Respiratory Medicine

Evaluation of pharmacist guided intervention using procalcitonin and respiratory virus testing

a b s t r a c t

Introduction: Acute Respiratory infections make up a sizable percentage of emergency department (ED) visits and many result in antibiotics being prescribed. procalcitonin has been found to reduce antibiotic use in both outpatient and critical care settings, yet remains underused in the ED. This study aimed to evaluate whether point of care molecular influenza And respiratory syncytial virus testing, PCT, and a pharmacist driven ed- ucational intervention in aggregate optimizes antibiotic and antiviral prescribing in the ED setting.

Methods: A randomized trial of the Cobas Liat Flu/RSV Assay, procalcitonin, and the use of pharmacist-led educa- tion in patients 0-50 years of age being seen in the ED for Influenza Like Illness (ILI) or acute respiratory illness. The study enrolled 200 ED patients between March 2018 and April 2022.

Results: There was little difference in antibiotic or antiviral prescribing between the intervention and control groups in this study (39%-32% = 7.0%, 95% CI: -6.2, 20.2, P = 0.30). However, a post-hoc analysis of the use of procalcitonin showed results were used as indicated in the ED (P = 0.001).

Conclusion: PCT can be used in both adult and pediatric populations to help guide the decision of whether to treat with antibiotics in the ED setting. Pharmacist guided education may not be a driving factor.

(C) 2023 Published by Elsevier Inc.

  1. Introduction

Influenza and RSV pose a significant Disease burden in terms of mor- bidity and mortality worldwide. acute respiratory tract infections account for 12.2% of all emergency department (ED) visits, and antibiotics are pre- scribed in 61% of these encounters [1]. Access to rapid diagnostic testing in the ED is one strategy to reduce inappropriate antibiotic use for respira- tory infections. Among the diagnostics tests used, procalcitonin tests (PCT) have the potential to significantly reduce the length of antibiotic therapy [2], as well as decrease antibiotic side effects [2,3]. Procalcitonin in adults have been linked to a reduction in antibiotic use in primary care [2,4,5], Inpatient units [2,6,7], and emergency departments [2,8,9] yet remain understudied in pediatric ED patients and as part of a con- certed Antimicrobial stewardship intervention.

There is a need to develop additional strategies to address inappro- priate Antibiotic prescribing for respiratory illnesses in the ED [1,10].

* Corresponding author.

E-mail addresses: [email protected] (A. Andrade), [email protected] (H. Bang), [email protected] (K. Reddick), [email protected] (B. Villasenor), [email protected] (N.K. Tran), [email protected] (L. May).

Implementing antibiotic stewardship programs in outpatient settings has become a national priority, with the goal of reducing adverse events, opportunistic infections including C. difficile, antibiotic resistance, hospi- tal costs, and lengths of stay [11,12].

  1. Methods

We conducted a pilot randomized clinical trial to evaluate both the use of the point of care (POC) Flu/RSV Assay, PCT, and pharmacist-led result-based education for ED physicians in aggregate compared to usual care. The study took place at a an urban-rural quaternary level 1 trauma medical center with 625 Hospital beds with an annual ED vol- ume of 85,000. The UC Davis Institutional Review Board approved this trial.

From March 2018 to February 2019, we enrolled patients <21 years old, who were evaluated by the clinician for suspected influenza like ill- ness or non-specific URI for whom the clinician ordered a POC flu/RSV assay. Enrollment during this period was lower than expected, and as a result of this in March 2019 we opened enrollment to patients <50 years old and removed the requirement of having a POC flu/RSV assay ordered to be eligible. The inclusion criteria were updated to include

https://doi.org/10.1016/j.ajem.2023.01.041 0735-6757/(C) 2023 Published by Elsevier Inc.

patients who were evaluated by the clinician for suspected influenza, including symptoms of ILI (fever, cough, sore throat) or non-specific URI for whom the clinician suspected RSV or influenza or lower respira- tory infections (with or without x-ray). Exclusion criteria during the study included patients who were pregnant, prisoners, or unable to give informed consent in English or Spanish. We also excluded patients for whom the physician was unwilling to wait for a PCT result. Having a PCT ordered as part of the clinical care plan did not exclude a patient from participation. Because of the COVID-19 pandemic and institutional research pause, the study closed for enrollment between March 14, 2020, and November 19, 2020. When enrollment resumed, the study excluded patients who tested positive for COVID-19. Excluding COVID-19 positive patients was not a protocol change but reflects a workflow modification to follow university policy. Screening occurred when research coordinators (RCs) were available and during ED phar- macist hours 7 am-1 am Monday through Friday, and 1 pm-1 am Satur- day and Sunday.

Consented patients in the ED were randomized into one of two arms. The patient, RC, and treating physician were not blinded to the patient’s allocation. Patients randomized to the intervention arm received PCT with a patient specific stewardship intervention. The stewardship inter- vention was pharmacist-led guidance about antibiotic and antiviral pre- scribing recommendations to the treating physician. Fig. 1 displays the

PCT algorithm used. Patients randomized to this arm had 1 mL of Blood drawn for the PCT to identify bacterial infections. Whenever pos- sible, the blood draw was timed with standard clinical labs, or from an IV if one was in place. The control arm received usual care per provider practice.

All enrolled patients were asked to participate in a 7-day and a 4- week follow-up phone call. All patients had a 30-day chart review to evaluate outcomes.

The (co-)primary outcome is the rates of Antibiotic and Antiviral prescriptions in the ED for influenza positive and negative patients.

The secondary outcome measures included symptoms resolution,

number missed school days and number of missed workdays. All were assessed at 7-days and 4-weeks.

Study data were collected and managed using REDCap electronic data capture tools hosted at UC Davis. We used standard descriptive sta- tistics to summarize patient characteristics at randomization; mean and standard deviation (SD) for continuous variables and frequency and proportion for categorical variables. We indicated the count of missing data for each variable. For the comparison of the primary outcomes, we used frequency and proportions by arm, and computed a point esti- mate of the difference along with 95% confidence interval (CI) and p– value. We did not adjust p-values for multiple comparisons but presented all outcomes analyzed (without selective reporting).

Image of Fig. 1

Fig. 1. PCT Algorithm1.

1 Algorithm used by pharmacists to make recommendations for antibiotic use based on procalcitonin values for patients with influenza-like illness, acute respiratory illness, or lower

respiratory tract infections (LRTI).

Fig. 2. Consort Diagram2.

2 Diagram showing subject enrollment, randomization, allocation, follow-up, and analysis.

Table 1

Patient characteristics at randomization (N = 200).

Intervention (N = 100)

Usual Care (N = 100)

institutional research restrictions due to COVID-19. See Fig. 2 for the CONSORT diagram.

Out of the 200 patients enrolled 51 were found to be positive for Influ- enza A, B, or RSV. 28 positives were in the intervention group and 23 pos-

Age, in month, mean (SD) 149 (157) 124 (140)

Gender, n Female 44 47

Race, n Black 18 18

White 46 (N = 74) 42 (N = 73)

Ethnicity, n Hispanic

49 (N = 99)

46

Education, n Some college

16 (N = 98)

11 (N = 98)

Height, in inches, mean (SD)

50.5 (16.5) (N = 80)

50.8 (14.9) (N = 77)

Weight, in kg, mean (SD)

40.0 (33.7) (N = 99)

38.7 (34.6) (N = 97)

Temperature, in Celsius mean (SD)

37.7 (1.1)

37.6 (1.0) (N = 99)

Influenza A, n

13

11

B, n

8

5

RSV, n

7

7

Sample size (N) is indicated when missing data are present.

Furthermore, we conducted a stratified analysis based on flu status. For primary (unstratified) analyses, we used Chi-square test (and Fisher exact test), and for stratified analyses, we used Mantel-Haenszel method. Secondary outcomes and post-hoc exploratory analyses were performed similarly. During statistical analyses, statisticians and other investigators were blinded to treatment identity (e.g., data analyses with A/B coding). All CIs and p-values are two-sided and unadjusted for multiple testing (e.g., for 2 primary outcomes). For all analyses, we used SAS 9.4 [13].

  1. Results

We enrolled 200 patients over the 4-year enrollment period includ- ing breaks in enrollment during the summer months and in 2020 for

itives were in the usual care group. Patient demographics are shown in Table 1. Overall, the intervention of PCT testing with pharmacist led inter- vention did not have a statistically significant effect on the rate of antibi- otic prescribing compared to the control group (39% – 32% = 7.0%, 95% CI:

-6.2, 20.2, P = 0.30 from Chi-square and 0.38 from Fisher exact) on Table 2. When stratified by influenza and RSV status, there was also no difference in antibiotic (94% (-4.5, 23.2), P = 0.18) and antiviral (1.0%

(-7.6, 9.2), P = 0.81) prescribing between the two groups (Table 3).

Our 7-day survey completion rate was 85.5% versus a 4-week follow-up completion rate of 77.0%. Out of our secondary outcomes, symptom resolution by day 7 (P = 0.09) is the only one trending in the direction of a difference with more patients in the intervention group reporting symptom resolution than the control one week after ED visit. See Table 4 for secondary outcome analyses.

We performed a post hoc analysis to investigate whether the procalcitonin results themselves drove provider prescribing of antibi- otics. Table 5 lists results stratified by PCT. ED physicians were likely to follow PCT guidelines when prescribing antibiotics for patients with PCT >0.25 and not prescribing when <0.25 (P = 0.001) as presented in Table 6. Results stratified by pediatric and adult populations are shown in Table 7.

  1. Discussion

In this study, pharmacist targeted physician education at the bedside to optimize antibiotic and antiviral prescribing did not appear to impact ED clinician decision making in following the guidelines.

Table 2

Primary outcomes analyses.

Outcome

Intervention (N = 100)

Usual Care (N = 100)

Difference in proportions (95% CI), P-value?

Antibiotics, yes

39

32

7.0% (-6.2, 20.2), P = 0.30/0.38

Antivirals, yes

12

10

2.0% (-6.7, 10.7), P = 0.65/0.82

* For overall (combined, primary outcome), Chi-square/Fisher exact test was used for P-value.

Table 3

Stratified by flu status.

Intervention

Usual Care

Difference in proportions (95% CI), P-value??

Flu A/B/RSV + (N = 31)

Flu/RSV – (N = 58)

Flu A/B/RSV + (N = 25)

Flu/RSV – (N = 65)

Antibiotics, yes

6

28

7

20

9.4% (-4.5, 23.2), P = 0.18

Antivirals, yes

11

1

9

0

1.0% (-7.2, 9.2), P = 0.81

?? For stratified analyses, patients with unknown flu status were excluded. Mantel-Haenszel method was used for CI and P-value.

Table 4

Secondary outcomes analyses.

Outcome

Intervention

Usual Care

P-valuea

n/N

n/N

Return to ED

19/100

16/100

0.71

Symptoms resolved by 7-days?

66/87

52/82

0.09

Symptoms resolved by 4-weeks?

62/76

N, mean (SD), median

61/77

N, mean (SD), median

0.84

School days missed by child at 7-days

N = 100, 2.6 (3.0), 0

N = 100, 2.6 (3.1), 0

0.91

Workdays missed at 7-days

N = 100, 2.5 (2.7), 2

N = 100, 3.1 (3.1), 2

0.24

School days missed by child at 4-weeks

N = 72, 1.8 (3.7), 0

N = 70, 1.4 (4.1), 0

0.16

Workdays missed at 4-weeks

N = 75, 0.9 (1.7), 0

N = 77, 1.2 (3.6), 0

0.43

a P-values were not adjusted for multiplicity. Data with unknown status were excluded in total n. For continuous variables, Wilcoxon test was used for p-values.

Table 5

Post-hoc exploratory analyses stratified by PCT status.

Intervention

Usual Care

P-value

PCT >= 0.25

(N = 26)

PCT < 0.25

(N = 67)

PCT >= 0.25

(N = 9)

PCT < 0.25

(N = 24)

Antibiotics yes

17

21

7

11

0.15

Antivirals yes

3

7

1

1

0.44

Table 6

Post-hoc exploratory analysis PCT & outcomes.

PCT >= 0.25

(N = 35)

PCT < 0.25

(N = 91)

P-value

Antibiotics yes

24

32

0.001

Antivirals yes

4

8

0.74

Nonetheless, a post hoc analysis showed that physicians do use procalcitonin to guide antibiotic use with or without pharmacist inter- vention. We suspect that the small sample size (which may be reason- able for pilot trials) and PCT becoming more common as a part of the usual care in our institution contributed to us not seeing a statistically significant difference in antibiotic prescribing between these two groups. Yet, clinical meaningfulness of the observed point estimates of differences (7-10%) along with corresponding CIs may warrant consid- eration [14] and could inform future study/trial designs.

Research on the use of rapid respiratory panels (RRP) in the ED have shown mixed results with respect to decreasing antibiotic prescribing in the ED, with one study finding an association between RRP use and de- creased antibiotic use for both pediatric and adult patients [15], and two studies on pediatric patients showing no/little decrease [16,17].

Procalcitonin in pediatric populations could likely be a tool to reduce inappropriate antibiotic prescribing but research is thin with respect to pediatrics. Even in adults, workflow considerations and heuristics are critical to the use of PCT in adult ED patients with acute respiratory tract infection. For example, a patient-level RCT of PCT in US hospitals published by Huang et al. in 2018 [18] found that there was no signifi- cant difference between a procalcitonin group and a control group re- garding antibiotic use, treatment duration, and adverse outcomes, although this could be due to increased antibiotic stewardship efforts in recent years and a lower number of patients with pneumonia en- rolled compared to other studies, or to biased selection of a population of subjects being admitted with lower respiratory tract infection for whom the decision to prescribe an antibiotic had already been made prior to the PCT result. Thus, implementation of PCT within clinical workflow, appropriate populations, and the stewardship context are critical to successful use in clinical decision making.

Additional study limitations included challenges to enrollment over

4 influenza seasons, interrupted by COVID-19. Institutional closure of research during the early part of the pandemic stopped enrollment tem- porarily. Furthermore, concerns around transmission of COVID-19 de- layed restarting enrollment, and a subsequent need to wait for a COVID-19 test to result and confirm negative COVID-19 prior to enroll- ment. Thus, the latter half of the study enrolled a higher acuity

population. At the end of the study, more patients had PCT ordered in the control group as compared to the beginning of the study. This was likely related to waiting for COVID-19 test to enroll patients which de- layed consent, and mildly ill patients were more likely to be discharged, while more critically ill patients stayed in the ED for further testing. In addition, particularly in pediatric patients, there was a shift in practice to more commonly ordering procalcitonin in patients being admitted and in adults being evaluated for respiratory illness. The UC Davis Med- ical Center introduced PCT testing in December 2014; this early adop- tion may also be a contributing factor in why we did not see a difference. It is possible our early adoption made physicians more will- ing to follow PCT results as part of their clinical decision making and aligns with the results of our ad hoc analysis.

  1. Conclusion

Procalcitonin can be used to guide antibiotic prescribing in adults and pediatric patients. There does not appear to be a significant impact of direct patient specific education and guideline provision in decision making around antibiotic use for respiratory tract infection patients in the ED; however, additional research is needed on the role of targeted interventions that incorporate PCT and point of care molecular tests in improving antimicrobial stewardship.

Funding

This investigator-initiated study was funded by Roche Diagnostics Corporation.

CRediT authorship contribution statement

Amia Andrade: Project administration, Writing – original draft, Methodology. Heejung Bang: Formal analysis, Writing – original draft. Katie Reddick: Investigation, Writing – review & editing. Bryan Villasenor: Investigation, Writing – review & editing. Nam K. Tran: Writing – review & editing. M.D. Larissa May: Conceptualization, Funding acquisition, Methodology, Supervision, Writing – review & editing.

Declaration of Competing Interest

Roche Diagnostics US Medical and Scientific Affairs sponsored this study though had no role in protocol development.

Drs. May and Tran have received fees for advisory board participa- tion and speaker honoraria from Roche.

Table 7

Post-hoc exploratory analysis stratified by pediatric vs. adult.

Intervention

Usual Care

P-value

Ped (N = 69)

Adult (N = 31)

Ped (N = 80)

Adult (N = 20)

Antibiotics yes

28

11

24

8

0.32

Antivirals yes

6

6

8

2

0.77

PCT was missing for 7 patients in Intervention and 67 patients in Usual Care for consistency and clarity.

Dr. Bang is partly supported by the National Institutes of Health through grant UL1 TR001860.

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