Evaluation of the Roche Cobas Liat Flu/RSV Assay for Management of Influenza in the Emergency Department
Phase: NA
Conditions: Influenza, Human
Sponsor: University of California, Davis

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TITLE: EVALUATION OF THE ROCHE COBAS LIAT FLU/RSV ASSAY FOR 
MANAGEMENT OF INFLUENZA IN THE ED 
PI: Larissa May, MD, MSPH, MSHS, Director of ED Antibiotic Stewardship, UC Davis 
Co-PI: Nam Tran, PhD, Associate Director, Point of Care Testing Center for Teaching and 
Research, UC Davis 
Version: October 24, 2018 
A. Objective
Roche Cobas Liat Flu/RSV POC Assay and procalcitonin testing as part of a stewardship 
intervention optimizes antiviral treatment and reduces antibiotic treatment for ED patients (under 
50 years of age) with suspected influenza or RSV v. standard care  using a prospective, patient-
randomized design. In addition to the primary outcome, we will evaluate secondary outcomes 
including aggregate physician adherence to CDC guidelines for the treatment of influenza, 
antibiotic duration, hospital admission, and emergency department (ED) return visits within 30 
days for patients diagnosed with influenza and RSV. Additional secondary outcomes would 
include time to resolution of symptoms, return to school/work, and subsequent healthcare 
utilization (e.g. doctor visits) obtained through patient self-report. 
Hypothesis: The rapid waived POC assay and procalcitonin, as part of a stewardship 
intervention will lead to reduced antibiotic treatment by 20 percentage points compared to the 
control group for antibiotic non-responsive conditions including ILI and nonspecific URI and 
will increase appropriate antiviral treatment of patients with influenza at high risk recommended 
to receive treatment by 20 percentage points. 
B. Background and Significance and Preliminary Studies
Influenza and Respiratory Syncytial Virus (RSV) impose a serious disease burden in terms of 
morbidity and mortality. In the US alone, these illnesses are estimated to contribute to mean 
annual 51,203 and 17,358 deaths, respectively1. RSV infections are estimated to result in 
approximately 1 of 334 all hospitalizations in children under the age of 5 years each year in the 
U.S2. There is no effective antiviral treatment for RSV, and nosocomial RSV outbreaks are
mainly controlled by isolation of infected cases3, indicating the need for rapid diagnosis. Those
especially at risk of complications from influenza include children who are under 2 years of age,
adults 65 years or older, and those with immune suppression and underlying cardiopulmonary
disease4 5.  Antiviral treatment has been shown to decrease risks of influenza-related
complications in both of these age groups, with treatment most effective if administered within
two days of diagnosis6, 7. However, previous lack of an accurate AND rapid point of care test
for influenza makes prompt diagnosis of influenza a challenge, leading to significant over- and
under-treatment with antiviral drugs8.
The Centers for Disease Control and Prevention (CDC) currently recommend antiviral treatment 
for any patient with suspected influenza who is hospitalized or has severe or complicated 
illness9. In outpatients, antiviral treatment is recommended for patients at high risk of 

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complications due to age or chronic medical conditions9. However, the use of antivirals without 
any test result leads to not only unnecessary treatment, but also the risk of antiviral resistance10. 
Furthermore, physician adherence to these guidelines is low8,11, likely due to knowledge of these 
risks. 
Antiviral under-treatment can be attributed to the poor sensitivity of current rapid diagnostic 
tools. For one, influenza-like illness (ILI) is defined by the CDC as the presentation of fever 
(temperature of 100°F [37.8°C] or greater) and cough or sore throat12. These non-specific 
symptoms contribute to the low sensitivity and specificity of clinical diagnosis, which are 
approximately 64% and 67%, respectively13. This sensitivity drops even further for those who 
meet the CDC criteria of patients at high risk for influenza-related complications. An 
observational cohort study found that the sensitivity of ILI reached only 31% for adult patients 
response8. Thus, sensitivity of clinical diagnosis may be lowest for those who need antiviral 
treatment the most. Rapid influenza antigen tests are more specific, easy to use, and only take 15 
to 30 minutes, but have a low sensitivity comparable to provider diagnosis13,  14. Procalcitonin 
has been demonstrated in multiple clinical trials to provide value in guiding antibiotic use 
particularly in respiratory infections for both adults and pediatric patients15,16
,
17. 
Unfortunately fewer than 40% of patients who are recommended to receive treatment for 
influenza receive it in the ED18. There are a variety of reasons for poor compliance with 
guidelines, including lack of awareness, poor understanding of the potential severity of 
influenza, and lack of accurate rapid diagnostic tests. There is great potential for rapid, 
accurate PCR-based influenza and RSV testing to increase prompt antiviral treatment in high 
risk-patients, decrease antibiotic use in virally infected patients, and improve infection control. 
CLIA waived rapid, accurate testing could guide better diagnosis and management and improve 
patient outcomes. 
C. Study Population
Inclusion criteria: Patients <50 who are evaluated by the clinician for suspected influenza, 
including symptoms of ILI (fever >38 C and cough or sore throat) or non-specific URI for 
whom the clinician suspects RSV or influenza or lower respiratory infection (with or without 
ordering a chest xray).  
Exclusion criteria: Patients who are pregnant, prisoners, or are unable to give informed consent 
in English or Spanish. Patients with influenza-like illness and upper respiratory symptoms for 
whom the provider is unwilling to wait for procalcitonin results. 
Sample size: We plan to enroll 100 patients in each arm over a 12 month period (influenza 
season), which will have 80% power to detect a true 20 percentage point reduction in antibiotic 
use and 20 percentage point increase in adherence to guideline recommendations for antiviral 
treatment. 

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D. Study Timelines
Each subject will participate actively participate in this study for  4 weeks. Additionally, after 30 
 described below in 
SectionWe anticipate that it will take us one year from study implementation to enroll the 
required number of subjects. We anticipate that the primary analyses will be completed 2 years 
after beginning the study. 
E. Study Endpoints
The primary study endpoint is the determination of whether use of the Roche Liat Flu/RSV 
Assay and procalcitonin testing, as part of a stewardship intervention optimizes antiviral 
treatment and reduces antibiotic treatment for ED patients with suspected influenza. The 
secondary study endpoints are aggregate physician adherence to CDC guidelines for the 
treatment of influenza, antibiotic duration, hospital admission, ED return visits within 30 days 
for patients diagnosed with influenza and RSV, time to resolution of symptoms, return to 
school/work, and subsequent healthcare utilization (e.g. doctor visits) obtained through patient 
self-report. 
F. Research Design and Methods
This will be a prospective, patient-oriented, pilot randomized clinical trial to evaluate (in 
aggregate) both the use of the Flu/RSV Assay, procalcitonin, and the use of pharmacist-led 
education for providers in the interpretation of these test results. Children and adults <50 years 
of age who present to the pediatric ED of the UC Davis Medical Center with influenza-like 
illness (ILI),upper or lower respiratory infection (URI) will be eligible to participate. 
Consented patients in the pediatric ED will be randomized into two arms: The intervention arm 
will receive procalcitonin with a patient specific stewardship intervention during the ED visit. 
The intervention will be pharmacist-led and include direct delivery to clinicians of information 
about interpreting test results and recommendations for antiviral-treatment for high-risk patients, 
and infection control precautions for patients being hospitalized with a positive RSV or influenza 
test and avoidance of antibiotics where not indicated. Clinician adherence to treatment guidelines 
with and without the educational intervention will be compared. Patients randomized to this arm 
will also have 1 ml of blood drawn for procalcitonin (PCT) analysis to identify bacterial 
infections. This sample will be taken at the time of a blood draw for standard clinical labs, or 
from an IV if one is in place. If no blood draw is ordered for standard of care and/or no IV is 
placed, patients will be given the option to consent to an extra needle stick for the purpose of 
research if both the clinician and patient agree to wait for the test result. Interpretation of the 
procalcitonin where obtained will be included in the intervention by the ED pharmacist. We will 
use the following protocol to guide clinicians in recommendations for antibiotic therapy. 
Procalcitonin will be an adjunct to guiding decision making for antibiotic use and will provide 
added value for both patients diagnosed with RSV and flu, as well as promote reduced antibiotic 
use for patients who do not have diagnosed flu or RSV and help guide appropriate treatment for 
those patients suspected of having LRTI. We will use a conservative protocol in both infants 
and older children similar to the figure attached but with a cutoff of 0.5 for recommendation of 
initiation of therapy in patients suspected of having LRTI. 

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The second arm will be standard care. 
Physicians and patients will not be blinded to test type. Tests will be performed on a real-time 
basis in the ED. All results will be delivered via standard of care through the EMR. 
For each of these groups, data of the frequency and duration of antibiotic administration, 
antiviral use, adherence to evidence based guidelines for treatment of influenza, disposition, 
concomitant diagnoses, isolation, hospitalizations, and unscheduled return visits or readmissions 
within a 30 day period will be collected and compared. In addition, we will compare 
procalcitonin levels for patients diagnosed with RSV or influenza by the Roche LIAT in the test 
arm compared to those found to have evidence of bacterial infection based on chest xray, blood 
culture, and other ancillary tests. Where not recommended, reason for antibiotic use will be 
documented by the pharmacist and abstracted from chart review. 
Research coordinators will contact patients and/or parents at 1 and 4 weeks after enrollment for 
self-reported secondary outcomes including symptom resolution, return to school/work, and 
follow up healthcare visits, medication adherence (to antibiotics and/or antivirals), and adverse 
events. 
G. Data Management and Confidentiality
All members of the researcher team will be trained in the ED EMR and HIPAA according to IRB 
and hospital policy. All records will be stored on a password protected computer or UCD 
encrypted shared drive, or locked in a file cabinet, accessible only to researchers. All data will be 
coded and the linking code will be kept separate from the main data analysis file. 
H. Withdrawal of Subjects
Subjects may be withdrawn from the study without their consent if: 
Their treating physician feels it is no longer prudent for the patient to participate in the 
study. 
I. Risks and Side Effects
For the primary subjects we will be using identifiable protected health information, therefore 
there are inherent possible confidentiality risks. However, all identifiable data is accessible only 
to trained users and clinicians who have passwords to the EMR system. Any confidentiality 
risks are minimal. Identifiable information will be stored in a password-protected database, 

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where patients will be assigned code numbers. Medical information will be stored in a separate 
password-protected database, sorted by code numbers. At the completion of the data analysis all 
identifiers will be erased from the records. 
In addition, we plan to analyze aggregate clinical practice patterns through structured data forms. 
No identifiable data on the clinician will be recorded on research forms. No information on staff 
This study also presents several possible physical risks to the subjects randomized to Arm 1 of 
this study. Risks related to venipuncture for those who consent to an extra needle stick include 
pain, bruising, bleeding, or infection at the blood drawing site. The total volume of blood 
obtained for this study in the ED will not exceed 1 mL. 
J. Benefits
This study may benefit the general public by improving clinical diagnosis and management of 
influenza. 
K. Provisions to Protect the Privacy Interests of Subjects
Patients being considered for enrollment into this study will be approached in their ED rooms to 
assess their interest and willingness to participate in this study. Patients may request that those 
present step outside or remain in the room during the informed consent process and discussion. 
L. Costs To Subjects
Procalcitonin testing will be provided at no cost to the subjects and funded by Roche. Patients 
will not be charged for the procalcitonin testing and it will not be submitted for insurance 
reimbursement. 
M. Subject Compensation
Subjects will receive a $10 gift card for their participation in the study. 
N. Facilities and Equipment
Drs. May and Tran are both graduates of NIH-supported clinical research training programs 
(e.g., K30, K12/KL2) with extensive experience conducting clinically-oriented translational 
research and emerging national reputations in their respective areas. We collectively feel that 
clinical outcomes studies are an essential and much needed step to demonstrate the real value 
and impact of molecular testing. Dr. May was recruited specifically to UC Davis to direct the 
first ED based antibiotic stewardship program in the nation to our knowledge and will leverage 
her expertise in translating rapid molecular diagnostic testing to improve clinical outcomes in the 
ED setting. UC Davis is also an up-and-coming research institution nationally and the UC Davis 
Department of Emergency Medicine is among the most highly respected academic and research- 
oriented emergency departments in the United States. The pediatric ED is a member of the 
national Pediatric Emergency Care and Research Network, which has been funded by NIH for 
many years and participated in numerous pediatric clinical trials including a focus on infectious 
diseases. The UC Davis Department of Emergency Medicine is well suited for this project, 
having demonstrated broad and sustained growth in its research program and productivity over 
the past decade. The Department demonstrates its support for research with a robust research 

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infrastructure, which includes a Vice Chair for Research, two Research Managers (one focused 
on multicenter research), and four full-time clinical research coordinators. 
O. Devices
I confirm that all investigational devices will be labelled in accordance with FDA regulations and 
stored and dispensed in such a manner that they will be used only on subjects and be used only 
by authorized investigators. 
P. Statistical Analysis
We will use standard descriptive statistics to summarize patient characteristics at randomization; 
mean and standard deviation (SD) for continuous variables and frequency and proportion for 
categorical variables. We will indicate the count of missing data for each variable. For the 
comparison of the primary outcomes, we will use frequency and proportions by arm, and 
compute a point estimate for the difference along with 95% confidence interval (CI) and p-value. 
We will stratify analysis based on flu status. For primary analyses (unstratified), we will use a 
Chi-square test (and Fisher exact test), and for stratified analyses, we used Mantel-Haenszel 
method. Secondary outcomes will be performed similarly. Statisticians and other investigators 
will remain blinded to treatment identity (e.g., data analyses with A/B coding). For all analyses, 
we will use SAS 9.4 (SAS Institute, Cary, NC).

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Q. References & Literature Cited
1 Thompson WW, Shay DK, Weintraub E, et al. Mortality Associated With Influenza and Respiratory Syncytial 
Virus in the United States. JAMA. 2003;289(2):179-186. 
2 Hall CB, Weinberg GA, Iwane MK, et al. The burden of respiratory syncytial virus infection in young children. N 
Engl J Med. 2009;360(6):588-598. 
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virus is present in the neonatal intensive care unit. J. Med. Virol. 2015 
4 Zhou H, Thompson WW, Viboud CG, Ringholz CM, Cheng PY, Steiner C, Abedi GR, Anderson LJ, Brammer L, 
Shay DK. Hospitalizations associated with influenza and respiratory syncytial virus in the United States, 1993-2008. 
Clin Infect Dis. 2012 May;54(10):1427-36 
5 CDC. Children, the Flu, and the Flu Vaccine. (2015, August 21). Retrieved October 26, 2015, from 
http://www.cdc.gov/flu/protect/children.htm 
6 Lizheng S, Loveless M, Spagnuolo P, Zhang M, Liu S, Liu J, Xu Y, Chen E, and Han J. Antiviral Treatment of 
Influenza in Children: A Retrospective Cohort Study. Advances in Therapy Adv Ther. 2014;31(7) 735-50. 
7 CDC. Use of Antivirals. (2015, February 25). Retrieved October 26, 2015, from 
http://www.cdc.gov/flu/professionals/antivirals/antiviral-use-influenza.htm 
8 Dugas AF, Valsamakis A, Atreya MR, Thind K, Manchego PA, Faisal A, Gaydos CA, and Rothman RE. Clinical 
Diagnosis of Influenza in the ED. The American Journal of Emergency Medicine. 2015. n. pag. 
9 CDC. Use of Antivirals. (2015, February 25). Retrieved October 26, 2015, from 
http://www.cdc.gov/flu/professionals/antivirals/antiviral-use-influenza.htm 
10 Li TCM, Chan MCW, Lee N. Clinical Implications of Antiviral Resistance in Influenza. Hagedorn C, ed. Viruses. 
2015;7(9):4929-4944. 
11 Dugas AF, Monteforte B, Puri A, Awad M, Hsieh Y, Rothman R. ED Compliance with Influenza Antiviral 
Recommendations. The American Journal of Emergency Medicine. 2014;32(12): 1550-552. 
12 CDC. Overview of Influenza Surveillance in the United States. (2015, October 13). Retrieved October 26, 2015, 
from http://www.cdc.gov/flu/pdf/weekly/overview.pdf 
13 Petrozzino JJ, Smith C, Atkinson MJ. Rapid diagnostic testing for seasonal influenza: an evidence-based review 
and comparison with unaided clinical diagnosis. Journal of Emergency Medicine 2010; 39(4): 476-490.e1. 
14 Stein J, Louie J, Flanders S, Maselli J, Hacker JK, Drew WL, Gonzales R. 2005. Performance characteristics of 
clinical diagnosis, a clinical decision rule, and a rapid influenza test in the detection of influenza infection in a 
community sample of adults. Ann. Emerg. Med. 46:412 419. 
15 Rhee C.Using Procalcitonin to Guide Antibiotic Therapy.Open Forum Infect Dis. 2016 Dec 7;4(1):ofw249. 
16 Schuetz P1, Albrich W, Mueller B.Procalcitonin for diagnosis of infection and guide to antibiotic decisions: past, 
present and future.BMC Med. 2011 2;9:107. 
17 Baumann P1, Baer G1, Bonhoeffer J2, Fuchs A3, Gotta V3, Heininger U1, Ritz N1,3, Szinnai G4, Bonhoeffer 
J1.Procalcitonin for Diagnostics and Treatment Decisions in Pediatric Lower Respiratory Tract Infections. 
Front Pediatr. 2017 

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18 Dugas AF, Valsamakis A, Atreya MR, Thind K, Alarcon Manchego P, Faisal A, Gaydos CA, Rothman RE. 
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