Impact of a poorly performing point-of-care test during the 2017-2018 influenza season
Authors: Julian W Tang, Janice Blount, Carina Bradley, Bernadette Donaghy, Carol Shardlow, Srini Bandi, Caroline Baxter, Ann Hunter, Simon Range, Tommy TY Lam
Journal: Journal of Infection (2018)

A recent study by Vilca et al.1Vilca LM Verma A Bonati M Campins M Impact of influenza on outpatient visits and hospitalizations among pregnant women in Catalonia, Spain.J Infect. 2018; (pii: S0163-4453(18)30211-1[Epub ahead of print])https://doi.org/10.1016/j.jinf.2018.06.015Abstract Full Text Full Text PDF Scopus (10) Google Scholar demonstrated the burden of influenza infection in pregnant women in Spain. Bedside or point-of-care testing (POCTs) allows earlier influenza detection and treatment, though the performance of such tests versus their cost is often difficult to balance for optimal, cost-effective clinical utility. Respiratory virus POCTs are becoming more common in hospitals, with most targeting influenza and/or respiratory syncytial virus (RSV). A reliable positive influenza result allows infection control and clinical teams to quickly isolate and treat patients, or discharge patients home on antivirals to avoid the risk of infecting other patients or staff. However, an unreliable test (i.e. giving false influenza positive–FP, or false negative–FN results) can cause a lot of disruption, with patients being unnecessarily isolated and treated on the basis of a FP result, or being nursed in a shared bay, potentially causing an outbreak, based on a FN result. Hence the importance of the initial choice, and subsequent performance monitoring of any selected POCT throughout the season. For the 2017-2018, we used the influenza nucleoprotein (NP) antigen-based BD Veritor Flu A + B test (Becton Dickinson UK Ltd., Berkshire, England) on adult haematology (bone marrow transplant), acute and chronic (including cystic fibrosis) respiratory, and general paediatric (which included RSV testing) wards. Each clinical team was left to use the test on patients of their choice, depending on perceived clinical and infection control needs. After a respiratory swab (adults) into virus transport medium (VTM, Sigma-Virocult, Medical Wire, Wiltshire, UK), or a nasopharyngeal aspirate (younger children) were collected for the POCT, the residual was tested, as routine, on the Virology laboratory PCR-based assay. This respiratory virus panel (AusDiagnostics UK Ltd., Chesham, UK) detected: influenza A/B, RSV A/B, entero/rhinoviruses, parainfluenza viruses types 1-4, adenoviruses, rhinoviruses, coronaviruses (229E, OC43, NL63, HKU1), human metapneumoviruses). The POCT and the 'gold standard' laboratory results were compared at mid-season (Feb 2018) and end-of-season (May 2018) (Table 1). Whilst the specificity of the influenza A, B and RSV remained mostly within the POCT kit-specified limits across all patient populations, the sensitivities varied dramatically from 0-100%.Table 1Performance of BD Veritor A + B point-of-care test during 2017-2018 influenza season. RSV – respiratory syncytial virus; Sens – sensitivity; Spec – specificity; ND – not done.Ward/CentreMid-season (Feb 2018)End-of-season (May 2018)Influenza AInfluenza BRSVInfluenza AInfluenza BRSVSensSpecSensSpecSensSpecSensSpecSensSpecSensSpecAcute respiratory (n = 575)21.190.11.7100NDND22.7890.522.46100NDNDCystic fibrosis/ long-stay respiratory (n = 49)01000100NDND095.80100NDNDAdult haematology (n = 45)10096.9098.45NDND66.795.2097.6NDNDPaediatrics (n = 177 – influenza; 176 - RSV)6096.562.510079.598.4557.1496.477010081.8197.6 Open table in a new tab In the acute respiratory patients the influenza A sensitivity was only 21–23% and < 3% for influenza B throughout the season. This indicated that the POCT and laboratory tests did not agree on the positive results of most samples, particularly for influenza B. By end-of-season, on the POCT, there were 47/575 FP, and 61 FN test results for influenza A; 0/575 FP and 119/575 FN test results for influenza B. In the chronic respiratory patients, there was no influenza A or B positive result agreed upon by both the POCT and the laboratory test, hence a sensitivity of 0% for both viruses. By end-of-season, there were 2/49 FP and 1/49 FN test results for influenza A; 0/49 FP and 5/49 FN test results for influenza B. In the adult haematology patients, there were only 2 influenza A patients confirmed as positive by both POCT and laboratory testing (100% sensitivity, mid-season), with an additional FN on the POCT by end-of-season (6.7% sensitivity), but no influenza B positive patients confirmed by either test (0% sensitivity). Overall, by end-of-season, there were 2/45 FP and 1/45 FN for influenza A; 1/45 FP and 4/45 FN for influenza B. The best overall performance by the POCT was in the paediatric population, with influenza A and B sensitivities of 57–60% and 62–70%, respectively, with 6/177 FP and 3/177 FN for influenza A; 0/177 FP and 3/177 FN for influenza B. The RSV sensitivities (79-82%) were within the range reported in the POCT kit insert, with 4/176 FP and 16/176 FN. Previous studies published for this POCT reported higher sensitivities for influenza A (70-80% to > 90%) and B (67-77%, to > 90%),2Mese S Akan H Badur S Uyanik A Istanbul Rapid Test Study GroupAnalytical performance of the BD veritor™ system for rapid detection of influenza virus A and B in a primary healthcare setting.BMC Infect Dis. 2016; 16: 481https://doi.org/10.1186/s12879-016-1811-9Crossref PubMed Scopus (10) Google Scholar, 3Ndegwa LK Emukule G Uyeki TM Mailu E Chaves SS Widdowson MA et al.Evaluation of the point-of-care Becton Dickinson Veritor™ Rapid influenza diagnostic test in Kenya, 2013-2014.BMC Infect Dis. 2017; 17: 60https://doi.org/10.1186/s12879-016-2131-9Crossref Scopus (9) Google Scholar, 4Dunn J Obuekwe J Baun T Rogers J Patel T Snow L Prompt detection of influenza A and B viruses using the BD Veritor™ System Flu A+B, Quidel® Sofia® Influenza A+B FIA, and Alere BinaxNOW® Influenza A&B compared to real-time reverse transcription-polymerase chain reaction (RT-PCR).Diagn Microbiol Infect Dis. 2014; 79: 10-13https://doi.org/10.1016/j.diagmicrobio.2014.01.018Crossref PubMed Scopus (52) Google Scholar, 5Bell JJ Anderson EJ Greene WH Romero JR Merchant M Selvarangan R Multicenter clinical performance evaluation of BD Veritor™ system for rapid detection of respiratory syncytial virus.J Clin Virol. 2014; 61: 113-117https://doi.org/10.1016/j.jcv.2014.05.020Crossref PubMed Scopus (18) Google Scholar though the performance of any test can vary seasonally, with changes in the circulating viruses. Most of the FN results on the POCT were likely due to low viral loads, however, other causes may be possible. Some samples were sequenced as part of routine UK surveillance (Respiratory Virus Unit, Colindale, London, UK), and a limited sequence analysis showed the presence of the influenza A/H3N2 V197I NP mutation in some patient samples (Figure S1), though none of these had also been tested on the POCT. This mutation contributes to escape from the NP-specific cytotoxic T lymphocytes.6Bragstad K Nielsen LP Fomsgaard A The evolution of human influenza A viruses from 1999 to 2006: a complete genome study.Virol J. 2008; 5: 40https://doi.org/10.1186/1743-422X-5-40Crossref PubMed Scopus (85) Google Scholar, 7Rimmelzwaan GF Berkhoff EG Nieuwkoop NJ Smith DJ Fouchier RA Osterhaus AD Full restoration of viral fitness by multiple compensatory co-mutations in the nucleoprotein of influenza A virus cytotoxic T-lymphocyte escape mutants.J Gen Virol. 2005; 86: 1801-1805Crossref PubMed Scopus (52) Google Scholar, 8Deyde V Garten R Sheu T Smith C Myrick A Barnes J et al.Genomic events underlying the changes in adamantane resistance among influenza A(H3N2) viruses during 2006-2008.Influenza Other Respir Viruses. 2009; 3: 297-314https://doi.org/10.1111/j.1750-2659.2009.00103.xCrossref Scopus (19) Google Scholar In fact, among the Oct 2017-Apr 2018 UK influenza A/H3N2 sequences available in influenza sequence databases (Global Initiative on Sharing All Influenza Data-GISAID: https://www.gisaid.org/), 462/500 had already acquired the V197I NP mutation compared to just 46/455 in 2016/2017. This coincides with the markedly reduced sensitivity of BD Veritor test seen this season (most of the POC-tested samples were not routinely sequenced). For influenza B, one of our patient samples contained a novel V62A NP mutation (Figure S2). Sequences downloaded from the same database showed that this mutation has increased in proportion recently, from 32.4% (11/34) during Oct 2016-Apr 2017, to 49.6% (204/411) during Oct 2017-Apr 2018. The potential impact of these influenza A/H3N2 or B NP mutations on diagnostic assays targeting this region warrants further investigation. However, the impact on individual commercial assays will be difficult to assess as this requires proprietary knowledge of the assay design. Reasons for the FP results are more difficult to determine, but some may have been due to occasional transcription errors of the POCT results by ward staff. This was difficult to confirm as the older version BD Veritor test kit that was used had no facility to record the result or the operator details electronically. All results were hand-written by the ward staff in results books kept beside the POCT. Whatever the reasons, the poor performance of this POCT during this season led to some patients (with FP results) being unnecessarily treated and isolated, and others (with FN results) being left untreated and nursed in open bays, with the potential to cause outbreaks. As a result of this experience, for this season, we are looking at alternative, more sensitive and specific, PCR-based (or similar) molecular detection POCTs.9Young S Illescas P Nicasio J Sickler JJ Diagnostic accuracy of the real-time PCR cobas® Liat® Influenza A/B assay and the Alere i Influenza A&B NEAR isothermal nucleic acid amplification assay for the detection of influenza using adult nasopharyngeal specimens.J Clin Virol. 2017; 94: 86-90https://doi.org/10.1016/j.jcv.2017.07.012Crossref PubMed Scopus (33) Google Scholar, 10Popowitch EB Miller MB Comparison of the Xpert Flu/RSV XC and Xpress Flu/RSV Assays.J Clin Microbiol. 2018; 56 (pii: e00278-18)https://doi.org/10.1128/JCM.00278-18Crossref Scopus (10) Google Scholar We would like to acknowledge the Respiratory Virus Unit, Public Health England, Colindale, London, UK for their support in sequencing some of the influenza samples described in this study Download .pdf (2.48 MB) Help with pdf files Download .pdf (.75 MB) Help with pdf files