Diagnostic Accuracy of Commercially Available Tests for Respiratory Syncytial Virus: A Scoping Literature Review in the COVID-19 Era

Background: Non-pharmaceutical interventions to prevent the spread of coronavirus disease 2019 also decreased the spread of respiratory syncytial virus (RSV) and influenza. Viral diagnostic testing in patients with respiratory tract infections (RTI) is a necessary tool for patient management; therefore, sensitive and specific tests are required. This scoping literature review evaluated the analytical validity of commercially available sample-to-answer RSV diagnostic tests in different contexts. Content: PubMed and Embase were queried for studies reporting on the analytical validity of tests for RSV in patients with RTI (published January 2005-January 2021). Sensitivity and specificity of RSV tests and information on study design, patient, and setting characteristics were extracted from 77 studies that met predefined inclusion criteria. A literature gap was identified for studies of RSV tests conducted in adult-only populations (5.3% of total sub-records), and in outpatient (7.5%) or household (0.8%) settings. Overall, RSV tests with analytical time >30 min had higher sensitivity (62.5-100%) versus RSV tests with analytical time [≤]30 min (25.7-100%), this sensitivity range could be partially attributed to the different modalities (antigen versus molecular) used. Molecular-based rapid RSV tests had higher sensitivity (66.7-100%) and specificity (94.3-100%) than antigen-based RSV tests (25.7-100% and 80.3-100%). Summary: Molecular-based RSV tests should be considered for first-line use when possible, given their high sensitivity and specificity and that adults with RTI typically have low viral load, necessitating a highly sensitive test. This review benefits healthcare professionals by summarizing the diagnostic accuracy data available for commercially available RSV tests.

given their high sensitivity and specificity and that adults with RTI typically have low viral 4 7 load, necessitating a highly sensitive test. This review benefits healthcare professionals by 4 8 summarizing the diagnostic accuracy data available for commercially available RSV tests. . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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The copyright holder for this preprint this version posted February 15, 2022. ;https://doi.org/10.1101https://doi.org/10. /2022 4 IMPACT STATEMENT (100/100 words) 5 1 Viral diagnostic testing in patients with respiratory tract infection is a powerful tool for The data suggest that molecular-based RSV tests have higher sensitivity and specificity than 5 6 antigen-based tests, thus should be considered for first-line use for timely diagnosis and to 5 7 detect infections in adults with low level viral load. Future studies should investigate the 5 8 diagnostic accuracy of RSV tests in adults and in outpatient/household settings.

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The copyright holder for this preprint this version posted February 15, 2022. ; https://doi.org/10.1101/2022.02.14.22270927 doi: medRxiv preprint INTRODUCTION 1 9 8 analytical times (Supplemental Table 2). analytical time >30 min (66.2% vs 33.8% of included sub-records; Table 1). The analytical 2 0 2 times taken from the manufacturer's data sheet for each test are shown in Supplemental Table   2  0  3 2. Most studies assessed RSV tests in mixed (49.6% of included sub-records) or pediatric 2 0 4 . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) 1 1 (38.3%) populations, were prospective in design (62.4% of included sub-records), used rRT-2 0 5 PCR as the reference standard (68.4%), and were industry sponsored (65.4%; Fig. 2). In all 2 0 6 studies evaluated, a nasopharyngeal swab was the specimen type most used (48.9% of 2 0 7 included sub-records; Fig. 2). Most patients were recruited when they were admitted to the 2 0 8 hospital (42.1%) or from mixed (34.6%) settings (Fig. 2). notably small percentage of studies conducted in adult-only patients (5.3%), few conducted in 2 1 3 outpatient settings (7.5%) and only one study was conducted in a household setting (Table 1).  100% and specificity: 80.3-100%; Table 2). This trend for higher diagnostic accuracy in 2 2 6 molecular-vs antigen-based RSV tests with analytical time ≤ 30 min was preserved in all but 2 2 7 one of the categories (specificity in the emergency department/outpatient setting) when the 2 2 8 . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted February 15, 2022. ;https://doi.org/10.1101https://doi.org/10. /2022 1 2 sensitivity and specificity ranges were broken down by patient age and setting in which the 2 2 9 test was carried out (Table 2).
The sensitivity values of molecular-based tests was highest for those that detected RSV only 2 3 1 (93-100%), followed by RSV and influenza (66.7-100%), then multiplex (≥3 viruses 2 3 2 detected) platforms (62.5-100%; all Supplemental Table 3). Such summary statistics should 2 3 3 be interpreted with caution given the differences in sensitivity between different tests with  Table 4). There was a variety of sensitivity and specificity ranges for the 14 RSV tests included in this 2 4 1 review that were assessed under CLIA guidance (Fig. 3 used. Molecular-based rapid RSV tests had higher sensitivity and specificity ranges than 2 5 7 antigen-based RSV tests, which aligns with CDC guidance to use molecular testing for RSV where available (11). The results from this scoping literature review showed a notable gap in studies of diagnostic allow for efficient triage and treatment decisions (e.g., local infection control guidance could 2 6 3 be followed in a timely manner). This could be particularly important for elderly patients who days after the onset of symptoms (31); therefore, accessible at-home or POC testing could be 2 7 0 a valuable tool in timely infection control. Approximately half of all studies included in this review used a nasopharyngeal swab as the 2 7 2 majority specimen type. Notably, it has been shown that the diagnostic accuracy of some immunofluorescence-based RSV tests is higher in nasopharyngeal aspirates, relative to nasal 2 7 5 swabs (32, 33). However, there is no difference in test performance between aspirate and 2 7 6 swab specimens when using molecular-based RSV testing (32, 34). Additionally, mid-2 7 7 . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) 1 4 turbinate nasal swabs have been shown to have a comparative viral load to nasopharyngeal 2 7 8 swabs in infants <2 years old (35) and are equally sensitive for the diagnosis of multiple 2 7 9 respiratory viruses in adults (36). The advantages of using a nasal swab rather than a 2 8 0 nasopharyngeal aspirate/swab are that it is less invasive for the patient and easier for clinical 2 8 1 staff to transport (32, 34).

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The gold standard for RSV testing, rRT-PCR, was the most used comparator assay across all to affect the calculated sensitivity and specificity value of an index test; for example, a immunofluorescence is used as the reference standard compared with rRT-PCR (37).

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A systematic review and meta-analysis of the sensitivity and specificity of RSV rapid (95% CI 76-83) and 97% (95% CI 96-98), respectively (37). In addition, there was a large 2 9 0 disparity observed in sensitivity of RSV tests between studies in pediatric patients (81% and Alere BinaxNOW RSV) (38). Furthermore, while RSV rapid antigen-based tests are 2 9 5 thought to be useful for diagnosis in infants, sensitivity values as low as 7.6% have been 2 9 6 reported for a particular brand of rapid antigen-based test in this age group (39). In some clinical contexts, the use of multiplex tests for more than one respiratory virus may  for tests for RSV only relative to multiplex tests. The evidence outlined in this paper highlights the need for healthcare professionals to 3 1 5 consider the spectrum of respiratory disease, not just SARS-CoV-2 or influenza, and consider 3 1 6 how viral diagnostic testing could inform their patient management and treatment decisions. If clinicians do not test for RSV, it leads to selection bias and potentially an underestimation the patient. Healthcare professionals should assess the benefits and drawbacks of each RSV 3 2 0 testing method and decide which would be most appropriate in their practice. Factors to 3 2 1 consider include the site of testing, the location of the testing instrument, the age and immune status of the individual being tested, end user of the test, where the test results will be  . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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One strength of this scoping review is its comprehensive and structured search strategy, 3 2 6 which has maximized the capture of relevant information. In addition, this review has 3 2 7 considered a broad spectrum of molecular and non-molecular RSV tests with different 3 2 8 analytical times. An inherent limitation of scoping reviews is that the data synthesis is based on the values extracted from any given study; therefore, results may not be comparable in 3 3 0 terms of methodology, limiting the meaningful conclusions that can be drawn from 3 3 1 differences in the sensitivity and specificity between RSV tests from different studies. However, the purpose of this scoping review was not to analyze but to summarize the 3 3 3 published data available. and adjust for differences in settings where the RSV test was performed, seasonality, and 3 3 7 staff utilization of RSV tests. The use of POC testing for influenza and RSV across four that further studies are warranted to explore the effects of testing for RSV on patient  In conclusion, different clinical situations (e.g., the clinical laboratory of a large hospital vs 3 4 4 an outpatient clinic) will require different diagnostic solutions. Given the higher sensitivity and specificity of molecular-based testing over antigen-based modalities for RSV infection, available RSV tests, this review provides a reference point for healthcare professionals to 3 4 9 . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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The copyright holder for this preprint this version posted February 15, 2022. ; 1 7 investigate which test is suitable for their practice. Presently, there are several monoclonal 3 5 0 antibodies and vaccines in development for RSV prevention and some promising anti-viral 3 5 1 therapeutic agents for RSV treatment (44). The concurrent use of viral diagnostic testing will 3 5 2 be become increasingly important to identify the effectiveness and appropriateness of these 3 5 3 products in the future. The authors would like to acknowledge Melanie Yarbrough (Washington University School review. Support for study design and data analysis was provided by Heather Small, PhD, other product names and trademarks are the property of their respective owners. This review was funded by Roche Diagnostics International Ltd, Rotkreuz, Switzerland. Ethical approval was not applicable for this review. Author contributions 3 7 0 . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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All authors contributed to the conceptualization of the study, the writing of the original draft  Janssen and Merck and fees for participation in advisory boards from Janssen, Sanofi-Pasteur, Health Care System; and is the principal investigator for RADx UP testing Core. JPD is an  The data supporting this review were derived from publicly available databases.

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