published.
This research was financed by the contributing departments, without additional external funding sources.The authors declare that they have no conflict of interest.The odds ratio of systolic blood pressure, lowest measurement, was calculated per decrement of 1 mm Hg.

Table 1 . Continued
IQR, interquartile range; PCR, polymerase chain reaction; SD, standard deviation.Depending on normality testing (Shapiro Wilk) median (IQR), respectively, mean (SD) are shown for continuous variables, P values obtained by Wilcoxon rank-sum test respectively unpaired t test.Categorical variables are shown with number (%) in each category, P values obtained by chi-squared test.Comorbidities according to US Centers for Disease Control and Prevention health and age factors that are known to increase a person's risk of serious complications from the flu [14].Liver disease: cirrhosis, chronic hepatitis B, chronic hepatitis C, and liver transplant.Heart disease: congenital heart disease, congestive heart failure, and coronary artery disease.Renal failure: chronic renal failure and kidney transplant Immunosuppression: Compromised immune response due to HIV, hematoncologic malignancy or cancer under chemotherapy or radiation treatment, or immunosuppressive medication.
Abbreviations: BMI, body mass index; COPD, chronic obstructive pulmonary disease; CRP, C-reactive protein; CT, computed tomography; ICU, intensive care unit; a Corrected for contaminations.b c Abnormal breath sound on lung auscultation includes rales and obstructive breath sounds.

Table 2 . Multivariable Logistic Regression, Risk Factors for Bacteremia in Patients With Flu-like Symptoms; Variables Associated With Positive Blood Culture With P < .05
Number of observations n = 523.Area under receiver operating characteristic curve: 0.843.a The odds ratio of CRP was calculated for each increase in 1 mg/L. b