key: cord-0809199-uw8yb2fa
authors: Azijli, Kaoutar; Minderhoud, Tanca C.; de Gans, Carlijn J.; Lieveld, Arthur W.E.; Nanayakkara, Prabath W.B.
title: Optimal use of procalcitonin to rule out bacteremia in patients with possible viral infections
date: 2022-05-19
journal: J Am Coll Emerg Physicians Open
DOI: 10.1002/emp2.12621
sha: a2de2a29d4b7c474de15cffe1f16574c922a64a3
doc_id: 809199
cord_uid: uw8yb2fa

OBJECTIVE: During the winter, many patients present with suspected infection that could be a viral or a bacterial (co)infection. The aim of this study is to investigate whether the optimal use of procalcitonin (PCT) is different in patients with and without proven viral infections for the purpose of excluding bacteremia. We hypothesize that when a viral infection is confirmed, this lowers the probability of bacteremia and, therefore, influences the appropriate cutoff of procalcitonin. METHODS: This study was conducted in the emergency department of an academic medical center in The Netherlands in the winter seasons of 2019 and 2020. Adults (>18 years) with suspected infection, in whom a blood culture and a rapid polymerase chain reaction test for influenza was performed were included. RESULTS: A total of 546 patients were included of whom 47 (8.6%) had a positive blood culture. PCT had an area under the curve of 0.85, 95% confidence interval (95% CI) 0.80–0.91, for prediction of bacteremia. In patients with a proven viral infection (N = 212) PCT < 0.5 μg/L had a sensitivity of 100% (95% CI 63.1–100) and specificity of 81.2% (95% CI 75.1–86.3) to exclude bacteremia. In patients without a viral infection, the procalcitonin cutoff point of < 0.25 μg/L showed a sensitivity of 87.2% (95% CI 72.6–95.7) and specificity of 64.1 % (95% CI 58.3–69.6). CONCLUSION: In patients with a viral infection, our findings suggest that a PCT concentration of <0.50 μg/L makes bacteremia unlikely. However, this finding needs to be confirmed in a larger population of patients with viral infections, especially because the rate of coinfection in our cohort was low.

Annually more than 20% of adult emergency department visits occur because of severe infections. 1 The most frequent presenting symptoms are fever and respiratory complaints. It is difficult to distinguish between a viral and bacterial cause of these complaints based on clinical symptoms because the complaints in viral and bacterial disease show great overlap. 2, 3 During the winter season in the Netherlands, this clinical dilemma is encountered more often as the incidence of viral infections rises. This is usually caused by the annual influenza epidemic;

however, in 2020, this epidemic was curtailed by the coronavirus disease 2019 (COVID- 19) pandemic. Rapid diagnosis of viral infections has become easier because of the wide availability of a rapid polymerase chain reaction test. 4 However, despite a positive viral test, clinicians often prescribe antibiotics, 5, 6 because viral infections predispose patients to bacterial coinfection, especially in the elderly and mortality in those cases is higher. [7] [8] [9] The rate of bacterial coinfection in viral infections is highly variable.

In influenza bacterial coinfection rates varying from 2% to 65% have been reported. 7 However, few studies have been conducted in the emergency department (ED), and most of the available data stem from the intensive care unit (ICU). A recent meta-analysis reported a rate of bacterial coinfection in patients with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) at presentation of 3.5 %. 10 The rate of bacterial coinfections with other viruses such as rhinovirus or respiratory syncytial virus (RSV) has been mostly reported from ICU, which is hard to extrapolate to ED patients. 11

Estimated rates of unnecessary antibiotic use at the ED are between 30% and 60%, and it has been described as the most preventable cause of antibiotic resistance. [12] [13] [14] A recent report by the World Health

Organization found that antibiotic resistance could lead to a significant increase in economic costs and 10 million annual deaths globally by 2050 without a sustained effort to contain it. 15 To reduce antibiotic use and identify bacterial coinfection more accurately, biological markers such as procalcitonin (PCT) have been used but with conflicting results. 16, 17 However, a retrospective study by Goodlet 20 raised concerns on using PCT as a rule-out tool, due to limited sensitivity.

One of the explanations for the different results might be that PCT has been used with several cutoffs (< 0.10 µg/L, < 0.25 µg/L, < 0.5 µg/L).

In a review of PCT algorithms, it was advised to take the pretest likelihood of bacterial infection into account to choose the appropriate cutoff. [20] [21] [22] [23] The Bottom Line

Unnecessary antibiotic use in viral infections may be prevented by using procalcitonin levels to rule out a bacterial coinfection. This single-center prospective study of 546 emergency department patients with 212 viral infections had 8 (3.8%) with concomitant positive blood cultures, all of whom had a procalcitonin >0.5 mg/L. This suggests that a procalcitonin level <0.5 mg/L makes bacteremia less likely in the setting of a confirmed viral infection.

The aim of this study was to investigate if the PCT cutoff to exclude bacteremia should be different in patients with and without confirmed viral infections, presenting during a viral epidemic or pandemic. We hypothesized that if a viral infection was found, this lowered the probability of bacteremia and therefore influenced the appropriate cutoff of PCT.

This study was observational and the PCT values were not used in clinical practice at the time. The study was conducted prospectively. The study was approved by the local medical ethics committee, a waiver for informed consent was obtained.

The study was planned to run during 2 winter seasons, with the aim to use the influenza seasons. The first inclusion period was from January 2019 to April 2019, and the second inclusion period was from January 2020 until April 2020, coinciding with the start of the COVID-19

pandemic.

The Amsterdam University Medical Center (UMC) is a large teaching hospital with an estimated 30,000 ED presentations annually. Amsterdam UMC is an academic hospital with different training programs including emergency medicine residency training. Most patients seen in our ED were either referred by a general practitioner for acute review or are undergoing outpatient treatment at our facility.

All patients 18 years and older for whom a blood culture and a viral test were ordered in the ED were included. This was a consecutive sample of patients.

In our hospital, testing for influenza, was based on the case definition of the National Institute for Public Health and Environment, which includes fever and respiratory symptoms. 24 Testing for the novel SARS- 

Bacteremia was defined as true positive blood cultures. All blood cultures are processed with the BACTEC system (Becton Dickinson). Culture results were reported in the electronic health system (EPIC).

Positive blood culture results were routinely reviewed by a microbiologist. To establish true positivity, the student entering the patients' data in Castor checked if a microbiologist had written a comment on the culture result. In case no microbiologist assessment was available, contamination was assessed according to pre-established criteria (National Nosocomial Infection Surveillance parameters and surveillance criteria for bloodstream infection). 25 In the final data set, contaminated cultures were reclassified as negative cultures. PCT was measured using the Elecsys BRAHMS PCT assay. Viral testing was performed by Cepheid Xpert Flu A/B/RSV XC assay in 2019 and by the Cepheid Xpert SARS-CoV-2/Flu/RSV assay in 2020. If more extensive viral testing was deemed indicated by the treating physician, the result was used in our analysis. All patients with a positive viral test were considered to have a confirmed viral infection.

We identified eligible patients through the microbiology orders. The microbiology laboratory generated a list of patients for the research team in whom both a viral test and a blood culture was ordered in the ED, once a week. Baseline data of patients were then gathered from the electronic health record by trained students, using a script and predefined answer fields. These data were entered in a clinical data management platform, Castor EDC, 26 in compliance with Good Clinical Practice regulations.

The primary outcome was the diagnostic accuracy of PCT to exclude bacteremia at the predefined cutoffs of < 0.10 µg/L, Secondary outcomes were the difference between incidence of bacteremia in patients with and without viral infection and the use of antibiotics.

All data analyses were performed in SPSS version 26 

Due 

Reporting was done in concordance with the guideline for Standards for Reporting diagnostic Accuracy (STARD) 2015. 27

During the study period a total of 767 patients presented with suspected infection at the ED. A total of 221 patients were excluded because of missing data; they lacked either blood culture (n=212), PCT (n=30), or both values. Figure 1 displays 

The median PCT in the total study population (n=546) was 0.15 µg/L (IQR 0.06-0.57). The area under the curve (AUC) was 0.86 (95% CI 0.81-0.91) and is displayed in Figure 2 . The sensitivity, specificity, PPV and NPV, and LRs at the prespecified cutoffs are presented in Table 2 . Table 3 . In the group with a viral infection, the sensitivity was 100% (95% CI 63.1-100) and specificity was 81.2% (95% CI 75.1-86.3). Table 4 .

Eleven patients had a PCT < 0.5 µg/L but a true positive blood culture.

None had a proven viral infection. The patient characteristics are summarized in Table S3 . None of these patients died within 30 days of this 

An important limitation is that this study focuses on bacteremia. Blood cultures are the gold standard for detecting bacteria in blood. However, a negative blood culture is no guarantee that there is no bacterial infection. Patients with pneumonia have low rates of bacteremia. 28 In addition, patients previously treated with antibiotics before presentation at the ED might have lower yield of blood culture. 29 Another limitation is that this study has a very low rate of bacterial coinfection. This may limit the generalizability of our findings. However, the rate of coinfection in COVID-19 has been reported as 3.5%, which is comparable to our findings. The low rate of coinfection we found is probably explained This might influence the probability of bacteremia and limit external validity.

Although all patients underwent influenza A/B/RSV, and in 2020 SARS-CoV-2 testing, we did not limit our analysis to patients with influenza, RSV, and SARS-CoV-2. We pooled all viral infections that were found, because we expected any viral explanation for infectious complaints would make the chance of also having bacteremia smaller.

In SARS-CoV-2 infection it has become clear that the incidence of bacterial (co)infection is very low. The sensitivity analysis, excluding the SARS-CoV-2 patients, did not meaningfully change our results.

Our study found that PCT performed better in patients with a viral infection, with a higher cutoff than in patients without viral infection.

Previous publications have already advocated to vary the cutoff of PCT based on the likelihood of (severe) bacterial infection. Our results indicate that PCT is a promising tool to rule out bacteremia in patients with a viral infection. This finding needs to be confirmed in a larger population of patients with viral infections, especially because the rate of coinfection in our cohort was low. In patients without a viral infection, PCT needs to be interpreted with caution, especially in patients with a short duration of symptoms.

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Optimal use of procalcitonin to rule out bacteremia in patients with possible viral infections

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

None to declare