Clinical Infectious Diseases

REVIEW ARTICLE

Rapid Molecular Tests for Influenza, Respiratory Syncytial

Virus, and Other Respiratory Viruses: A Systematic Review
of Diagnostic Accuracy and Clinical Impact Studies
Laura M. Vos,1 Andrea H. L. Bruning,2 Johannes B. Reitsma,3 Rob Schuurman,4 Annelies Riezebos-Brilman,4 Andy I. M. Hoepelman,1 and
Jan Jelrik Oosterheert1
1
Department of Infectious Diseases, University Medical Center Utrecht, Utrecht University, 2Department of Medical Microbiology, Amsterdam University Medical Center, University of Amsterdam,
and 3Julius Center for Health Sciences and Primary Care, and 4Department of Microbiology and Virology, University Medical Center Utrecht, Utrecht University, The Netherlands

We systematically reviewed available evidence from Embase, Medline, and the Cochrane Library on diagnostic accuracy and clinical
impact of commercially available rapid (results <3 hours) molecular diagnostics for respiratory viruses as compared to conventional
molecular tests. Quality of included studies was assessed using the Quality Assessment of Diagnostic Accuracy Studies criteria for
diagnostic test accuracy (DTA) studies, and the Cochrane Risk of Bias Assessment and Risk of Bias in Nonrandomized Studies of
Interventions criteria for randomized and observational impact studies, respectively. Sixty-three DTA reports (56 studies) were
meta-analyzed with a pooled sensitivity of 90.9% (95% confidence interval [CI], 88.7%–93.1%) and specificity of 96.1% (95% CI,
94.2%–97.9%) for the detection of either influenza virus (n = 29), respiratory syncytial virus (RSV) (n = 1), influenza virus and RSV
(n = 19), or a viral panel including influenza virus and RSV (n = 14). The 15 included impact studies (5 randomized) were very het-
erogeneous and results were therefore inconclusive. However, we suggest that implementation of rapid diagnostics in hospital care
settings should be considered.
Keywords. rapid test; molecular diagnostics; diagnostic accuracy; impact; review.

Acute respiratory tract infections (RTIs) have a high disease lower RTI [6]. Although being faster in comparison to conven-
burden and are the third cause of death worldwide [1, 2]. tional techniques, RT-PCR–based diagnostics still took up to 48
Respiratory viruses predominate as causative pathogens in hours from sampling to result [6], whereas nowadays we have ac-
patients hospitalized with acute RTI, accounting for 50%–66% cess to rapid diagnostics with turnaround times of >1 hour [11].
of microbiological etiologies [3–5]. Rapid identification of Whether these rapid methods lead to improved patient out-
viral etiologies may improve effective patient management by comes, however, is still under debate. First, there is a wide range of
influencing decision making on antibiotic treatment, antiviral rapid tests available with large differences in diagnostic accuracy.
therapy, hospital admission, length of stay, and implementation Reviews evaluating accuracy of available rapid tests for respira-
of infection-control measures to prevent further transmission tory viruses either included a heterogeneous group of tests in-
[2, 6]. It may also lead to avoidance of unnecessary costs and cluding both ultrarapid but less sensitive antigen-based tests and
antimicrobial resistance by reducing unnecessary prescriptions more sensitive but slightly slower molecular tests [11–13], com-
of antibiotics [7–10]. pared rapid tests to outdated techniques as viral culture or immu-
About a decade ago, the transition from conventional tech- noassays [13], focused on only 1 or 2 viral pathogens, mostly
niques as viral cultures and immunoassays to reverse-­transcription influenza virus [11], or focused on 1 specific assay [14, 15]. To
polymerase chain reaction (RT-PCR) techniques did not result in guide physicians and hospitals in their choice for rapid diagnostic
a reduction in overall antibiotic use in hospitalized patients with tools and how to value and interpret their results, a diagnostic
test accuracy (DTA) review of available molecular rapid tests as
Received 5 November 2018; editorial decision 7 January 2019; accepted 16 January 2019;
compared to the best available reference standard—RT-PCR or
published online January 28, 2019. other molecular methods—is essential. Second, even with tests
Correspondence: L. M. Vos, Department of Infectious Diseases, University Medical Center
that demonstrate high accuracy, there are conflicting conclusions
Utrecht, Utrecht University, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands (l.m.vos-6@
umcutrecht.nl). on whether implementation of these tests results in better patient
Clinical Infectious Diseases®  2019;69(7):1243–53 outcomes. A review on clinical impact of rapid molecular tests
© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society
of America. This is an Open Access article distributed under the terms of the Creative Commons
that summarizes and assesses sources of heterogeneity to explain
Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which these discrepant results is therefore highly needed.
permits non-commercial re-use, distribution, and reproduction in any medium, provided the original
work is properly cited. For commercial re-use, please contact [email protected]
In this review, we provide an overview of available molec-
DOI: 10.1093/cid/ciz056 ular rapid tests that can provide results for the detection of

Review of Rapid Molecular Tests for Viruses • CID 2019:69 (1 October) • 1243
respiratory viruses within 3 hours. We systematically summa- quality of the included studies was reviewed using the Quality
rize quality and meta-analyze results of DTA studies and sys- Assessment of Diagnostic Accuracy Studies (QUADAS-2) cri-
tematically review studies evaluating the clinical impact of teria [17] for DTA studies, the Cochrane Risk of Bias tool [18]
rapid molecular testing for respiratory viruses. for randomized clinical impact studies, and the Risk of Bias in
Nonrandomized Studies of Interventions (ROBINS-I) tool [19]
METHODS for nonrandomized clinical impact studies.
We followed the guidance provided by the Cochrane DTA
Working Group [16]. This systematic review was registered Statistical Analysis
in the Prospero database under CRD42017057881. A system- Sensitivity and specificity were calculated using 2 × 2 contin-
atic literature search for both DTA and clinical impact stud- gency tables for all index tests from the included DTA studies.
ies was conducted (Supplementary Materials 1A). The search Sensitivities and specificities of individual studies with their
was performed in Medline, Embase, and the Cochrane Library corresponding 95% confidence intervals (CIs) were presented
on 31 August 2017. Inclusion and exclusion criteria and the in paired forest plots. We used the bivariate random-effects
screening process are described in Supplementary Materials model to meta-analyze the logit-transformed sensitivities and
1B and 1C, respectively. Data extraction for both DTA and specificities to obtain a summary estimate together with a
clinical impact studies was conducted in a systematic man- random-effects 95% confidence and prediction interval. This
ner (Supplementary Materials 1D and 1E). Methodological model takes into account the precision by which sensitivities

Summary of evidence search and selection: DTA and impact studies

Search (n = 4197)
MEDLINE (n = 1869)
Identification

EMBASE (n = 2119)
Cochrane Library (n = 209)

Duplicates excluded
(n = 1255)

Title/abstract screening
(n = 2942)
Screening

Records excluded
(n = 2782)

Full text screening

(n = 160) Records excluded
(n = 127)
Non-rapid index test (n=47)
Non-molecular index test (n=9)
No PCR as reference test (n=10)
Influenza and/or RSV not tested (n=3)
Precommercial test (n=10)
Conference abstract (n=31)
Eligibility

DTA studies included Impact studies included Non-available full text (n=11)
Language non-English/Dutch (n=3)
(n = 29) (n = 4) Review/ modelling study (n=3)

Records included after

cross reference check
(n = 38)
RTI or synonym not in ti/ab (n=31)
Included

DTA studies included Impact studies included Rapid or synonym not in ti/ab (n=18)
Virus not in ti/ab (n=7)
(n = 56) (n = 15) No abstract (n=2)

Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) flowchart. Abbreviations: DTA, diagnostic test accuracy; PCR, polymerase chain
reaction; RSV, respiratory syncytial virus; RTI, respiratory tract infection; ti/ab, title/abstract.

1244 • CID 2019:69 (1 October) • Vos et al

and specificities have been estimated in each study using the Table 1. Characteristics of the Reports (N = 63) from the 56 Included Diagnostic Test
Accuracy Studies
binomial distribution (ie, weighted average) and incorporates
any additional variability beyond chance that exists between Characteristic No. (%)
studies (ie, random-effects model). Results were plotted in
Study design
receiver operating characteristic (ROC) space with 95% con- Cohort study 28 (44.4)
fidence and 95% prediction intervals. The 95% confidence Case-control study 28 (44.4)
region reflects the precision of the pooled point estimate, Partially cohort and partially case-control 7 (11.1)
Data collection
whereas the 95% prediction region represents the region in
Prospective 25 (39.7)
which the individual results of a new, large study evaluating Retrospective 29 (46.0)
the diagnostic accuracy of the same rapid assay are to be ex- Both prospective and retrospective 9 (14.3)
pected. In these plots, sensitivity and specificity estimates of Virus evaluated

the most frequently described assays were pooled per assay. Influenza A and Ba 29 (46.0)
Influenza A, B, and RSVb 20 (31.7)
Heterogeneity between studies was assessed by subgroup anal-
Panel of virusesc 14 (22.2)
yses using bivariate random-effects regression for different Study population
study populations, different assays, different viruses that were Children 8 (12.7)
assessed, different study designs, and studies with different Adultsd 7 (11.1)

quality. For clinical impact studies, a descriptive summary of Children and adults 26 (41.3)
Not reported 22 (34.9)
the quality of included studies was given. Results of clinical
Patient symptoms
impact studies were not pooled quantitatively, but presented Patients with ILI or symptoms of an RTIe 36 (57.1)
per clinical outcome arranged by study quality. All analyses Symptoms not described 27 (42.9)
were performed in R Studio, and ROC plots were made using Tests evaluated
AdvanSure (LG Life Sciences)f 3 (4.8)
Stata version 11 software.
Alere i Influenza A&B assay (Alere) 14 (22.2)
Aries Flu A/B & RSV assay (Luminex)f 2 (3.2)
RESULTS
Cobas Liat Influenza A/B (Roche Diagnostics) 5 (7.9)
Diagnostic Accuracy Enigma MiniLab (Enigma Diagnostics Ltd)f 1 (1.6)

After screening (Figure 1), 63 separate reports were included FilmArray (BioFire Diagnostics) 10 (15.9)
Cepheid Xpert Flu Assay (Cepheid) 9 (14.3)
in the meta-analysis from 56 individual DTA study publica-
ePlex RP Panel (GenMark Diagnostics)f 1 (1.6)
tions (Supplementary Materials 2). The main characteristics PLEX-ID Flu Assay (Abbott Molecular)f 1 (1.6)
of the included DTA reports are described in Table 1. The me- RIDAGENE Flu & RSV kit (R-Biopharm AG)f 1 (1.6)
dian sample size in these reports was 95 patients (interquar- Roche RealTime (Roche Diagnostics)f 2 (3.2)

tile range [IQR], 49–196). The included reports evaluated 13 Simplexa Flu A/B & RSV kit (Focus Diagnostics) 9 (14.3)
Verigene Respiratory Virus Plus test (Nanosphere) 5 (7.9)
commercial molecular rapid diagnostic tests. Of these, the
Reference standard
most frequently studied tests were the Alere i Influenza A&B In-house or laboratory-developed RT-PCR 22 (34.9)
assay (Alere, Scarborough, Maine; 14 reports), Cobas Liat Commercial RT-PCRg 41 (65.1)
Influenza A/B (Roche Diagnostics, Indianapolis, Indiana; 5 See Supplementary Materials 2 for the reference list of studies.

reports), FilmArray (BioFire Diagnostics, Salt Lake City, Utah; Abbreviations: ILI, influenza-like illness; RSV, respiratory syncytial virus; RTI, respiratory tract infec-
tion; RT-PCR, reverse-transcription polymerase chain reaction.
10 reports), Cepheid Xpert Flu Assay (Cepheid, Sunnyvale, a
Among these studies, 1 study (Salez et al, 2013) only validated the Cepheid Xpert Flu Assay for

California; 9 reports), Simplexa Flu A/B & Respiratory Syncytial influenza B.

b
Among these studies, 1 study (Peters et al, 2017) only validated the Alere i Influenza A&B assay for RSV.
Virus (RSV) kit (Focus Diagnostics, Cypress, California; 9 c
FilmArray (15 viral targets): RSV-A, RSV-B, influenza A/H1, influenza A/H3, influenza untypable, influ-
reports), and Verigene Respiratory Virus Plus (Nanosphere, enza B, parainfluenza virus types 1–4, human metapneumovirus (hMPV), adenovirus, enterovirus/rhi-
novirus, coronavirus NL63, coronavirus HKU1. For some studies, this panel was only partially validated.
Northbrook, Illinois; 5 reports). AdvanSure (14 viral targets): RSV-A, RSV-B, influenza A, influenza B, parainfluenza virus 1–3, hMPV,
bocavirus, adenovirus, rhinovirus, and coronaviruses OC43, 229E, and NL63. ePlex RP panel (21 viral tar-
The quality of the included DTA studies (n = 56) was gets): RSV-A, RSV-B, RSV untypable, influenza A/H1, influenza 2009 A/H1N1, influenza A/H3, influenza
A untypable, influenza B, parainfluenza virus types 1–4, hMPV, bocavirus, adenovirus, enterovirus/rhino-
assessed using the QUADAS-2 criteria and is summarized in virus, Middle East respiratory syndrome coronavirus, and coronaviruses OC43, 229E, NL63, and HKU1.
Supplementary Figure 1. The biggest concern in terms of quality d
Two adult studies only included immunocompromised patients (Steensels et al, 2017 and
Hammond et al, 2012).
was that a minority (35%) of included studies gave a clear de- e
Among studies that included symptomatic patients, 14 studies included patients with ILI (8 cohort
scription of their selection criteria and/or used a cohort de- studies, 4 case-control studies, and 2 with both a symptomatic cohort; 21 included patients with
symptoms of an upper or lower RTI and 2 that included patients with symptoms that were not
sign for inclusion of patients or specimens. In terms of flow, further specified.
f
17% of studies used samples that were frozen between index Full affiliations of index tests not mentioned in text: AdvanSure (LG Life Sciences, Seoul, Korea),
Aries Flu A/B & RSV assay (Luminex Corporation, Austin, Texas), Enigma MiniLab Influenza A/B &
and reference testing, used multiple different molecular ref- RSV (Enigma Diagnostics, Salisbury, United Kingdom), ePlex respiratory pathogen panel (GenMark
Diagnostics, Carlsbad, California), PLEX-ID Flu assay (Abbott Molecular, Des Plaines, Illinois),
erence standards, and/or excluded samples that had invalid RIDAGENE Flu & RSV kit (R-Biopharm AG, Darmstadt, Germany), and Roche RealTime Ready
Influenza AH1N1 Detection Set (Roche Diagnostics, Indianapolis, Indiana).
results on either the index test or reference standard. For the g
One study used 2 different commercial PCR methods or composite reference with concordance
index test, in the majority of studies it was unclear whether of at least 2 multiplex PCR methods (Popowitch, 2013).

Review of Rapid Molecular Tests for Viruses • CID 2019:69 (1 October) • 1245
 Assay Sample size Year Sensitivity (%, 95% CI) Specificity (%, 95% CI)

Alere i Influenza A&B

Beckmann 436 2015
Bell 230 2014
Chapin 278 2015
Chiarella 114 2016
Davis 589 2017
Hazelton 201 2015
Hurtado 93 2015
Jokela 140 2015
Nguyen 96 2016
Nie 356 2014
Nolte 129 2016
Peters 114 2017
Riazzo 70 2015
Young 87 2017
Pooled

Cepheid Xpert Flu Assay

DiMaio 200 2012
Dugas 281 2014
Li 122 2012
Novak-Weekley 598 2012
Popowitch 212 2015
Salez 127 2012
Salez 90 2013
Salez 281 2015
Wahrenbrock 128 2016
Pooled

Cobas Liat Influenza A/B

Binnicker 197 2015
Chen 1141 2015
Melchers 121 2017
Nolte 129 2016
Young 87 2017
Pooled

FilmArray
Andersson 128 2014
Babady 358 2012
Butt 88 2014
Hammond 33 2012
Hayden 176 2012
Pierce 280 2012
Piralla 152 2014
Popowitch 300 2013
Renaud 59 2012
Van Wesenbeeck 146 2013
Pooled

Simplexa Flu A/B & RSV kit

Alby 350 2013
Hindiyeh 170 2013
Ko 241 2013
Landry 448 2014
Riazzo 70 2015
Selvaraju 730 2014
Steensels 150 2017
Svensson 210 2014
Woodberry 492 2013
Pooled

Verigene Respiratory Virus plus test

Alby 350 2013
Butt 55 2014
Cho 228 2015
Hwang 170 2014
Van Wesenbeeck 144 2013
Pooled

Other assays
Cho (AdvanSure) 437 2014
Douthwaite (Enigma MiniLab) 567 2016
Esposito (RIDA®GENE) 424 2015
Jung (AdvanSure) 454 2015
Juretschko (Aries Flu A/B & RSV assay) 2479 2017
Nijhuis (ePlex RP panel) 343 2017
Rheem (AdvanSure) 320 2012
Tang (PLEX-ID Flu assay) 2617 2013
Tham (Roche RealTime) 419 2012
Tham (Roche RealTime) 419 2012
Voermans (Aries Flu A/B & RSV assay) 447 2016
Pooled

0 20 40 60 80 100 0 20 40 60 80 100

Figure 2. Forest plot for sensitivity (left) and specificity (right) (% with 95% confidence interval) of all study reports (N = 63), stratified and pooled per assay (top to bottom).
In one study (Salez 2012), no negative tested samples were included, so specificity could not be calculated for this study and was therefore excluded from the pooled anal-
ysis. For specificity, 4 studies had an outstandingly low specificity due to the case-control design with inclusion of a very low number of virus-negative patients: 37 negative
patients, of whom 22 tested false positive with the Alere i Influenza A&B assay (Chapin 2015), 2 negative patients, of whom 1 tested false positive with FilmArray (Butt 2014),
3 negative patients, of whom 2 tested false positive with the Verigene Respiratory Virus Plus test (Butt 2014), and 29 negative patients, of whom 10 tested false positive with
the ePlex RP panel (Nijhuis 2017). Please see Supplementary Materials 2 for the reference list of studies. Abbreviation: CI, confidence interval.

results were interpreted without knowledge of the results of the A&B assay to 99.0% (95% CI, 98.3%–99.6%) for the Simplexa
reference test. Flu A/B & RSV kit (P = .000). The specificity of assays detect-
Overall, the pooled sensitivity of all rapid molecular tests was ing a panel of viruses (eg, the FilmArray, AdvanSure, and ePlex
90.9% (95% CI, 88.7%–93.1%) and the pooled specificity was RP panel) was significantly lower than the specificity of assays
96.1% (95% CI, 94.2%–97.9%). Forest plots for both sensitivity detecting only influenza virus and/or RSV (P = .009). Subgroup
and specificity of all included studies are shown in Figure 2. analyses based on differences in study design showed increased
ROC plots with sensitivity and specificity of the most frequently sensitivity of cohort studies as compared to case-control studies
assessed assays are depicted in Figure 3. Subgroup analyses were (P = .009). The pooled sensitivity of studies that only included
conducted to investigate heterogeneity in sensitivity and speci- children (n = 8) was 93.0% (95% CI, 91.5%–94.5%) as com-
ficity (Table 2). The sensitivity of the different index tests ranged pared to a pooled sensitivity of 79.8% (95% CI, 70.7%–88.9%)
from 81.6% (95% CI, 75.4%–87.9%) for the Alere i Influenza in adults (n = 7) (P = .01), whereas the pooled specificity was

1246 • CID 2019:69 (1 October) • Vos et al

Figure 3. Receiver-operating characteristic (ROC) curve plots of most frequently evaluated rapid molecular diagnostic tests: Alere i Influenza A&B assay (A), Cepheid Xpert
Flu Assay (B), Cobas Liat Influenza A/B (C), FilmArray (D), Simplexa Flu A/B & Respiratory Syncytial Virus kit (E), and Verigene Respiratory Virus Plus test (F). The size of the
circles indicates the sample size of the individual studies. The pooled summary estimate is represented by the square, the 95% confidence region by the finely dotted lines,
the 95% prediction region by the striped lines, and the ROC curve by the continuous line.

higher in adults (98.6% [95% CI, 95.5%–100%]) as compared to microbiological laboratory. Seven studies were sponsored by
child studies (80.8% [95% CI, 73.1%–88.4%]) (P = .001). the manufacturer of the diagnostic test [20, 21, 23–25, 28, 29].
The median number of included patients in the studies was 300
(IQR, 121–630) and most studies (n = 9) included only adult
Clinical Impact patients [1, 20, 21, 24–26, 28, 30, 34]. The FilmArray was used
After screening (Figure 1), we included 15 clinical impact most frequently (11 of 15 studies) as a diagnostic intervention
studies [1, 20–33]. Characteristics of included clinical im- test [1, 20, 21, 24, 25, 27–31, 33].
pact studies are described in Table 3. The implemented diag- The quality assessment of all studies is summarized in
nostic rapid molecular test was combined with procalcitonin Supplementary Figure 2. All nonrandomized studies suf-
measurements in 2 studies [21, 30]. Two studies implemented fered from potential confounding bias and bias in outcome
guidelines on treatment decisions based on the rapid test results measurements.
[20, 21], whereas in other studies no changes in treatment rec- The results of the impact studies were very heterogeneous.
ommendations and antibiotic stewardship were made or treat- Clinical outcomes for each study are categorized and summa-
ment consequences of rapid testing were not described. Five rized in Table 4, with studies of higher quality at the top. The
studies were randomized diagnostic impact trials [1, 20, 21, 24, turnaround time of the rapid molecular tests vs reference mo-
25], 6 studies used a nonrandomized before-after design [23, lecular techniques was significantly faster in all studies that
26–29, 32], and 4 studies were observational noncomparative assessed turnaround time (n = 10) [1, 20, 23–25, 27–29, 31,
studies [22, 30, 31, 33]. Only 1 study included patients at >1 32]. Implementation of rapid molecular tests did not decrease
center [22]. Three studies [1, 20, 31] placed the rapid test at the the number of antibiotic prescriptions or the duration of an-
point of care, whereas others located the diagnostic test at the tibiotic treatment. Only 1 multivariable adjusted before-after

Review of Rapid Molecular Tests for Viruses • CID 2019:69 (1 October) • 1247
Table 2. Accuracy Estimates From Subgroup Analyses Using Bivariate Random-effects Regression

Characteristic No. of Studies Pooled Sensitivity, % (95% CI) P Valuea Pooled Specificity, % (95% CI) P Valuea

Population age group

Children 8 93.0 (91.5–94.5) .010 80.8 (73.1–88.4) .001
Adults 7 79.8 (70.7–88.9) 98.6 (95.5–100)
Population symptoms
Respiratory/ILI 34 90.4 (87.2–93.7) .655 96.2 (93.6–98.7) .478
Unclear 29 91.4 (88.6–94.2) 94.8 (91.9–97.7)
Viruses
Influenza 29 87.9 (83.7–92.1) .078b 97.4 (94.2–100) .009b
Influenza + RSV 19 94.1 (90.9–97.4) 96.4 (93.6–99.2)
Panel of viruses 14 91.8 (88.7–95.0) 88.8 (82.7–95.0)
Index test
Alere i Influenza A&B 14 81.6 (75.4–87.9) .000c 94.0 (86.0–100) .623
Cobas Liat Influenza A/B 5 98.1 (90.8–100) 99.7 (88.5–100)
FilmArray 10 89.2 (86.4–92.0) 96.1 (90.5–100)
Simplexa Flu A/B & RSV 9 99.0 (98.3–99.6) 98.2 (93.3–100)
Verigene RV Plus test 5 96.2 (88.0–100) 97.1 (87.6–100)
Cepheid Xpert Flu 9 94.9 (91.1–98.6) 100 (97.8–100)
Study design
Cohort 28 94.7 (92.5–96.8) .009 96.5 (94.3–98.8) .147
Case-control 28 88.8 (85.2–92.5) 91.2 (84.5–97.9)
Prospective or retrospective study
Prospective 25 91.4 (89.2–93.6) .461 95.9 (93.4–98.5) .200
Retrospective 29 89.7 (86.0–93.4) 91.9 (85.7–98.1)

Abbreviations: CI, confidence interval; ILI, influenza-like illness; RSV, respiratory syncytial virus.
a
P values are calculated comparing sensitivity and specificity of ≥2 groups, using an independent sample t test for 2 groups and a 1-way analysis of variance for >2 groups.
b
Post hoc test using Tukey honestly significant difference (HSD) gives a significant result between influenza and panel of viruses (P = .008); between influenza + RSV and panel of viruses
(P = .036); no significant result between influenza and influenza + RSV.
c
Post hoc test using Tukey HSD gives significant result between Alere i Influenza A&B and Cobas Liat Influenza A/B (P = .001); between Alere i Influenza A&B and Simplexa Flu A/B & RSV
(P = .000); between Alere i Influenza A&B and Verigene RV Plus (P = .007); between Alere i Influenza A&B and Cepheid Xpert Flu (P = .002); no significant result between the other groups.

study [23] reported a significantly lower percentage of anti- not differ between the intervention and control groups [1, 20,
biotic prescriptions in the patients tested with the Simplexa 21, 23, 29, 30]. In terms of efficiency, 1 study reported lower
Flu A/B & RSV kit during the second season as compared to costs of therapy with the use of a rapid molecular test [24] and
patients tested with the laboratory-developed RT-PCR during 2 studies reported a reduction in the number of chest radio-
the first season. One other before-after study [29] reported a graphs in influenza virus–positive patients [22, 28]. There was
significant reduction in duration of antibiotic treatment. Both no effect on the use of isolation facilities in 2 studies [1, 29]
studies were not adjusted for differences in the proportion but 1 unadjusted before-after study reported a significant re-
of influenza virus–positive patients, which was significantly duction in the mean droplet isolation days, a reduction in iso-
higher during the second (intervention) season. Oseltamivir lation days for suspected influenza (0.4 vs 2.7 days; P < .001),
prescriptions were more appropriate in influenza virus–pos- and an increase in isolation days for confirmed influenza virus
itive patients according to 1 randomized study [1] and 1 infection (1.1 vs 0.9 days; P = .16) [32].
nonrandomized study [26]. Two other nonrandomized com-
parative studies showed no effect of rapid testing on oseltami-
DISCUSSION
vir prescriptions [23, 28]. The number of hospital admissions
was not reduced by rapid molecular testing [1, 22, 26, 28], but In our meta-analysis, DTA studies for molecular rapid tests for
2 studies, among which 1 was a randomized study, showed a respiratory viruses showed that these tests are accurate with a
decreased length of hospital stay among admitted patients [1, pooled sensitivity of 90.9% (95% CI, 88.7%–93.1%) and a pooled
28]. Length of hospital stay was not reduced in 4 other studies, specificity of 96.1% (95% CI, 94.2%–97.9%). In our subgroup
among which 2 were randomized studies [20, 21, 23, 29] that, analysis, the Cobas Liat Influenza A/B system was most reliable
however, were smaller and potentially underpowered as com- for the detection of influenza virus, with a sensitivity of 98.1%,
pared to the randomized study that showed a significant ef- and the Simplexa Flu A/B & RSV kit was most reliable for detec-
fect [1]. Safety outcomes as mortality, serious adverse events, tion of influenza virus and RSV with a sensitivity of 99.0%. The
and intensive care unit admissions and/or readmissions did FilmArray simultaneously tests for a panel of 15 viruses with a

1248 • CID 2019:69 (1 October) • Vos et al

Table 3. Characteristics of Studies Included in the Review of Clinical were observed in the majority of the (high-quality) studies. No
Impact Studies (n = 15)
effect was seen on antibiotic prescriptions, duration of antibi-
otic therapy, use of in-hospital isolation measurements, or the
Characteristic No. (%)
number of hospital admissions.
Study design
This is the first systematic review to compare and pool the
Randomized controlled trial 5 (33.3)
Cohort study with before-after design 6 (40.0) diagnostic accuracy of multiple rapid molecular assays and to
Cohort study without control group 4 (26.7) analyze clinical outcomes. Other systematic reviews on this
Single-center study 14 (93.3) topic have either included nonrapid molecular assays [36,
Study population 37], only focused on 1 or 2 particular assays [14, 15, 38], or
Children 2 (13.3)
also included nonmolecular rapid tests with lower sensitiv-
Adults 9 (60.0)
Children and adults 2 (13.3)
ity as compared to molecular assays [11, 12, 39, 40]. Studies
Not reported 2 (13.3) have shown superior accuracy of molecular assays com-
Sample size pared with rapid antigen tests [11], and pooling the results
Eligible patients, No., median (IQR)a 475 (232–945) of assays that use different underlying techniques gives pes-
Included patients, median (IQR) 300 (121–630) simistic estimates of the diagnostic accuracy of molecular
Intervention group patients, median (IQR) 151 (72–347)
tests [41]. Potential practical concerns of molecular tests as
Control group patients, median (IQR)b 149 (50–205)
Symptoms of patients
compared to antigen tests, such as increased costs, longer
Patients with ILI or symptoms of RTI 10 (67.7) turnaround times, and more complicated procedures, have
(Eventual) symptoms unclear 5 (33.3) largely been overcome with recent technological innovations
Tests evaluated [4]. Molecular tests are replacing antigen-based rapid assays.
Alere i Influenza A&B assay 1 (6.7)
Therefore, further comparisons should be using molecular
FilmArrayc 11 (73.3)
assays as a gold standard. In this review we included both
Cepheid Xpert Flu assay 2 (13.3)
Simplexa Flu A/B & RSV kit 1 (6.7) pathogen-specific singleplex and multiplex assays detecting
Reference standard a range of respiratory viruses, whereas in most reviews and
 In-house or laboratory-developed RT-PCR and/or 11 (73.3) studies there is special focus on assays that detect only 1 or 2
other routine viral pathogen test
pathogens, mainly influenza virus [11, 38, 40] and sometimes
No comparison for clinical outcomes 4 (26.7)
Clinical outcomes
RSV [12]. Viral pathogens other than influenza virus and
Antibiotics 11 (73.3) RSV also have a high burden of disease [42], and their detec-
Oseltamivir 5 (33.3) tion may have clinical consequences as antiviral treatment
Hospital admission 4 (26.7) [43] and application of isolation measurements in a hospital
Length of hospital stay 7 (46.7) setting. Depending on the clinical setting and patient popu-
Isolation measurements 3 (20.0)
lation, assays that are capable of detecting a panel of viruses
Safety outcomes 6 (40.0)
No. of radiographs and other investigations 2 (13.3)
may therefore be of increased interest when rapid tests are to
Turnaround time 10 (67.7) replace conventional molecular tests.
Data are presented as No. (%) unless otherwise indicated.
To determine which rapid test to implement, the overall
Abbreviations: ILI, influenza-like illness; IQR, interquartile range; RSV, respiratory diagnostic accuracy of a multiplex test may then be more im-
syncytial virus; RTI, respiratory tract infection; RT-PCR, reverse-transcription polymerase
chain reaction.
portant than its individual pathogen accuracy, whereas in the
a
In 4 studies, the number of eligible patients was unclear (Chu 2015, Keske 2017, Muller current diagnostic accuracy reviews, overall sensitivity and
2016, and Xu 2013).
b
specificity are often given per virus instead of per assay [11, 12,
In 4 studies, no control group was used for comparison (Busson 2017, Keske 2017,
Timbrook 2015, and Xu 2013). 39]. However, it should be noted that judging discrepant viral
results similarly for multiplex and singleplex assays will result
c
In 2 studies, the FilmArray (partially) was a combined diagnostic intervention with procal-
citonin measurement (Branche 2015 and Timbrook 2015).
in poorer diagnostic accuracy, mainly specificity, of multiplex
assays. Therefore, when comparing different available rapid
sensitivity of 89.2%. Overall, molecular tests had better sensi- molecular assays—for example, Simplexa Flu A/B & RSV and
tivity in children than adults, presumably due to higher viral FilmArray—it should always be noted that differences in diag-
loads in children [35]. Studies on the clinical impact of rapid nostic accuracy between these assays can result from testing a
molecular testing had large variation in design and quality. different number of viral pathogens while the diagnostic accu-
Nevertheless, they unanimously found significantly decreased racy per individual viral pathogen may be similar.
turnaround times. In addition, a reduced length of hospital stay, Former studies assessing the effect of testing with conven-
increased appropriate use of oseltamivir in influenza virus–pos- tional multiplex assays providing results within 24–48 hours
itive patients, and a potential reduction in costs and additional showed no effect on antibiotic treatment and hospital length of
radiographs as compared to conventional molecular methods stay [6, 44]. However, more rapid testing for respiratory viruses

Review of Rapid Molecular Tests for Viruses • CID 2019:69 (1 October) • 1249
Table 4. Overview of Clinical Outcomes Presented in Included Clinical Impact Studies (n = 15)

Outcome per study Sample size

(author, year, country) Study design (n) Effect - intervention vs control/ odds ratio (OR) P-value Conclusion

Antibiotic prescriptions
Brendish, 2017 (UK) RCT (1:1) 714 84% vs 83% .84 No decrease in antibiotic
prescriptions
Andrews, 2017 (UK) RCT (quasia) 522b 75% vs 77% .99
c
Chu, 2015 (USA) Before-after, multivariate 350 63% vs 76% <.001
Rogers, 2014 (USA) Before-after, univariate 1136 72% vs 73% .61
Rappo, 2016 (USA) Before-after, univariate 337d 66% vs 61% .35
Linehan, 2017 (Ireland) Before-after, univariate 67e 33% vs 76% <.001
Busson, 2017 (Belgium) Cohort, no control group 69 In 36.2% of patients antibiotic prescriptions -
were avoided
Keske, 2017 (Turkey) Cohort, no control group 359d 45% of virus positive patients received -
antibiotics
Duration of antibiotic therapy
Branche, 2015 (USA) RCT (1:1) 300 Median 3 days [IQR 1–7] vs 4 [0–8] .71 No decrease in duration
of antibiotic therapy
Brendish, 2017 (UK) RCT (1:1) 714 Mean 7.2 days [SD 5.1] vs 7.7 [4.9] .32
Andrews, 2017 (UK) RCT (quasia) 522b Median 6 days [IQR 4–7] vs 6 [5–7.3] .23
Gilbert, 2016 (USA) RCT (quasif) 127 Mean 1053/1000 patient-days [SD 657] vs .07
472/1000 [1667]
Gelfer, 2015 (USA) RCT (quasif) 18d Mean 683/1000 patient-days [SD 317] vs .052
917/1000 [220]
Rogers, 2014 (USA) Before-after, univariate 1136 Mean 2.8 days [SD 1.6] vs 3.2 [SD 1.6] .003
Rappo, 2016 (USA) Before-after, univariate 212e Median 1 vs 2 days .24
Keske, 2017 (Turkey) Cohort, no control group 160d Mean 6.5 days [SD 3.7] in virus positive -
patients
Oseltamivir prescriptions
Brendish, 2017 (UK) RCT (1:1) 714 18% vs 14% .16 More appropriate osel-
tamivir use in influenza
positive patients
94e 91% vs 65% .003
Chu, 2015 (USA) Before-after, univariate 350 55% vs 45% .05
40e 100% vs 100% 1.00
136g 45% vs 43% .60
Rappo, 2016 (USA) Before-after, univariate 212e 61% vs 61% .96
Linehan, 2017 (Ireland) Before-after, univariate 68e 95% vs 72% <.01
Xu, 2013 (USA) Cohort, no control group 97e 81% of influenza positive patients received -
oseltamivir
Length of hospital stay
Branche, 2015 (USA) RCT (1:1) 300 Median 4 vs 4 days NS Reduction in length of
hospital stay
Brendish, 2017 (UK) RCT (1:1) 714 Mean 5.7 days [SD 6.3] vs 6.8 [7.7]h .044
Andrews, 2017 (UK) RCT (quasia) 545 Median 4.1 days [IQR 2.0–9.1] vs 3.3 .28
[1.7–7.9]
Rappo, 2016 (USA) Before-after, multivariatei 212e Median 1.6 days [IQR 0.3–4.8] vs 2.1 .040
[0.4–5.6]
Rogers, 2014 (USA) Before-after, univariate 1136 Mean 3.2 days [SD 1.6] vs 3.4 [1.7] .16
Chu, 2015 (USA) Before-after, univariate 350 Median 4 days [range 1–164] vs 5 [0–117] .33
Timbrook, 2015 (USA) Cohort, no control group 601d Median 1 day [IQR 0–3] in virus positive -
patients
Hospital admissions
Brendish, 2017 (UK) RCT (1:1) 714 92% vs 92% .94 No reduction in hospital
admissions
Rappo, 2016 (USA) Before-after, univariate 337d 76% vs 74% .60
Linehan, 2017 (Ireland) Before-after, univariate 69e 45% vs 88% <.001

1250 • CID 2019:69 (1 October) • Vos et al

Table 4. Continued

Outcome per study Sample size

(author, year, country) Study design (n) Effect - intervention vs control/ odds ratio (OR) P-value Conclusion
Busson, 2017 (Belgium) Cohort, no control group 69 5.8% of hospitalizations was avoided -
Safety
Branche, 2015 (USA) RCT (1:1) 300 No difference in-hospital deaths, SAEs, new NS Safety is not affected
pneumonia cases or 90-day post-hospitaliza-
tion visits
Brendish, 2017 (UK) RCT (1:1) 714 30-day readmission 13% vs 16% .28
30-day mortality 3% vs 5% .15
ICU admission 3% vs 2% .36
Andrews, 2017 (UK) RCT (quasia) 545 30-day readmission 19% vs 20% .70
30-day mortality 4% vs 4% .79
Rogers, 2014 (USA) Before-after, univariate 1136 Mortality 0% vs 0% 1.00
ICU admission 0% vs 0% 1.00
Chu, 2015 (USA) Before-after, univariate 350 Mortality 2% vs 4% .68
ICU admission 31% vs 25% .19
Timbrook, 2015 (USA) Cohort, no control group 601d ICU admission in 8.8% of virus positive -
patients
(1) Costs; (2a) no. of / (2b) any additional chest radiographs; (3a) use of / (3b) time in isolation facilities
Gilbert, 2016 (USA) RCT (quasif) 127 (1) $8308/1000 patient-days [SD 10165] vs .02 Potential reduction in
$11890/1000 [11712] costs and additional
X-rays
Rappo, 2016 (USA) Before-after, multivariatei 188e (2a) Median 1 [IQR 1-1] vs 1 [1–2] .005
Busson, 2017 (Belgium) Cohort, no control group 28e (2b) 25% reduction of X-rays in influenza -
positive patients
Brendish, 2017 (UK) RCT (1:1) 385j (3a) 33% vs 25% .12
50e 74% vs 57% .24
Rogers, 2014 (USA) Before-after, univariate 1136 (3b) 2.9 days [SD 1.6] vs 3.0 [1.7] .27
Muller, 2016 (Canada) Before-after, univariate 125 (3b) Droplet isolation: 3.5 days vs 6.0 <.001
Turnaround time
Brendish, 2017 (UK) RCT (1:1) 714 Mean 2.3 hours [SD 1.4] vs 37.1 [21.5] <.001 Significantly faster
Andrews, 2017 (UK) RCT (quasia) 545 Median 19 hours [IQR 8.1–31.7] vs 39.5 <.001
[25.4–57.6]k
Gilbert, 2016 (USA) RCT (quasif) 127 Mean 2.1 hours [SD 0.7] vs 26.5 [15] <.001
Gelfer, 2015 (USA) RCT (quasif) 59 Mean 1.8 hours [SD 0.3] vs 26.7 [16] <.001
Chu, 2015 (USA) Before-after, multivariatec 350 Median 1.7 hours [range 0.8–11.4] vs 25.2 <.001
[2.7–55.9]
Rogers, 2014 (USA) Before-after, univariate 1136 Mean 6.4 hours [SD 4.9] vs 18.7 [8.2]l <.001
Pettit, 2015 (USA) Before-after, univariate 1102 Mean 3.1 hours vs 46.4 <.001
Rappo, 2016 (USA) Before-after, univariate 212e Median 1.7 hours [IQR 1.6–2.2] vs 7.7 .015
[0.8–14]
Muller, 2016 (Canada) Before-after, univariate 125 Mean 3.6 hours vs 35.0 -
Xu, 2013 (USA) Cohort, no control group 2537 Median 1.4 hours -

Abbreviations: ED, emergency department; ICU, intensive care unit; IQR, interquartile range; NS, not significant; PCR, polymerase chain reaction; RCT, randomized controlled trial; SAE,
serious adverse event; SD, standard deviation.
a
Quasi randomized randomization process with rapid viral molecular testing on even days of the month and reference laboratory PCR testing on odd days.
b
Analysis for antibiotic prescription performed in 522/545 patients due to missing data on antibiotic prescriptions for 13 patients in control arm and ten in intervention arm.
c
Multivariate analysis adjusting for confounders age, location of sample collection, receipt of influenza vaccine, immunosuppressed status and pregnancy.
d
Subgroup analysis in virus positive patients. In the study of Gelfer (2015) among these virus positive patients only the patients who received antimicrobials were included. In the study of
Keske (2017) these virus positive patients included only inpatients, and for the duration of antibiotic therapy only patients with inappropriate antibiotic use were included.
e
Subgroup analysis in influenza positive patients. In the study of Busson (2017) among these influenza positive patients only the patients who were tested with rapid molecular tests during
working hours and who were still in the ED during the test result were included. In the study of Rappo (2016) among these influenza positive patients only the patients who received a chest
radiograph were included in the multivariate analysis for the number of chest radiographs.
f
Quasi randomized randomization process with rapid viral molecular testing during one-week and reference laboratory PCR testing during the following week and so on.
g
Subgroup analysis in influenza negative patients.
h
Adjusted for in-hospital mortality.
i
Multivariate analysis adjusting for confounders age, immunosuppressed status, asthma and admission to ICU.
j
Analysis for isolation facility use were only available from patients included during the second season of inclusion.
k
In the study of Andrews (2017) patients were admitted to an Acute Medical Unit of Medical Assessment Centre before inclusion in the study. The turnaround time was calculated as the
time from admission to result and therefore also covers the time from admission until the swab was actually taken (during which time the assessment of eligibility for inclusion and informed
consent procedure were performed).
l
In the study of Rogers (2014) patients were included at the Emergency Department, but also after admission, leading to a longer time to result.

Review of Rapid Molecular Tests for Viruses • CID 2019:69 (1 October) • 1251
might improve the impact on clinical outcomes as results are associated viral loads of included patients, for example, which
available before any initial treatment or management is estab- were factors that were poorly reported. Furthermore, with an
lished by the treating physician. To our knowledge, this is the assay level comparison of diagnostic accuracy, the multiplex
first review to specifically assess the clinical impact of rapid mo- assays are disadvantaged. The more viruses that an assay tests
lecular tests, and not rapid antigen tests, without a restriction in for, the bigger the chance of any discrepant results with the ref-
the detection of influenza virus and RSV [45, 46]. The included erence test. Therefore, as mentioned before, when interpreting
studies, even the high-quality randomized studies [1, 20, 21, 24, the results of a head-to-head comparison of the accuracy of
25], show heterogeneous results. The location of the rapid test, different assays, the number of tested pathogens should also be
which was at the point of care in only 3 studies, may affect turn- taken into account and results should be interpreted carefully.
around times and thereby clinical outcomes. Apart from other In conclusion, rapid molecular tests for viral pathogen de-
differences in design, and in analysis and power, differences in tection provide accurate results. Even though results on clin-
the implementation strategy might partially explain these dis- ical impact of rapid diagnostic tests are conflicting, there is
crepancies. First, education and training of personnel and phy- high-quality evidence that rapid testing might decrease the
sicians on the implemented rapid test, its diagnostic accuracy, length of hospital stay and might increase appropriate use of
and its potential effects on clinical outcomes may contribute to oseltamivir in influenza virus–positive patients, without leading
its effect on clinical outcomes [33]. Second, a combination of a to adverse results. We therefore suggest considering implemen-
rapid test and a result-based guideline on subsequent clinical tation of rapid molecular tests within hospital settings and rec-
management options might have more impact than a stand-a- ommend performance of high-quality randomized studies.
lone diagnostic test, even though the 2 studies describing the
implementation of a diagnostic bundle did not show any sig- Supplementary Data
nificant effects of their implementation, which might be par- Supplementary materials are available at Clinical Infectious Diseases on-
tially explained by limited adherence to these guidelines [20, line. Consisting of data provided by the authors to benefit the reader, the
posted materials are not copyedited and are the sole responsibility of the
21]. A complicating factor therein is that identification of a authors, so questions or comments should be addressed to the correspond-
viral pathogen from a respiratory tract sample may not neces- ing author.
sarily attribute causation [2]. Third, a combination of a rapid
test and another diagnostic as procalcitonin [21, 30] or other Notes
Author contributions. L. M. V. contributed to the design, search,
biomarker-based assays [47] may increase the persuasiveness of
screening, data extraction, data analysis, data interpretation, production of
the rapid viral test on whether there is a bacterial or viral caus- the figures, and writing of the report. A. H. L. B. contributed to the search,
ative pathogen. However, current evidence for the effect of the screening, data interpretation, and writing of the report. J. B. R., R. S.,
combination of respiratory viral testing and procalcitonin on A. R.-B., and A. I. M. H. contributed to data interpretation and writing of
the report. J. J. O. contributed to design, data interpretation, and writing of
clinical outcomes is disappointing [21]. the report.
Strengths of our systematic review and meta-analysis of DTA Potential conflicts of interest. All authors: No reported conflicts.
studies are that we followed a standardized protocol for the All authors have submitted the ICMJE Form for Disclosure of Potential
Conflicts of Interest. Conflicts that the editors consider relevant to the con-
inclusion of studies, quality assessment, data extraction, and tent of the manuscript have been disclosed.
statistical analysis. To be as complete as possible, we did not ex-
clude studies with a less optimal study design (eg, case-control References
studies). We evaluated heterogeneity using subgroup analyses. 1. Brendish NJ, Malachira AK, Armstrong L, et al. Routine molecular point-of-care
testing for respiratory viruses in adults presenting to hospital with acute respi-
Furthermore, we assessed the clinical impact of rapid molecular ratory illness (ResPOC): a pragmatic, open-label, randomised controlled trial.
testing for respiratory viruses. Since quantitative pooling of clin- Lancet Respir Med 2017; 5:401–11.
2. Zumla A, Al-Tawfiq JA, Enne VI, et al. Rapid point of care diagnostic tests for
ical impact results was not feasible due to heterogeneity in study viral and bacterial respiratory tract infections—needs, advances, and future pros-
design and quality, we made overall conclusions for clinical end- pects. Lancet Infect Dis 2014; 14:1123–35.
3. Clark TW, Medina MJ, Batham S, Curran MD, Parmar S, Nicholson KG. Adults
points that were assessed by at least 2 studies based on majority hospitalised with acute respiratory illness rarely have detectable bacteria in the
votes of studies with highest quality and power. Also, an over- absence of COPD or pneumonia; viral infection predominates in a large prospec-
tive UK sample. J Infect 2014; 69:507–15.
view of available clinical impact studies may have important
4. Brendish NJ, Schiff HF, Clark TW. Point-of-care testing for respiratory viruses in
implications for the design of future clinical impact studies. Our adults: the current landscape and future potential. J Infect 2015; 71:501–10.
review also has some limitations. First, due to poor reporting 5. Jain S, Williams DJ, Arnold SR, et al; CDC EPIC Study Team. Community-
acquired pneumonia requiring hospitalization among U.S. children. N Engl J Med
in DTA studies, we had missing information for our subgroup 2015; 372:835–45.
analyses. Second, there was substantial residual heterogeneity 6. Oosterheert JJ, van Loon AM, Schuurman R, et al. Impact of rapid detection of
viral and atypical bacterial pathogens by real-time polymerase chain reaction for
between DTA studies that could not be explained by our sub- patients with lower respiratory tract infection. Clin Infect Dis 2005; 41:1438–44.
group analyses. Residual heterogeneity and thereby differences 7. Gonzales R, Malone DC, Maselli JH, Sande MA. Excessive antibiotic use for acute
respiratory infections in the United States. Clin Infect Dis 2001; 33:757–62.
in diagnostic accuracy might have been caused by differences 8. Smith SM, Fahey T, Smucny J, Becker L. Antibiotics for acute bronchitis. Cochrane
in sampling types [48] and duration of clinical symptoms and Database Syst Rev 2014; 3:CD000245.

1252 • CID 2019:69 (1 October) • Vos et al

 9. McCullers JA. The co-pathogenesis of influenza viruses with bacteria in the lung. 29. Rogers BB, Shankar P, Jerris RC, et al. Impact of a rapid respiratory panel test on
Nat Rev Microbiol 2014; 12:252–62. patient outcomes. Arch Pathol Lab Med 2015; 139:636–41.
10. Hawkey PM. The growing burden of antimicrobial resistance. J Antimicrob 30. Timbrook T, Maxam M, Bosso J. Antibiotic discontinuation rates associated with
Chemother 2008; 62:1–9. positive respiratory viral panel and low procalcitonin results in proven or sus-
11. Merckx J, Wali R, Schiller I, et al. Diagnostic accuracy of novel and traditional pected respiratory infections. Infect Dis Ther 2015; 4:297–306.
rapid tests for influenza infection compared with reverse transcriptase poly- 31. Xu M, Qin X, Astion ML, et al. Implementation of FilmArray respiratory viral
merase chain reaction. Ann Intern Med 2017; 167:395–409. panel in a core laboratory improves testing turnaround time and patient care. Am
12. Bruning A, Leeflang M, Vos J, et al. Rapid tests for influenza, respiratory syncytial J Clin Pathol 2013; 139:118–23.
virus, and other respiratory viruses: a systematic review and meta-analysis. Clin 32. Muller MP, Junaid S, Matukas LM. Reduction in total patient isolation days with
Infect Dis 2017; 65:1026–32. a change in influenza testing methodology. Am J Infect Control 2016; 44:1346–9.
13. Chartrand C, Tremblay N, Renaud C, Papenburg J. Diagnostic accuracy of rapid 33. Keske Ş, Ergönül Ö, Tutucu F, Karaaslan D, Palaoğlu E, Can F. The rapid diagnosis
antigen detection tests for respiratory syncytial virus infection: systematic review of viral respiratory tract infections and its impact on antimicrobial stewardship
and meta-analysis. J Clin Microbiol 2015; 53:3738–49. programs. Eur J Clin Microbiol Infect Dis 2018; 37:779–83.
14. Babady NE. The FilmArray respiratory panel: an automated, broadly multiplexed 34. Ducharme FM, Zemek R, Chauhan B, et al. Determinants of oral corticosteroid
molecular test for the rapid and accurate detection of respiratory pathogens. responsiveness in wheezing asthmatic youth (doorway): a multicentre prospec-
Expert Rev Mol Diagn 2013; 13:779–88. tive cohort study of children with acute moderate or severe asthma exacerbations.
15. Salez N, Nougairede A, Ninove L, Zandotti C, de Lamballerie X, Charrel RN. Am J Respir Crit Care Med 2015; 191:S314–5.
Xpert Flu for point-of-care diagnosis of human influenza in industrialized coun- 35. Granados A, Peci A, McGeer A, Gubbay JB. Influenza and rhinovirus viral load
tries. Expert Rev Mol Diagn 2014; 14:411–8. and disease severity in upper respiratory tract infections. J Clin Virol 2017;
16. Deeks JJ, Bossuyt PM, Gatsonis C, et al. Cochrane handbook for systematic reviews 86:14–9.
of diagnostic test accuracy version 1.0. 2010. Available at: http://srdta.cochrane.org/. 36. Cohen-Bacrie S, Halfon P. Prospects for molecular point-of-care diagnosis of
Accessed 9 February 2017. lower respiratory infections at the hospital’s doorstep. Future Virol 2013; 8:43–56.
17. Whiting PF, Rutjes AWS, Westwood ME, et al. Research and reporting methods 37. Doan Q, Enarson P, Kissoon N, Klassen TP, Johnson DW. Rapid viral diagnosis
accuracy studies. Ann Intern Med 2011; 155:529–36. for acute febrile respiratory illness in children in the emergency department.
18. Higgins JPT, Altman DG, Gøtzsche PC, et al. The Cochrane Collaboration’s tool Cochrane Database Syst Rev 2009; 4:CD006452.
for assessing risk of bias in randomised trials. BMJ 2011; 343:1–9. 38. Huang HS, Tsai CL, Chang J, Hsu TC, Lin S, Lee CC. Multiplex PCR system
19. Sterne JA, Hernán MA, Reeves BC, et al. ROBINS-I: A tool for assessing risk of for the rapid diagnosis of respiratory virus infection: systematic review and
bias in non-randomised studies of interventions. BMJ 2016; 355:4–10. meta-analysis. Clin Microbiol Infect 2018; 24:1055–63.
20. Andrews D, Chetty Y, Cooper BS, et al. Multiplex PCR point of care testing versus 39. Chartrand C, Leeflang MM, Minion J, Brewer T, Pai M. Accuracy of rapid influ-
routine, laboratory-based testing in the treatment of adults with respiratory tract enza diagnostic tests: a meta-analysis. Ann Intern Med 2012; 156:500–11.
infections: a quasi-randomised study assessing impact on length of stay and anti- 40. Moore C. Point-of-care tests for infection control: should rapid testing be in the
microbial use. BMC Infect Dis 2017; 17:1–11. laboratory or at the front line? J Hosp Infect 2013; 85:1–7.
21. Branche AR, Walsh EE, Vargas R, et al. Serum procalcitonin measurement and 41. Vos LM, Riezebos-Brilman A, Hoepelman AIM, Oosterheert JJ. Rapid tests for
viral testing to guide antibiotic use for respiratory infections in hospitalized common respiratory viruses. Clin Infect Dis 2017; 65:1958–9.
adults: a randomized controlled trial. J Infect Dis 2015; 212:1692–700. 42. Gaunt ER, Harvala H, McIntyre C, Templeton KE, Simmonds P. Disease burden
22. Busson L, Mahadeb B, De Foor M, Vandenberg O, Hallin M. Contribution of a of the most commonly detected respiratory viruses in hospitalized patients cal-
rapid influenza diagnostic test to manage hospitalized patients with suspected in- culated using the disability adjusted life year (DALY) model. J Clin Virol 2011;
fluenza. Diagn Microbiol Infect Dis 2017; 87:238–42. 52:215–21.
23. Chu HY, Englund JA, Huang D, et al. Impact of rapid influenza PCR testing on 43. McKimm-Breschkin JL, Jiang S, Hui DS, Beigel JH, Govorkova EA, Lee N.
hospitalization and antiviral use: a retrospective cohort study. J Med Virol 2015; Prevention and treatment of respiratory viral infections: presentations on anti-
87:2021–6. virals, traditional therapies and host-directed interventions at the 5th ISIRV
24. Gilbert D, Gelfer G, Wang L, et al. The potential of molecular diagnostics and Antiviral Group conference. Antiviral Res 2018; 149:118–42.
serum procalcitonin levels to change the antibiotic management of communi- 44. Vallières E, Renaud C. Clinical and economical impact of multiplex respiratory
ty-acquired pneumonia. Diagn Microbiol Infect Dis 2016; 86:102–7. virus assays. Diagn Microbiol Infect Dis 2013; 76:255–61.
25. Gelfer G, Leggett J, Myers J, Wang L, Gilbert DN. The clinical impact of the detec- 45. Ko F, Drews SJ. The impact of commercial rapid respiratory virus diagnostic tests on
tion of potential etiologic pathogens of community-acquired pneumonia. Diagn patient outcomes and health system utilization. Expert Rev Mol Diagn 2017; 17:917–31.
Microbiol Infect Dis 2015; 83:400–6. 46. Egilmezer E, Walker GJ, Bakthavathsalam P, et al. Systematic review of the impact
26. Linehan E, Brennan M, O’Rourke S, et al. Impact of introduction of Xpert flu of point-of-care testing for influenza on the outcomes of patients with acute res-
assay for influenza PCR testing on obstetric patients: a quality improvement pro- piratory tract infection. Rev Med Virol 2018; 28:1995.
ject. J Matern Fetal Neonatal Med 2018; 31:1016–20. 47. van Houten CB, de Groot JAH, Klein A, et al. A host-protein based assay
27. Pettit NN, Matushek S, Charnot-Katsikas A, et al. Comparison of turnaround to differentiate between bacterial and viral infections in preschool children
time and time to oseltamivir discontinuation between two respiratory viral panel (OPPORTUNITY): a double-blind, multicentre, validation study. Lancet Infect
testing methodologies. J Med Microbiol 2015; 64:312–3. Dis 2017; 17:431–40.
28. Rappo U, Schuetz AN, Jenkins SG, et al. Impact of early detection of respiratory 48. Kim C, Ahmed JA, Eidex RB, et al. Comparison of nasopharyngeal and oropha-
viruses by multiplex PCR assay on clinical outcomes in adult patients. J Clin ryngeal swabs for the diagnosis of eight respiratory viruses by real-time reverse
Microbiol 2016; 54:2096–103. transcription-PCR assays. PLoS One 2011; 6:2–7.

Review of Rapid Molecular Tests for Viruses • CID 2019:69 (1 October) • 1253